diff --git "a/GCI/evidence_tables/experimental_evidence/train_datesplit.csv" "b/GCI/evidence_tables/experimental_evidence/train_datesplit.csv" new file mode 100644--- /dev/null +++ "b/GCI/evidence_tables/experimental_evidence/train_datesplit.csv" @@ -0,0 +1,3368 @@ +Label,Experimental Category,Reference,Explanation,Score Status,Points (default points),Reason for Changed Score,url,primary_index,pmid +Knock in of C749A and V760E (C744A and V755E) in Mouse,Model Systems Non-human model organism,"Hilander T, et al., 2018, PMID: 29228266","The first hmtAlaRS substitution C749A is equivalent to the editing-deficient E. coli mutant C666A. Structural prediction suggests that its substitution for alanine severely disrupts the editing activity +The second hmtAlaRS mutant V760E mimics the sti mouse mutation A734E. This is a structural residue supporting the architecture of the editing site and forming hydrophobic interactions with conserved alanine, leucine and valine +( C744A or V755E) +Both mutations are embryonic lethal in the homozygous state (Figure ​(Figure2C) +Our heterozygous mtAlaRS mice were completely normal, Results further illustrate that heterozygosity for a severe mtAlaRS editing defect is not pathogenic. +IN E.COLI EXPRESSING hmtAlaRS +Determination of post-transfer editing of mischarged Ser-tRNAAla showed that the C749A mutant was severely defective in editing while the initial velocity of the post-transfer editing activity of the V760E mutant was only slightly reduced (Figure ​(Figure1E1E and F). In vitro mis-aminoacylation assay demonstrated that the C749A mutant generated considerably more Ser-tRNAAla than the wild type synthetase, consistent with its abolished post-transfer editing activity (Figure ​(Figure1G).1G). The V760E mutant produced less Ser-tRNAAla than the severe mutant, but also more than the wild type enzyme.",Score,1 (2),0.5 (embryonic lethal) + 0.5 (increase in mischarging of Ser tRNA Ala),https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_583e237c-18f6-4427-a04f-82ea0f020daf-2022-04-18T160000.000Z,1,PubMed:29228266 +Review of mitochondrial translation disorders,Biochemical Function A,"Boczonadi V, et al., 2018, PMID: 29980628",See PMID: 16476954 for MT-TA related myopathy,Score,2 (0.5),>10+ genes with mitochondrial disease association implicated in mitochondrial translation,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_583e237c-18f6-4427-a04f-82ea0f020daf-2022-04-18T160000.000Z,1,PubMed:29980628 +Muscle and Cardiac RC assay and BN Page Patient 2,Functional Alteration Patient cells,"Sommerville EW, et al., 2019, PMID: 30285085","CI (<25%) and CIV (5%) activity markedly reduced in patient 2 skeletal muscle and cardiac muscle +Biochemical analysis of mitochondrial respiratory chain complex activities (Fig. 1C) revealed markedly decreased complex I and complex IV activities with low complex III activity in Patient 1 and Patient 2 skeletal muscle relative to controls. Similarly, severe complex I and complex IV activities with low complex III activity were also noted in the cardiac muscle from Patient 2, relative to age-matched controls. +There was marked loss of MT-COI (complex IV) and NDUFB8 (complex I) subunits with a mild reduction of UQCRC2 (complex III)",Score,1.5 (1),"0.5 (Combined Oxphos def muscle) + 0.5 (combined oxphos def heart) + 0.5 (reduction un expression of subunits NDUFB8, UQCRC2, MT0CO1 on WB), +However functional alteration max will be reached so only 1 pt can be counted",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_583e237c-18f6-4427-a04f-82ea0f020daf-2022-04-18T160000.000Z,1,PubMed:30285085 +transport of N-retinylidene-PE,Biochemical Function B,"Quazi F, et al., 2012, PMID: 22735453","ABCA4 facilitates removal of all-trans-retinal following photoexcitation. Phototransduction relies on membrane receptors and transporters. In the visual cycle, energy from a photon allows photoreceptors to convert 11-cis retinal to all-trans-retinal. In order to restore light sensitivity, the all-trans form must be converted back to 11-cis retinol. Flipping the all-trans isomer of N-retinylidene-PE across the membrane helps with the visual cycle and removal of all-trans-retinal from disc membranes. This suggested role of ABCA4 in the visual cycle is consistent with the accumulation of toxic bisretinoid compounds in patients with Stargardt disease.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_38729563-bf36-48ae-929e-fa69a225de39-2022-10-06T160000.000Z,4,PubMed:22735453 +Rescue of a mouse model of PFIC3 by human ABCB4 mRNA,Rescue Non-human model organism,"Wei G, et al., 2021, PMID: 33340584","The rescue construct restored canalicular expression of ABCB4, restored biliary phosphatidylcholine content (Fig. 3D), decreased serum liver enzymes indicating liver injury and hepatomegaly (Figs. 3E-3G) and promoted hepatocyte-driven liver regeneration, leading to improvement of inflammation, duct phenotypes, and fibrosis (Figs. 4A-4D). Inflammatory phenotypes were improved as well (Figs. 5 and 6).",Score,2 (2),"Due to the use of human ABCB4 mRNA for rescue and the degree of success of the fold-change of rescue across multiple phenotypes, default scoring has been recommended.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_009134d7-b79c-4a90-9bae-c1f302439258-2022-11-23T170000.000Z,5,PubMed:33340584 +DUH Zebrafish,Model Systems Non-human model organism,"Liu H, et al., 2014, PMID: 24498303","The major phenotype in humans is the presence of hypo- and hyperpigmented skin macules. Therefore, the loss of melanocytes in zebrafish closely matches the human phenotype.",Score,0.5 (2),"The effect of morpholino injection was not assayed by the authors, so it's unclear if their morpholinos led to an overall knockdown or induced aberrant splicing of the transcript. Further, loss of function of ABCB6 has been shown to be fully tolerated in humans, with het and hom carriers of truncating alleles showing no phenotypes. Therefore, the score has been reduced, as the mechanism of disease is unclear.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_93bbbc0a-5f6f-4d80-b560-3265d7b89ed3-2024-04-26T180000.000Z,7,PubMed:24498303 +Gonzalez-Cabo_C. elegans,Model Systems Non-human model organism,"González-Cabo P, et al., 2011, PMID: 21464130","Homologue of the ABCB7 gene is abtm-1 +-- Abtm-1-depleted animals produce arrested embryos (embryonic lethality) that have morphogenetic defects and unusual premature, putative apoptotic events. +-- abtm-1(RNAi) animals that do reach adulthood show accumulation of ferric iron and increased oxidative stress; despite the increased level of oxidative stress in abtm-1(RNAi) animals, they have an increased life span +-- abtm-1(RNAi) worms have a pattern of alterations in life span, defecation, motility, and other behaviors indicative of mitochondrial impairment (slow and reduced growth, adults smaller in size, some form aberrant gonads or lack gonads completely, those with gonads have egg laying defect, ultradian rhythms/disrupted defecation, and locomotion defect evidenced by thrashing assay)",Score,3 (2),0.5 (embryonic lethal) + 2 (phenotype recapitulation) + 0.5 (biochemistry),https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_f3ff096d-abfb-47df-8ac1-c942a98828b0-2023-09-28T160000.000Z,8,PubMed:21464130 +Mice homozygous for splice-site mutation in ABCC9,Model Systems Non-human model organism,"Smeland MF, et al., 2019, PMID: 31575858","Mice homozygous for stop variant in ABCC9 showed reduced fraction shortening and increase in left ventricular internal dimension in diastole (normalized to body length), mirroring the mild dilatation observed in human.",Score,1 (2),The mice studied here were homozygous for ABCC9 stop variant. The humans described carried heterozygous variants in ABCC9. We therefore chose to downgrade the default score of 2 to 1.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_8be22ebc-f0f5-4de5-9c2a-382ebd02c533-2020-11-13T170000.000Z,10,PubMed:31575858 +Gene expression in DCM vs. normal hearts,Expression B,"Alimadadi A, et al., 2020, PMID: 31948008","ABCC9 expression was downregulated in dilated cardiomyopathy vs. controls and ischemic cardiomyopathy +vs. controls",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_8be22ebc-f0f5-4de5-9c2a-382ebd02c533-2020-11-13T170000.000Z,10,PubMed:31948008 +ABCD4 - LMBD1 interaction,Protein Interaction,"Kawaguchi K, et al., 2016, PMID: 27456980","Using multiple methodologies (immunofluorescence microscopy; subcellular fractionation followed by Western blot; co-IP), the authors demonstrate overlapping cellular localization patterns for ABCD4 and LMBD1. This is due to a physical interaction between the two proteins. The authors show that this interaction is necessary and sufficient for ABCD4 localization.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_902c9288-f6bd-4068-9a5f-652b49583d93-2023-12-22T190000.000Z,13,PubMed:27456980 +ABCD4 - cobalamin transport activity,Biochemical Function B,"Kitai K, et al., 2021, PMID: 33845046","ABCD4 is involved in cobalamin uptake, performing the final step of transporting cobalamin across the lysosomal membrane and into the cytosol. Cobalamin is a necessary cofactor for enzymes involved in MMA and cysteine metabolism. Therefore, loss of ABCD4 function leads to lost enzyme activity, causing disease.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_902c9288-f6bd-4068-9a5f-652b49583d93-2023-12-22T190000.000Z,13,PubMed:33845046 +Klett_Mouse,Model Systems Non-human model organism,"Klett EL, et al., 2004, PMID: 15040800","Sterol levels measured by GC in plasma and tissues (liver, spleen, brain) showed that in the knock-out mice, plasma cholesterol levels of homozygous and heterozygous mice were decreased by 52% and 26%, and plasma campesterol and sitosterol levels were 8- and 36-fold higher, compared to wild-type; liver and spleen cholesterol content were reduced by ~50%, while campesterol and sitosterol were increased 5- and 22-fold, compared to wild-type. No significant differences in brain sterol levels were noted, as expected. Plant sterols were almost undetectable in heterozygous mice. +RT-PCR to detect expression levels of other genes regulating sterol metabolism showed that Abcg5 was reduced by >60% and HMG-CoA was reduced by ~80%. Also, HMG-CoA reductase and Cyp7a1 enzyme activities were reduced by 30% and 60% in heterozygous and homozygous knock-out mice. +The authors studied if the localization of Abcg5 was affected in Abcg8-/- knockout mice. Western blotting with three different anti-Abcg5/sterolin-1 on liver and intestine of Abcg8-/- mice showed the detection of a 75 kDa band, which is the immature (un-glycosylated) Abcg5 in wild-type and knock-out mice, but 2 of the 3 antibodies detect the mature 93 kDa Abcg5 in the wild type, but not in the knock-out mice. Immunohistochemistry in intestinal sections with the same antibodies showed apical pattern of staining of Abcg5 and localization to the villi of the enterocytes. Similar results were obtained on liver sections +Biliary sterol secretion analyzed in mice showed that the sterol and phospholipid contents in Abcg8-/- mice were reduced, compared to wild-type. Forced biliary sterol secretion by infusion of tauroursodeoxycholic acid (TUDC) in knockout mice showed a trend of lower phospholipid secretion during both the depletion and infusion phase and almost no stimulated sterol secretion was noted during the depletion phase, which increased minimally upon infusion. Analysis by GC of bile collected from knock-out mice showed a significantly diminished ability to secrete cholesterol, but the ability to secrete sitosterol and campesterol were maintained, compared to wild-type mice. +The authors note that Abcg8/sterolin-2 is necessary for hepatobiliary cholesterol secretion in mice, but may not be for plant sterol secretion; however, there may be other mechanisms than via sterolins to export sterols.",Score,2 (2),"PMID: 23926302 adds evidence that Abcg8-/- mice that were fed a high plant sterol diet showed hemolytic anemia and severe macrothrombocytopenia with platelet size increasing to that of mice lacking GPIbα. Together, the evidence is scored default points.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_af59edc2-1148-4dca-b804-192639017b65-2020-07-14T202806.911Z,15,PubMed:15040800 +Impaired lipolysis in ABHD5 mutants in COS-7 cells,Functional Alteration Non-patient cells,"Tseng YY, et al., 2022, PMID: 35173175","PMID: 35173175: mutation of the binding pocket residues G113S, S117A or D110N, which interact with ATGL for activation of lipolysis suppressed activation of PNPLA2, as shown by increased lipid droplet accumulation in COS-7 cells transfected with the mutants versus COS-7 cells harboring wild-type ABHD5",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_19bf65b3-0c75-46e2-8796-5664ce6dd371-2022-08-02T160000.000Z,17,PubMed:35173175 +MCAD -/- Mice,Model Systems Non-human model organism,"Tolwani RJ, et al., 2005, PMID: 16121256","MCAD -/- mice displayed many characteristics of human MCAD deficiency, including newborn loss, intolerance to cold, biochemical changes in blood, tissues and urine.",Score,3 (2),Mouse model recapitulates disease.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_fb987774-0e5b-4466-924f-6f19fccc6599-2018-01-23T170000.000Z,20,PubMed:16121256 +Range of residual activity,Functional Alteration Patient cells,"Sturm M, et al., 2012, PMID: 23028790",Demonstrated a correlation between octanoyl-CoA oxidation rate in lymphocytes and the clinical outcome.,Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_fb987774-0e5b-4466-924f-6f19fccc6599-2018-01-23T170000.000Z,20,PubMed:23028790 +Dickinson novel developmental phenotypes,Model Systems Non-human model organism,"Dickinson ME, et al., 2016, PMID: 27626380","Human phenotype of confirmed homozygous or compound heterozygous loss of function alleles in ACAT2 have not yet been described or reported. The model system phenotype of abnormal embryo size, abnormal body wall morphology and complete penetrance preweaning lethality (MP:0001697, MP:0003385, MP:0011100 respectively) may indicate that loss of both functional alleles of ACAT2 is incompatible with life in mammals. Other variation affecting gene function may cause a severe phenotypes in humans, but no evidence for this currently exists.",Score,0.5 (2),"Down-scoring this model in recognition that no human phenotype has yet been observed/reported and so this model cannot be said to re-capitulate the human disease. However, still giving a score since this model suggests the gene ACAT2 as a candidate for severe human disease.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7cb46678-6e33-4d34-86ba-fdf59e59fb80-2021-01-25T194853.212Z,25,PubMed:27626380 +TPP1 TEL patch deletion,Model Systems Cell culture model,"Sexton AN, et al., 2014, PMID: 25128433",Telomere length remained stable in wild-type and heterozygous ΔL/+ cells (n = 2 independent cell lines examined) but progressively decreased in homozygous ΔL/ΔL cells (n = 4 independent cell lines examined).,Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c29b6517-54ab-414e-a3ab-e5aa006e0d54-2024-02-20T170000.000Z,26,PubMed:25128433 +TPP1–TIN2 interaction,Protein Interaction,"Kocak H, et al., 2014, PMID: 25233904","Wild-type TPP1 and TPP1-K170∆ efficiently precipitated with TINF2, whereas TPP1-P491T showed a modest (approximately twofold) reduction in TINF2 association.",Score,0 (0.5),TINF2 has not yet been curated.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c29b6517-54ab-414e-a3ab-e5aa006e0d54-2024-02-20T170000.000Z,26,PubMed:25233904 +ACD Function,Biochemical Function B,"Henslee G, et al., 2021, PMID: 33446513","Telomere biology disorders, largely characterized by shortened telomere lengths, are caused by variants in genes associated with telomere replication, structure, or function. When ACD function is impaired, this results in telomere shortening and features of TBD.",Score,1 (0.5),"Several studies support these functions which lead to telomere shortening, a known feature of telomere biology disorders",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c29b6517-54ab-414e-a3ab-e5aa006e0d54-2024-02-20T170000.000Z,26,PubMed:33446513 +III-4 FCL studies,Functional Alteration Patient cells,"Neumann MA, et al., 2020, PMID: 33028849","Significant decrease of ACO2 on western blot of FCLs +Significantly reduced basal, maximal, and spare respiration by OCR in fibroblasts",Score,1 (1),"Score 0.5 Significant decrease of ACO2 on western blot of FCLs ++0.5 Significantly reduced basal, maximal, and spare respiration by OCR in fibroblasts +Case is entered but will not be scored separately",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_2bca6e9c-e167-4862-bf45-3ec787b92f49-2023-10-19T040000.000Z,27,PubMed:33028849 +Aco1 del Yeast Complementation studies with inframe deletion,Rescue Non-human model organism,"Neumann MA, et al., 2020, PMID: 33028849",yeast aco1 del complemented with orthologous c.1699_1749del (p.567_583del17) did not rescue growth defect at 30C nor 35C similar to null control vs S112R (pathogenic in ClinVar ID:29584) which rescues at lower temp but not higher (37C),Score,0.5 (2),Score 0.5 points for aco1 orthologous deletion not rescuing growth deficit,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_2bca6e9c-e167-4862-bf45-3ec787b92f49-2023-10-19T040000.000Z,27,PubMed:33028849 +"Charif et al 2021, P15 fibroblast studies",Functional Alteration Patient cells,"Charif M, et al., 2021, PMID: 34056600","-ACO2 western blot shows reduced protein compared to control +-Normal CS activity, 50% aconitase activity +-mtDNA depletion <50% of control +-significant respiration defect with only citrate as substrate, restoration to WT with malate +Note: comparable activity levels to arOA cell line with c.36 + 5del; c.719G>C; p. Gly240Ala",Score,0.5 (1),Score 0.5 for reduction of ACO2 on western blot,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_2bca6e9c-e167-4862-bf45-3ec787b92f49-2023-10-19T040000.000Z,27,PubMed:34056600 +Fibroblasts studies on Marelli Patient,Functional Alteration Patient cells,", , PMID: 29564393","cultured skin fibroblasts showed a 50% decrease in aconitase activity in the presence of citrate and a 40% decrease in activity in the presence of cis-aconitate (compared with isocitrate dehydrogenase activity as a reference) +Score 0.5 points",Score,0.5 (1),Score 0.5 points for 50% decrease in aconitase activity,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5892fec8-dc8b-467b-abba-fb6be142bb7a-2023-10-19T040000.000Z,28,PubMed:29564393 +LCL studies in Bouwkamp patient,Functional Alteration Patient cells,", , PMID: 29577077","LCL studies showed significantly decreased (no exact value, but ~25% based on graph) aconitase activity in mitochondrial fraction and normal activity in cytoplasmic fraction, compared to control +Score 0.5 points +LCL studies also significant state 4 and attenuated maximal respiration by OCR, as well as respiratory control ratio (RCR)– score 0.5 points +Score 1 point total +Note: carrier sister who was unaffected had an affected RCR, but state 3 and maximal respiration were normal",Score,1 (1),"LCL studies showed significantly decreased (no exact value, but ~25% based on graph) aconitase activity in mitochondrial fraction and normal activity in cytoplasmic fraction, compared to control +Score 0.5 points +LCL studies also significant state 4 and attenuated maximal respiration by OCR, as well as respiratory control ratio (RCR)– score 0.5 points +Score 1 point total",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5892fec8-dc8b-467b-abba-fb6be142bb7a-2023-10-19T040000.000Z,28,PubMed:29577077 +Inflammatory Response,Functional Alteration Patient cells,"El Hajj HI, et al., 2012, PMID: 22508517","reduced ACOX1 activity (Fig. 1A), reduction in amount of peroxisomes (Fig. 1B), enlarged peroxisomes (Fig. 1C), accumulation of neutral lipids (Fig. 1C), accumulation of VLCFAs (PMID: 17458872) +Transcriptomic profiling showed upregulation of genes coding for cytokines and other proinflammatory proteins (IL-6, IL-8, several TNFα family members (3, 8, 9, 10A, 12, and 14), and interferon-inducible proteins, (Supplemental Table 1) +PCR array of 84 genes revealed alterations in gene regulation within the IL-1 pathway (Table 1) a proinflammatory cytokine +cytometric bead arrawy showed secretions of IL-6 and IL-8 cytokines were induced in patient cells, but TNF-alpha was not significantly changed, suggesting activation of IL-1 pathway with upregulation of its target genes IL-6 and IL-8 (Fig. 2), these were shown to likely be induced by MAPK and p38 MAPKK (Fig. 4)",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_96026ae4-050d-4eb5-849c-178c703a556e-2022-11-04T160000.000Z,30,PubMed:22508517 +Naturally Occuring CMAMMA Labrador Model,Model Systems Non-human model organism,"Sloan JL, et al., 2011, PMID: 21841779","Although the naturally-occuring laborador retriever model displayed many symptoms not necessarily recapitulated in human probands, such as severe neurodegeneration and altered development/functional motor defecits, it also clearly shows an elevation in malonic and methylmaonic acid in the blood and urine. As this biochemical abnormality is the specific disorder being curated, with other resulting symptoms being secondary, this model recapitualates the necessary phenotypes with a unique homozygous variant. +ModelVariant: ACSF3 c.1288G>A (p.Gly430Ser); orthologous to human p.Gly480",Score,2 (2),"As this naturally-occuring canine model recapitulates the primary biochemical abnormality observed in all CMAMMA probands, that being the elevation of both malonic and methylmalonic acid in urine, this model recieves default points. Although the score could potentially be increased, the presence of unexplained severe neurological symptoms suggests potential complicating factors.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b215e20c-7781-49a0-b473-9219cb07e0b9-2020-10-09T160000.000Z,31,PubMed:21841779 +Altered MMA Fibroblast Production and Rescue,Functional Alteration Patient cells,"Sloan JL, et al., 2011, PMID: 21841779","Methylmalonic Acid production was measured in three control fibroblasts and four patient fibroblasts. Every one of the patient fibroblasts demonstrated a significantly higher accumulation of MMA in the media compared to the controls (6, 2.4, 5.3 and 2.4 fold elevated for Subjects 1-4). Afterwards, fibroblasts from subjects 1, 3, and 4 were transduced with a lentivirus with either WT ACFS3 or GFP. The fibroblasts from the ACFS3 group all exhibited reduced MMA production similar to control fibroblasts treated in a similar fashion while the GFP-transduced fibroblasts were unaffected.",Score,1 (1),"Not only is MMA production clearly much higher in the patient fibroblast cell lines compared to the controls, expression of the WT ACSF3 brings the patient cell line production to the control levels while the GFP had no effect. This provides significant evidence implicating ACSF3 in this disorder and receives default points.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b215e20c-7781-49a0-b473-9219cb07e0b9-2020-10-09T160000.000Z,31,PubMed:21841779 +Immunofluorescence assay of F-actin in lymphoblastoid cell,Functional Alteration Patient cells,"Rivière JB, et al., 2012, PMID: 22366783","Protein levels and morphology in lymphoblastoid cell lines: No differences were seen in β- and γ-actin protein levels between two representative cell lines derived from individuals carrying either the ACTB recurrent mutation (encoding p.Arg196His) and controls, similar to what was described for a previously reported ACTB mutation. Comparable results were obtained with the other cell lines with mutated actin genes. The two representative mutant cell lines both had greatly increased F-actin content and multiple, anomalous F-actin–rich, filopodia-like protrusions compared to control cells, resulting in increased cell perimeter. They probed the stability of F-actin using latrunculin A, which binds actin monomers, thereby preventing their incorporation into growing filaments. Both representative mutant cell lines showed altered sensitivity to latrunculin A, albeit with different outcomes. They observed increased resistance to latrunculin A in mutant cells with the β-actin p.Arg196His alteration relative to controls, which is consistent with the effect of the previously reported p.Arg183Trp alteration. Immunofluorescent staining of F-actin in lymphoblastoid cell lines from the affected individuals showed patterns of cytoskeletal changes and abnormal accumulation of F-actin that were reproducible between independent cell lines carrying the same alteration.",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_fa13dfad-ab93-4521-874a-5ede8f608fe4-2021-10-26T165835.977Z,35,PubMed:22366783 +Luciferase reporter gene assay,Functional Alteration Non-patient cells,"Rangrez AY, et al., 2020, PMID: 31921954",decreased luciferase activity compared to WT.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3e9b4048-3003-4180-b891-fcf10d25a814-2020-08-12T160000.000Z,37,PubMed:31921954 +Perrin Conditional Knockout,Model Systems Non-human model organism,"Perrin BJ, et al., 2010, PMID: 20976199","6 week-old Actg1-flox Atoh1-cre mice has normal hearing thresholds at frequencies between 4 and 22 kHZ, and elevated thresholds at 32 kHz. By 18 weeks, these mice has significantly elevated thresholds at all frequencies tested. Varying the dose of gamma-actin changed the age of onset and rate of progression of hearing loss in mice.",Score,0 (2),"This mouse model is not scored as it does not contribute any additional data beyond the first mouse model, given that both are knockout models.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_db9f5d19-5ebc-4a1a-a4c3-79ff27f69a0e-2019-01-07T170000.000Z,40,PubMed:20976199 +Mouse Model,Functional Alteration Non-patient cells,"Braun SMG, et al., 2021, PMID: 33602870","Proliferation of NSPCs lacking BAF53a, was severely impaired in culture, with mutant cells stalled at G1 & G2/M phases of the cell cycle & a significant increase in anaphase bridges. +increase of apoptosis in cultured NSPC",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9278e3c0-9174-4aed-8c13-b34618e88825-2023-07-21T160000.000Z,41,PubMed:33602870 +Mouse Model,Model Systems Non-human model organism,"Braun SMG, et al., 2021, PMID: 33602870",this affected brain size and structure. Also has been shown to affected the maintenance of NSPCs in the cortical germinal zones which can be correlated with a neurodevelopmental disorder,Score,1 (2),This would not account for all phenotypes associated with this disorder,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9278e3c0-9174-4aed-8c13-b34618e88825-2023-07-21T160000.000Z,41,PubMed:33602870 +Rescue of conditional KO mouse by exogenous expression of nB,Rescue Non-human model organism,"Braun SMG, et al., 2021, PMID: 33602870","Following tamoxifen treatment of NSPCs a cell cycle block at both G1/S and G2/M in cells lacking BAF53a was observed. Restoring BAF53a expression, rescued the cell cycle block as did overexpression of BAF53b.",Score,1 (2),"supportive for the role of BAF53a in the pathway and regulation of neuronal differentiation, does not account for all clinical features.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9278e3c0-9174-4aed-8c13-b34618e88825-2023-07-21T160000.000Z,41,PubMed:33602870 +Mouse Model,Expression A,"Braun SMG, et al., 2021, PMID: 33602870","Baf53a is enriched in Sox2-expressing radial glia & TBR2-expressing intermediate progenitor cells in the ventricular & subventricular zones of the mouse embryonic cortex +BAF53a is restricted to the neural progenitors; BAF45a & BAF53a is confined to the proliferated regions (part of the neural progenitor-specific complex, npBAF) +The switch to BAF53b & BAF45b/c is considered the postmitotic neuron-specific complex & is expressed in differentiated zones",Score,0.25 (0.5),expression may not explain all the other clinical features,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9278e3c0-9174-4aed-8c13-b34618e88825-2023-07-21T160000.000Z,41,PubMed:33602870 +Chaikuad_Expression,Expression B,"Chaikuad A, et al., 2012, PMID: 22977237",Chaikuad et al. 2012 also looked at representative expression levels for transfected ALK2 (ACVR1 legacy name) constructs with variants found in humans with FOP. Expression for all the ALK2 variants was different from the control.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0439e75f-fc1b-4841-8c9a-17f3568ce8a4-2023-03-01T170000.000Z,43,PubMed:22977237 +Chaikuad_Protein,Protein Interaction,"Chaikuad A, et al., 2012, PMID: 22977237","FKBP12 (FKBP1B legacy name) is the 12 kDa FK506-binding protein that has been shown to compete for binding in the GS domain of ACVR1. Chaikuad et al. performed immunoprecipitation where C2C12 or HEK293 cells were transfected with FLAG-tagged ALK2 and HA-tagged FKBP12. They found that wild-type ALK2 (ACVR1 legacy name) and the p.Arg206His variant showed significant binding to FKBP12, whereas the interaction of p.Leu196Pro was essentially lost. All FKBP12 interactions were inhibited by FK506. The authors state that this data shows FKBP12 remains an important modulator of receptor function in the majority of FOP cases where mutations fall outside the core FKBP12-binding site.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0439e75f-fc1b-4841-8c9a-17f3568ce8a4-2023-03-01T170000.000Z,43,PubMed:22977237 +Cai_Functional Alteration,Functional Alteration Patient cells,"Cai J, et al., 2015, PMID: 26626181","Using flow cytometry, Cai et al. found that generation of endothelial cells significantly impaired in FOP hiPSCs compared with controls, while pericyte induction was slightly enhanced in FOP hiPSCs.",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0439e75f-fc1b-4841-8c9a-17f3568ce8a4-2023-03-01T170000.000Z,43,PubMed:26626181 +Deletion of Alk2 function leads to defection,Model Systems Non-human model organism,"Thomas PS, et al., 2012, PMID: 22536403",Mutant mice display aortic valve defects.,Score,1 (2),The model did not recapitulate the inheritance of the disease found in humans.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a34f19aa-a12e-483c-ae09-a0fce770647b-2023-08-14T160000.000Z,44,PubMed:22536403 +Lenviral/ADA2 gene rescue of HSPCs,Rescue Patient cells,"Hong Y, et al., 2022, PMID: 35529868","Transduction of the patient HSCs with the ADA2 lentivirus rescued CD34+ HSC decreases in ADA2 expression and activity and cell proliferation, and increases in pro-inflammatory cytokine production (TNFa, IFNg, IL6)",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e05f1338-6a58-4991-af3b-6433bd165a9f-2023-05-30T170000.000Z,47,PubMed:35529868 +Lenviral/ADA2 gene rescue of endothelial activation,Rescue Patient cells,"Hong Y, et al., 2022, PMID: 35529868",Transduction of macrophages with lentivirus carrying full length ADA2 resulted in rescue of decreased macrophage ADA2 expression and activation and increased pro-inflammatory cytokine production (TNFa and IFNg) to levels in healthy control macrophages,Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e05f1338-6a58-4991-af3b-6433bd165a9f-2023-05-30T170000.000Z,47,PubMed:35529868 +Expression in human tissues and cells,Expression A,"Gao ZW, et al., 2022, PMID: 35663977","HPA database information shows that ADA2 expression is enriched in the spleen, monocytes, and dendritic cells; immune cells have been shown to be affected in patients with ADA2 deficiency. In addition, ADA2 is shown to be present in (secreted into) human plasma (Fig. 8).",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e05f1338-6a58-4991-af3b-6433bd165a9f-2023-05-30T170000.000Z,47,PubMed:35663977 +Lora_cytoplasmic domain null TACE mouse,Model Systems Non-human model organism,"Lora J, et al., 2021, PMID: 33957124","These animals were viable and displayed less of the skin defects. However, the heart valve defects were still present.",Score,0.5 (2),"The heterozygous animals did not display a phenotype, which is inconsistent with the AD disease state in humans, so this model organism is being downgraded. Additionally, there is no particular evidence to support that the cytoplasmic domain is more critical for disease in humans, so this model is being further downgraded.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_8ad3a100-7a22-4065-aaa2-87c64a843486-2023-08-14T160000.000Z,48,PubMed:33957124 +Mouse model of Adam9 loss-of-function,Model Systems Non-human model organism,"Parry DA, et al., 2009, PMID: 19409519","The affected mice exhibit an abnormal gap between the RPE and the photoreceptor outer segment, which would normally be in contact (Figure 5B). The gap contains macrophages (Figure 5L). Outer nuclear layer thinning is observed (Figure 5D), as well as material deposited between the RPE and Bruch's membrane, which may be analogous to drusen deposits in humans (Figure 5K). These findings collectively show an adhesion defect at the interface between the photoreceptor outer segment and the RPE. This evidence of retinal degeneration was complemented by abnormalities in both rod- and cone-driven ERG responses (Figure 4), matching a feature of the human patients.",Score,1.5 (2),"The mice match the human patients in mode of inheritance, in electroretinogram responses that show both rod and cone involvement, and at the microscopic level where they indicate a role for Adam9 as an adhesion molecule critical to the structural integrity of the interface between the RPE and the photoreceptor outer segment. Scoring has been kept conservative to acknowledge potential overlap of some features with the other animal model scored (PMID: 20691256).",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c648ec73-186d-4680-93ea-29f5fdf91812-2022-09-01T160000.000Z,49,PubMed:19409519 +Leigh map,Biochemical Function A,"Rahman J, et al., 2017, PMID: 27977873",RNASEH1 is also an RNA-specific adenosine deaminase that results in a Leigh or Leigh-like phenotype (31271879: Souza et al. 2019).,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_03f538b5-43af-4699-9ddb-264077de21c9-2020-08-27T164642.352Z,54,PubMed:27977873 +Characterization of Adducin Loss of Function in Drosophila,Model Systems Non-human model organism,"Kruer MC, et al., 2013, PMID: 23836506","Genomic variants in ADD3 have been reported in association with motor deficits (spastic diplegia/quadriplegia). Therefore, locomotion and climbing deficits in this drosophila model are in line with this phenotype.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_8a858435-3e50-406f-8ec3-9f4e40b1c392-2022-08-15T180000.000Z,58,PubMed:23836506 +SAICAr and S-Ado metabolites in ADSL deficiency patients,Functional Alteration Patient cells,"Jurecka A, et al., 2015, PMID: 25112391","CSF, plasma and urine from ADSL deficiency patients show high levels of SAICAr and S-Ado as a key feature of diagnosis in demonstrating lack of ADSL enzyme function",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d282f565-84e4-4a47-9acc-77ee31bbe9f6-2020-09-07T160000.000Z,64,PubMed:25112391 +ADSL enzyme function,Biochemical Function B,"Jurecka A, et al., 2015, PMID: 25112391","ADSL deficiency is characterized by the presence of two dephosphorylated substrates of ADSL, succinylaminoimidazole cardoxamide riboside (SAICAr) and succinyladenosine (S-Ado) in urine, plasma and CSF, which are normally undetectable in healthy individuals",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d282f565-84e4-4a47-9acc-77ee31bbe9f6-2020-09-07T160000.000Z,64,PubMed:25112391 +Biochemical Function,Biochemical Function B,"Bensaid M, et al., 2009, PMID: 19136466","Authors observed that FMR2 co-localizes with the splicing factor SC35 in nuclear speckles, the nuclear regions where splicing factors are concentrated, assembled and modified. Similarly to what was reported for splicing factors, blocking splicing or transcription leads to the accumulation of FMR2 in enlarged, rounded speckles. FMR2 is also localized in the nucleolus when splicing is blocked. We show here that FMR2 is able to specifically bind the G-quartet-forming RNA structure with high affinity. Remarkably, in vivo, in the presence of FMR2, the ESE action of the G-quartet situated in mRNA of an alternativelyspliced exon of a minigene or of the putative target FMR1 appears reduced. Interestingly, FMR1 is silenced in the fragile X syndrome, another form of mental retardation. All together, our findings strongly suggest that FMR2 is an RNA-binding protein,which might be involved in alternative splicing regulation through an interaction with G quartet RNA structure.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ab4216e3-61b7-4542-ad3a-8788a7ef8b63-2017-10-20T040000.000Z,65,PubMed:19136466 +Protein Interaction,Protein Interaction,"Bensaid M, et al., 2009, PMID: 19136466","Authors observed that FMR2 co-localizes with the splicing factor SC35 in nuclear speckles, the nuclear regions where splicing factors are concentrated, assembled and modified. Similarly to what was reported for splicing factors, blocking splicing or transcription leads to the accumulation of FMR2 in enlarged, rounded speckles. FMR2 is also localized in the nucleolus when splicing is blocked. We show here that FMR2 is able to specifically bind the G-quartet-forming RNA structure with high affinity. Remarkably, in vivo, in the presence of FMR2, the ESE action of the G-quartet situated in mRNA of an alternativelyspliced exon of a minigene or of the putative target FMR1 appears reduced. Interestingly, FMR1 is silenced in the fragile X syndrome, another form of mental retardation. All together, our findings strongly suggest that FMR2 is an RNA-binding protein,which might be involved in alternative splicing regulation through an interaction with G quartet RNA structure.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ab4216e3-61b7-4542-ad3a-8788a7ef8b63-2017-10-20T040000.000Z,65,PubMed:19136466 +Functional Expression,Expression A,"Bensaid M, et al., 2009, PMID: 19136466","Authors observed that FMR2 co-localizes with the splicing factor SC35 in nuclear speckles, the nuclear regions where splicing factors are concentrated, assembled and modified. Similarly to what was reported for splicing factors, blocking splicing or transcription leads to the accumulation of FMR2 in enlarged, rounded speckles. FMR2 is also localized in the nucleolus when splicing is blocked. We show here that FMR2 is able to specifically bind the G-quartet-forming RNA structure with high affinity. Remarkably, in vivo, in the presence of FMR2, the ESE action of the G-quartet situated in mRNA of an alternativelyspliced exon of a minigene or of the putative target FMR1 appears reduced. Interestingly, FMR1 is silenced in the fragile X syndrome, another form of mental retardation. All together, our findings strongly suggest that FMR2 is an RNA-binding protein,which might be involved in alternative splicing regulation through an interaction with G quartet RNA structure.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ab4216e3-61b7-4542-ad3a-8788a7ef8b63-2017-10-20T040000.000Z,65,PubMed:19136466 +Functional Alteration,Functional Alteration Non-patient cells,"Bensaid M, et al., 2009, PMID: 19136466","Authors observed that FMR2 co-localizes with the splicing factor SC35 in nuclear speckles, the nuclear regions where splicing factors are concentrated, assembled and modified. Similarly to what was reported for splicing factors, blocking splicing or transcription leads to the accumulation of FMR2 in enlarged, rounded speckles. FMR2 is also localized in the nucleolus when splicing is blocked. We show here that FMR2 is able to specifically bind the G-quartet-forming RNA structure with high affinity. Remarkably, in vivo, in the presence of FMR2, the ESE action of the G-quartet situated in mRNA of an alternativelyspliced exon of a minigene or of the putative target FMR1 appears reduced. Interestingly, FMR1 is silenced in the fragile X syndrome, another form of mental retardation. All together, our findings strongly suggest that FMR2 is an RNA-binding protein,which might be involved in alternative splicing regulation through an interaction with G quartet RNA structure.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ab4216e3-61b7-4542-ad3a-8788a7ef8b63-2017-10-20T040000.000Z,65,PubMed:19136466 +Non-human model organism,Model Systems Non-human model organism,"Pepper AS, et al., 2009, PMID: 19888420","Different Ago2 null mutant D. Melanogaster larvae show defective neuronal branching patterns and synapse formation. The Ago2 null phenotype at the NMJ was shown to be rescued in D. melanogaster carrying an Ago2 genomic rescue construct. Loss of Ago2 results in increased (Drosophila Fragile X protein) dFMR1 in adult heads. Ago2 is shown to affect synapse formation and neuronal branching and to regulate dFMR1 expression, loss of which causes behavioral and developmental defects in the fly. This may correspond to neurological phenotype observed in LKS",Score,0.5 (2),"partial phenotypic overlap between human patients and fruit fly larvae, lower level model organism, however rescue supports the role of the Ago2 gene in the phenotype",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ec86c06a-f5a3-448d-be53-277bc91d12de-2023-09-15T160000.000Z,72,PubMed:19888420 +CRISPR-mediated knockdown of AGO2 in HEK293T cells,Functional Alteration Non-patient cells,"Lessel D, et al., 2020, PMID: 33199684",see above,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ec86c06a-f5a3-448d-be53-277bc91d12de-2023-09-15T160000.000Z,72,PubMed:33199684 +Mouse Model,Model Systems Non-human model organism,"Lancaster MA, et al., 2011, PMID: 21623382",cerebellum smaller (particularly vermis) and notable defects in Shh signaling (implicated in ciliopathies). Similar mouse phenotype to CEP290 KO mice.,Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d0d8d22f-cea6-4f4f-bc71-e85303dccac1-2021-10-26T143345.589Z,77,PubMed:21623382 +Zong Expression,Expression A,"Zong L, et al., 2015, PMID: 25986071",Immunolocalization of AIFM1 in mouse inner ear revealed localization to IHC and OHC cytoplasm and surrounding tissue.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a7afc3bb-7fce-45fd-a275-87277e22b1eb-2018-07-09T160000.000Z,78,PubMed:25986071 +Expression,Expression A,"Bénit P, et al., 2008, PMID: 18791645","AIFM 1 is expressed ubiquitously through all tissues including the brain. Figure 7 shows western blot analysis of AIF levels across mouse tissues including cerebellum, spinal cord, cortex, retina, skeletal muscle , kidney and liver. +The human protein atlas confirms that RNA expression is seen throughout the brain, protein expression is confirmed in the cerebellum only. https://www.proteinatlas.org/ENSG00000156709-AIFM1/tissue.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e917f93b-01ef-42e3-bf8d-b50a91f83f9c-2021-06-14T135732.582Z,79,PubMed:18791645 +C.elegans RNAi model,Model Systems Non-human model organism,"Troulinaki K, et al., 2018, PMID: 29531799","The AIFM1 homolog in c.elegans is WAH-1, reduction of WAF-1 levels using (RNAi) to approximately 40%, affected the expression of ETC complexes and mitochondrial respiration and resulting in reduced lifespan (fig 1). WAH-1 deficiency affected growth rate, body size, pharyngeal pumping, fertility, and defecation rhythm (Fig. 1b).Immunoblot analysis of ETC subunits showed decreased complex I subunit NUO-2/NDUFS3 expression in wah-1-silenced nematodes (Fig. 1c). The oxygen consumption rate (OCR) was reduced in wah-1 deficient nematodes, further indicating an impaired mitochondrial activity. In a transgenic fly line expressing GFP under the myo-3 promoter, depletion of WAH-1 was shown to result on mitochondria with an abnormal irregular appearance. +In the treated worms, levels of stress proteins were elevated (hsp6, gst4, sod3) but ROS levels were decreased (Fig2).",Score,0.5 (2),Recapitulation of OXPHOS deficiency in WAF-1 deficient worms.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e917f93b-01ef-42e3-bf8d-b50a91f83f9c-2021-06-14T135732.582Z,79,PubMed:29531799 +Knock-in mouse model,Model Systems Non-human model organism,"Wischhof L, et al., 2018, PMID: 29780003","At around 6 months of age, Aifm1 (R200 del) homozygous females and hemizygous males displayed hind limb clasping and developed kyphosis (Figure 1G,H, I, J), indicating potential muscle atrophy and innervation defects +Fig2 shows features associated with OXPHOS deficiency in the skeletal muscle of the knockin mice: Consistent with the early development of myopathy-like features, Aifm1 (R200 del) males exhibited an increased number of nemaline rod-like structures in skeletal muscle fibers between 3 and 6 months of age (Figure 2A,B, ) Histopathology D and E. +Aifm1 (R200 del) mice showed a more pronounced loss of COX-positive muscle fibers compared to Hq mutant animals at 3 months of age (Figure 2D E), indicating reduced CIV activity. SDH staining was similar in WT and mutant mice. At 3 months of age, Aifm1 (R200 del) animals exhibited a clear trend towards a decreased expression of CI and CIV subunits, which became even more significant at 6 months of age (Figure 2GeH) +Fig 3. Figure 3: Mutant AIF protein does not cause cerebellar degeneration but induces peripheral neuropathy. (Distinct from the Harlequin mouse which has an ataxia pehnotype associated with cerebellar degeneration) +Fig 3F, 3G Axonla swelling in 6 month mice and reduced levels of myelin basic protein and neurofilament at 12 months suggested that axonal neuropathy is secondary to muscle wasting.",Score,0.5 (2),"Recapitulation of OXPHOS deficiency within skeletal muscle tissue was demonstrated, this was consistent with the hind limb clasping and developed kyphosis phenotypes observed in mice. No brain pathology was reported in these mice. GDA is supported by biochemical recapitulation of disease.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e917f93b-01ef-42e3-bf8d-b50a91f83f9c-2021-06-14T135732.582Z,79,PubMed:29780003 +Zebrafish Model,Model Systems Non-human model organism,"Rissone A, et al., 2015, PMID: 26150473","Zebrafish had profound impairment of lymphoid and myeloid development. Similar to what was observed in vitro in patient fibroblasts and CD34+ bone marrow cells (Pannicke et al., 2009), zebrafish mutants presented an increased level of cellular oxidative stress leading to apoptosis and cell death.",Score,0.5 (2),"In zebrafish, AK2 knockdown, by frameshift or missense variant, showed hematopoietic defects without affecting general embryonic development. These results were confirmed by two different mutant alleles carrying frameshift mutations in zebrafish ak2 exon 1 and a missense mutation in exon 4. Zebrafish showed similar increased level of cellular oxidative stress leading to apoptosis and cell death as seen in patient cells but clinical phenotypes of AK2-deficiency are not recapitulated in zebrafish. Further analysis, in PMID: 31727854, showed that zebrafish ak2 is expressed in inner ear and neuromast structures and its deficiency severely affects the survival of hair cells in those structures through an increased level of oxidative stress and cell death, consistent with the hearing loss seen in patients. +Authors also state that mouse lines carrying homozygous ak2-inactivating retroviral insertions are embryonically lethal (unpublished data), consistent with results seen elsewhere in mice (PMID: 24548998).",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_aba98528-8032-4dd4-bd1d-5381b102323c-2021-05-20T150257.066Z,81,PubMed:26150473 +iPSC derived model,Model Systems Cell culture model,"Rissone A, et al., 2015, PMID: 26150473","To model the hematopoietic phenotype of RD in vitro, patient-derived iPSCs were grown in suspension culture to form embryoid bodies, dissociated into single cells, and plated in a CFU assay. AK2R175Q/R175Q iPSCs recapitulated the characteristic maturation arrest of the myeloid lineage at the promyelocyte stage that is observed in the bone marrow of RD patients (Pannicke et al., 2009), whereas the control demonstrated differentiation into mature neutrophils with distinctive nuclear segmentation. In addition to the maturation arrest, the quantitative potential of AK2-deficient cells to form mixed myeloid lineage colonies was significantly decreased. +Additionally, in AK2R175Q/R175Q-derived myeloid cells, the AMP/ADP ratio was markedly skewed toward AMP, whereas intracellular ADP levels were decreased. These data show that AK2 deficiency results in decreased cellular ADP supply, which may limit substrate availability for the ATP synthase and compromise cellular respiration.",Score,0.5 (1),The iPSC derived cell culture model recapitulates differentiation defect.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_aba98528-8032-4dd4-bd1d-5381b102323c-2021-05-20T150257.066Z,81,PubMed:26150473 +shRNA knockdown,Functional Alteration Non-patient cells,"Six E, et al., 2015, PMID: 26270350","To mimic the AK2 deficiency in RD, the authors knocked down AK2 expression in CB CD34+ progenitor cells. In the absence of AK2 expression, they found that hematopoietic progenitors could no longer differentiate along lymphoid or granulocyte lineages. In addition to this differentiation block, they observed a negative effect of AK2 knockdown on cell survival and proliferation in the context of differentiation. To study the relationship between AK2 and mitochondrial metabolism, several additional experiments were performed with the HL60 cell line. In AK2-deficient cells, there was an impairment of oxidative metabolism (low COX activity and low COX/LDH ratio).",Score,1 (0.5),"Taken as a whole, these results suggest that the AK2 signaling pathway is associated with the regulation of mitochondrial metabolism. In the absence of AK2 expression, the export of high-energy phosphate compounds from the mitochondrion is impaired. Energy failure and nucleotide disequilibrium affect cell survival, proliferation and differentiation, which in turn impair differentiation towards neutrophil and lymphoid lineages. Hence, these results highlight the close relationship between energy balance and cell differentiation and thus show how the impairment of mitochondrial metabolism can result in a profound immunodeficiency. +Follow-up in PMID: 19043416 found the downregulation of AK2 expression in human CD34+ cell induced a 17 to 27-fold reduction in myeloid cells and granulocyte precursors associated with a profound arrest in neutrophil differentiation.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_aba98528-8032-4dd4-bd1d-5381b102323c-2021-05-20T150257.066Z,81,PubMed:26270350 +Behavioral Analysis following Chronic Lithium Treatment,Rescue Non-human model organism,"Bergeron Y, et al., 2017, PMID: 28442992",Chronic lithium treatment restored the decreased phosphorylated GSK3α/β levels and rescued the depressive and anxiety-like behaviors in the Akt3 KO mice,Score,0 (2),This mouse phenotype is not associated with the human phenotype. The small head size is already recorded in a different functional assay.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6e3b524c-5d27-43d6-a0db-4f8f7cf1f872-2021-10-26T150030.155Z,87,PubMed:28442992 +Alas2 transgenic mouse exhibits porphyria.,Model Systems Non-human model organism,"Peng Y, et al., 2021, PMID: 33785075","The mouse model matches the mechanism of the human patients (ALAS2 gain-of-function) and successfully recapitulates some limited features of the human disease state of interest. Transgenic animals show symptoms associated with porphyria such as muscle weakness (Figure 1), reduced muscle mass (Figure 2), reduced muscle fiber diameter (Figure 3), and mitochondrial abnormalities in the muscle (Figure 4).",Score,0.5 (2),"The mouse model matches the mechanism of the human patients and shows that ALAS2 gain-of-function can in fact trigger disease. However, it exhibits porphyria-related (muscular) features rather than protoporphyria-related features such as photosensitivity, liver damage, etc.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_61e658f9-fdc9-4b3c-8788-80eb1ad83b0b-2022-03-27T181700.091Z,88,PubMed:33785075 +Neurotransmitter alterations in Aldh5a1-/- mouse embryos,Model Systems Non-human model organism,"Jansen EE, et al., 2008, PMID: 19040727","Succinic semialdehyde dehydrogenase deficiency is a disorder of the GABA degradation pathway where consecutive elevation of gamma-hydroxybutyric acid (GHB) and GABA occur. GABA and DHHA (4,5-dihydroxyhexanoic acid) were found to be significantly elevated at all gestational ages in Aldh5a1-/- mice,",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c3e57466-df2f-4045-b374-010dbd334bfc-2021-04-27T160000.000Z,90,PubMed:19040727 +Alteration of ALG14 in HEK293 cells,Functional Alteration Non-patient cells,"Cossins J, et al., 2013, PMID: 23404334","Subsequently two separate small interfering RNAs were used to silence endogenous ALG14 in HEK293 cells that were co-transfected with complementary DNA encoding the human acetylcholine receptor α, β, δ and ε subunits. They found that the number of receptors was reduced by more than half compared to normal cells, suggesting that ALG14 is indeed ‘crucial’ for getting acetylcholine receptors to the cell surface.",Review,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_809c40c4-1800-42ef-b56f-95a2c61f44ce-2024-02-21T170000.000Z,94,PubMed:23404334 +Rescue of alg2p.G336*/p.G336* medaka mutants,Rescue Non-human model organism,"Gücüm S, et al., 2021, PMID: 34106226","Without mRNA injection, homozygous alg2p.G336*/p.G336* mutants were absent. With the injection of either medaka or human alg2 mRNA, the survival of homozygous mutant embryos was restored. The injected mRNA also efficiently rescued the gross morphology phenotype and extended the lifespan by at least 16 days.",Score,1 (2),Not a mouse model,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_f7cb8bd0-58b2-4644-a041-76f42f564fbc-2023-11-15T170000.000Z,95,PubMed:34106226 +Medaka alg2 variants,Functional Alteration Non-patient cells,"Gücüm S, et al., 2021, PMID: 34106226","The medaka embryos with the introduced mutations displayed normal early embryonic development, but abnormalities became apparent just prior to hatching. The mutants exhibited multisystemic phenotypes similar to those observed in ALG2-CDG patients. +Comparing the N-glycan fingerprints of wild-type Alg2 medaka with the Alg2:p.G366* N-glycan fingerprints revealed severe hypo-N-glycosylation. There was a reduction in the levels of complex-type (48% less) and high-mannose-type (54% less) N-glycans. Both the human ALG2:p.G347Vfs26 protein (from the ALG2 index patient) and the medaka mutants expressing the Alg2:p.G336 protein exhibited prominent hypo-N-glycosylation. +""Note in the mutant craniofacial defects, including prominently shortened snout (bracket), persistent yolk sac (y), non-inflated swim bladder (sb), enlarged liver (unfilled arrowhead), secondary tubular heart (black arrowhead) and clogging of blood, slightly smaller eyes (e).""",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_f7cb8bd0-58b2-4644-a041-76f42f564fbc-2023-11-15T170000.000Z,95,PubMed:34106226 +Sheep model,Model Systems Non-human model organism,"Williams DK, et al., 2018, PMID: 30446691",Milder phenotypes were seen in some of the sheep and in mild hypophosphatasia in the patients.,Score,1 (2),Downgraded given the wide range of phenotypes of the sheep.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_354366d0-a7f6-472d-a7b2-4b16f6e328ac-2019-01-21T200000.000Z,103,PubMed:30446691 +Dog model,Model Systems Non-human model organism,"Kyöstilä K, et al., 2019, PMID: 30700765","Both dogs and humans experience generalized muscle weakness, deformed joints and hyperextension of distal joints, poorly mineralized bones. And decreased ALP levels and activity",Score,1 (2),Downgraded because did not fully recapitulate phenotype.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_64fd43a0-1c7d-4f34-906c-570d800492bc-2021-06-02T205406.157Z,105,PubMed:30700765 +"Alx expression in the developing head of mouse, chick, and f",Expression A,"McGonnell IM, et al., 2011, PMID: 21740507","Probands with mutant ALX3 alleles showcase defects in the are expressed in the mesenchyme of the facial prominences, particularly around the nasal region and at the distal tip of the mandible. Regular expression of ALX3 has been confirmed by multiple mouse models: Ten Berge et al. (1998) PMID:PMID: 9676189 and Beverdam et al. (2001) (PMID:11641221)",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1b460912-d5fd-4b7b-99da-ccd477fd8139-2022-10-13T160000.000Z,108,PubMed:21740507 +Stress granule formation,Biochemical Function A,"Thiyagarajan N, et al., 2012, PMID: 23047679",PMID: 27256390,Score,0 (0.5),Decisions by GCEP to ad to case-level variant scoring,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_4ee17299-56dd-40a7-8cec-9a316f3e46f2-2022-02-08T000000.000Z,112,PubMed:23047679 +ENU Mutagenesis ANK1 KO,Model Systems Non-human model organism,"Kildey K, et al., 2013, PMID: 24688720","Both hets and homozygous mice have increased reticulocyte counts compared to WT mice. Hom mice also had increased osmotic fragility of RBCs, although hets did not display a significant increase. Both hets and hom had a significant decrease in MCV (mean corpuscular volume) or RBCs consistent with human spherocytes.",Score,2 (2),"Although hets weren't as severely affected as homs, I did score this animal model the full default points because of the phenotype of heterozygous animals.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_82460b48-c4a5-4496-92ce-6fbad632d6d7-2021-03-24T160000.000Z,116,PubMed:24688720 +Osmotic fragility,Functional Alteration Non-patient cells,"Hao L, et al., 2019, PMID: 31016877",The cells transfected with the variant demonstrated significantly increased osmotic fragility as measured by increased % of cell rupture compared to those transfected with the WT ANK1.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_82460b48-c4a5-4496-92ce-6fbad632d6d7-2021-03-24T160000.000Z,116,PubMed:31016877 +Increased RBC turnover in patients with ANK1 variants,Functional Alteration Patient cells,"Huisjes R, et al., 2020, PMID: 31147440","RBCs from HS patients ANK1 variants had increased turnover (decreased HbA1c), which correlated with disease severity. The cells also had significantly reduced maximum deformability compared to healthy controls.",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_82460b48-c4a5-4496-92ce-6fbad632d6d7-2021-03-24T160000.000Z,116,PubMed:31147440 +Wt-Ank2 repres axon branching in cultured hippocampal neuron,Rescue Cell culture model,"Yang R, et al., 2019, PMID: 31285321",Expression of wt-Ank2 in ABe37f/f hippocampal neurons (from a mouse model with homozygous exon 37 deletion) repress axon branching,Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_097e646b-467f-4c08-95d6-958ed324562b-2020-12-15T175241.108Z,117,PubMed:31285321 +ANK2 mouse models,Model Systems Non-human model organism,"Yang R, et al., 2019, PMID: 31285321","Model organisms with Ank2 mutation showed a number of phenotypes observed in human autistic patients; including Increased repetitive behavior, deficit in vocal communication, deficit in social behavior, and decreased locomotor activity.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_097e646b-467f-4c08-95d6-958ed324562b-2020-12-15T175241.108Z,117,PubMed:31285321 +Increased axonal branching in neurons with Ank2 mutation,Functional Alteration Non-patient cells,"Yang R, et al., 2019, PMID: 31285321",Cultured hippocampal neurons from mouse models with Ank2 exon 37 deletion showed increased axonal branching relative to wild type cells.,Score,1 (0.5),"Many ASD-related genes function in synaptic signaling: increased axon branching has been reported in mice deficient in PTEN, in addition, DYRK1A (a microtubule kinase) and KATNA1 (a microtubule-severing protein), also affect axonal microtubules. Alteration of normal axonal function/or morphology is also observed in other genes mutated neurodevelopmental disorders, therefore, the score is upgraded.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_097e646b-467f-4c08-95d6-958ed324562b-2020-12-15T175241.108Z,117,PubMed:31285321 +ANKRD1 and MYPN Interaction,Protein Interaction,"Bang ML, et al., 2001, PMID: 11309420",The specific interaction of myopalladin's NH2-terminal region with a full-length CARP protein was confirmed by GST pull-down experiments,Score,0 (0.5),MYPN is classified as limited for association with HCM,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_8f241e6c-2fc8-4f23-b976-3b79d90fad3e-2023-02-08T170000.000Z,121,PubMed:11309420 +MEP/ERK and TGF-B1/Smad3 Signaling Pathways,Biochemical Function B,"Song Y, et al., 2012, PMID: 23227174",ERK1/2 and TGF-β/Smad3 are both signaling pathways often involved in development of cardiac hypertrophy. CARP decreases the activity of both the ERK1/2 and the TGF-β/Smad3 signaling pathways and subsequently attenuates cardiac hypertrophy and fibrosis in the hearts of CARP transgenic mice.,Review,0 (0.5),Phenotype is inconsistent with disease. Findings provide in vivo and in vitro experimental evidence suggesting that the ERK signaling pathway plays a critical role in mediating the partial inhibitory effect of CARP against cardiac hypertrophy.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_8f241e6c-2fc8-4f23-b976-3b79d90fad3e-2023-02-08T170000.000Z,121,PubMed:23227174 +CARP Overexpression,Model Systems Non-human model organism,"Song Y, et al., 2012, PMID: 23227174","Overexpression of CARP markedly inhibited phenylephrine-induced cardiomyocyte hypertrophy, as reflected by a decrease in myocyte area (Figure 1B and 1C) and reduced expression of the hypertrophic molecular markers α-actin, β-MHC, and ANF (Figure 1D and 1E). Together, these data indicate that overexpression of CARP in rat cardiomyocytes blocks phenylephrine-induced cardiac hypertrophy in vitro. +No overt physiological abnormalities were evident in CARP Tg mice under normal growth conditions, so CARP function in pathological cardiac hypertrophy via TAC was investigated. Overexpression of CARP in the heart reduces the hypertrophic response to TAC. Examination of gross heart morphology and analysis of myocyte area on histological sections after 4 weeks of TAC also revealed that the heart size was smaller and the cellular hypertrophy less in CARP Tg mice compared with WT animals. +Both LVPW;d and the ratios HW/BW and HW/TL were lower, and global heart size and myocyte area smaller, in CARP Tg mice than in WT animals after isoproterenol administration. These results indicate that overexpression of CARP markedly attenuates isoproterenol-induced cardiac hypertrophy. +This evidence suggests that CARP is an anti-hypertrophic factor, and thus is not similar to the HCM phenotype observed in humans.",Review,0 (2),Phenotype is not consistent with disease phenotype. Study results highlight the potential significance of CARP as an anti-hypertrophic factor.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_8f241e6c-2fc8-4f23-b976-3b79d90fad3e-2023-02-08T170000.000Z,121,PubMed:23227174 +Triple KO Model,Model Systems Non-human model organism,"Bang ML, et al., 2014, PMID: 24736439","The absence of all three MARP family members does not appear to have any effect on cardiac function in vivo, even though mutations in the Ankrd1 gene have been identified in patients with dilated and hypertrophic cardiomyopathy. The most likely explanation for this is that the identified Ankrd1 mutations have dominant negative effects by interfering with the binding of CARP to its many interaction partners, while complete absence of the MARPs has a less damaging effect and may be compensated for by other mechanisms.",Score,0 (2),"Potentially contradictory, does not recapitulate HCM phenotype",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_8f241e6c-2fc8-4f23-b976-3b79d90fad3e-2023-02-08T170000.000Z,121,PubMed:24736439 +ANKRD1 Overexpression by Ang II Stimulation and TAC,Model Systems Non-human model organism,"Chen C, et al., 2014, PMID: 25089522","Increased expression of ANKRD1 using recombinant adenoviral vectors carrying Ankrd1 in mice with transverse aortic constriction exacerbated pathological cardiac remodeling through activation of the calcineurin/nuclear factor of activated T-cells (NFAT) pathway, a signaling pathway known to have an important role in cardiac hypertrophy.",Score,0.5 (2),"Given the amount of overexpression and the fact that ANKRD1 alone did not produce the phenotype, the score has been decreased. Since Ankrd1 alone did not induce cardiac hypertrophy when no pathological stress was added, this suggests that Ankrd1 may be redundant and plays pathological stress-dependent role.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_8f241e6c-2fc8-4f23-b976-3b79d90fad3e-2023-02-08T170000.000Z,121,PubMed:25089522 +missense ANKS6 Gln441Arg mutation,Model Systems Non-human model organism,"Hoff S, et al., 2013, PMID: 23793029",Renal cysts,Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_62df8a40-0b65-46a4-89c8-51f26424c523-2021-08-25T160000.000Z,125,PubMed:23793029 +Recessive mutations in Anks6/Nek8 cause laterality defects,Model Systems Non-human model organism,"Czarnecki PG, et al., 2015, PMID: 25599650","The phenotypic spectrum of left-right asymmetry randomization, CHD and cystic kidney malformations represents a characteristic syndrome of perturbed IC-mediated signaling, exemplified here by the Roc and Streaker mutant mice, and consistent with findings in the inv/inv mouse and the NPHP3 and Nek8 knockout mouse models5,6,7. It is phenotypically distinct from other ciliopathy syndromes, including the Joubert-syndrome related disorders, Meckel-Gruber syndrome or Bardet-Biedl syndrome, and the lack of reported neural tube closure and CNS patterning defects, retinitis pigmentosa or obesity suggests that the IC regulates a different and very specific set of ciliary functions. We note IC disruption having not been directly implicated in motile ciliary dysfunction. Notably, previous work in the inv/inv mouse demonstrated normal nodal ciliary motility but a defective nodal flow pattern22. At that time, an abnormally shaped node was hypothesized as the origin of the defective flow and heterotaxy, but more recently proposed models may justify revisiting nodal flow and signaling in the inv/inv mouse23",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_62df8a40-0b65-46a4-89c8-51f26424c523-2021-08-25T160000.000Z,125,PubMed:25599650 +ANKS6-NEK8 co-localization by co-IP,Protein Interaction,"Czarnecki PG, et al., 2015, PMID: 25599650","In order to identify interaction partners of NEK8, we performed large-scale immunoprecipitation (IP) experiments from mIMCD3 cells stably expressing FLAG-NEK8. Upon SDS-PAGE and silver staining (Fig. 1a), two signals near 75 kDa and 110 kDa were identified by mass spectrometry as NEK8, the bait protein, and the Ankyrin repeat and SAM domain-containing protein 6, ANKS6, respectively. When we subjected total FLAG-NEK8 and control IMCD cell immunoprecipates to direct mass spectrometric analysis, we confirmed ANKS6 as binding partner, along with other proteins (Fig. 1b). We focused our attention on ANKS6, the gene product mutated in the Han:SPRD cy/+ rat model of polycystic kidney disease11, which was recently found to be an IC protein responsible for a human autosomal-recessive nephronophthisis-like syndrome18. As in Hoff et al., we confirmed that morpholino-induced knockdown of ANKS6 in zebrafish results in laterality defects reminiscent of NEK8 morphant phenotypes6 (Supplementary Table 1).",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_62df8a40-0b65-46a4-89c8-51f26424c523-2021-08-25T160000.000Z,125,PubMed:25599650 +Rescue of CMG2/ATXR2 expression by proteasome inhibitors,Rescue Patient cells,"Deuquet J, et al., 2011, PMID: 21328543",CMG2 protein levels could be restored to approximate control levels as the protein was properly targeted to the plasma membrane and signalling competent (Fig 8A).,Score,0.5 (1),Downgraded as it is a therapeutic approach rather than experiment using WT to rescue the phenotype,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0368b332-6765-451e-867b-71dd93e05ae4-2022-11-22T170000.000Z,129,PubMed:21328543 +Antxr2 mice knockout,Model Systems Non-human model organism,"Bürgi J, et al., 2017, PMID: 28604699",Uteri of Antxr2-/- female mice are highly enriched in collagen VI (Fig 3a). HFS patient nodules showed accumulation of collagen VI.,Score,0.5 (2),Downgraded as it does not fit human disease phenotype,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0368b332-6765-451e-867b-71dd93e05ae4-2022-11-22T170000.000Z,129,PubMed:28604699 +Double knockout female mice,Rescue Non-human model organism,"Bürgi J, et al., 2017, PMID: 28604699","Antxr2-/-::Col6a1-/- double knockout mice are fertile, with complete restoration of the uterine myometrial layers",Score,0 (2),Not scoring - does not fit human disease phenotype,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0368b332-6765-451e-867b-71dd93e05ae4-2022-11-22T170000.000Z,129,PubMed:28604699 +Collagen VI degradation inhibited in patient fibroblast,Functional Alteration Patient cells,"Bürgi J, et al., 2017, PMID: 28604699",Markedly reduced CMG2 mRNA expression in patient's fibroblast (Supp Fig 6b). Patient's fibroblasts were unable to degrade collagen VI even if the complex was found associated with cells.,Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0368b332-6765-451e-867b-71dd93e05ae4-2022-11-22T170000.000Z,129,PubMed:28604699 +IHC of ANXA11 c.1086+1G>A mutation carrier ALS case,Expression B,"Sainouchi M, et al., 2021, PMID: 34099057",IHC of CNS tissues from the ALS patient carrying an ANXA11 c.1086+1G>A mutation showed ANXA11 positive neuronal cytoplasmic inclusions. There was also significant co-localisation of ANXA11 with TDP-43 and p62 within such inclusions. (Fig. 3),Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_4dca2f56-87c6-4ac7-97bf-0889883b8e63-2021-11-12T215939.032Z,130,PubMed:34099057 +Yeast Three Hybrid Analysis,Protein Interaction,"Candiello E, et al., 2016, PMID: 27411398",Other AP-1 complex proteins AP1S1/AP1S2 are implicated in syndrome intellectual disability.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b3519527-9a80-4f0e-9ea6-c4244eb2ee33-2022-11-02T190000.000Z,132,PubMed:27411398 +Yeast Three Hybrid Analysis,Protein Interaction,"Candiello E, et al., 2016, PMID: 27411398",Other AP-1 complex proteins AP1S1/AP1S2 are implicated in syndrome intellectual disability.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d636cccc-aa9c-4927-ae40-538bf34d0620-2022-11-02T190000.000Z,133,PubMed:27411398 +Rescue in AP1S1-MO zebrafish,Rescue Non-human model organism,"Montpetit A, et al., 2008, PMID: 19057675","Rescued animals grew to the same size at wt animals and had similar levels of skin pigmentation with no evidence of epithelial disorganization. Intracellular localization was not as strong as that seen in wt animals, but was significantly higher than in morphants, and the protein was localized properly (Fig. 2G-I). Further, the motor defect observed in morphants was absent in the rescued animals (data not shown).",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b9559de4-1945-47fa-bea5-336d376eec0e-2022-06-10T160000.000Z,134,PubMed:19057675 +AP1S1-MO Zebrafish,Model Systems Non-human model organism,"Montpetit A, et al., 2008, PMID: 19057675","The morphant fish have mottled, disorganized skin lacking in pigment and with disorganized basement membrane/cell junction proteins, consistent with the epidermal phenotypes observed in MEDNIK patients. Further, interneuron number was reduced in the morphant CNS, consistent with human patient intellectual disability.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b9559de4-1945-47fa-bea5-336d376eec0e-2022-06-10T160000.000Z,134,PubMed:19057675 +Rescue in AP1S1-KO Cells,Rescue Cell culture model,"Klee KMC, et al., 2020, PMID: 32306098","Previous work showed that while apical-basal polarity was properly established and maintained in AP1S1-KO cells, there were defects in establishing and maintaining the epithelial barrier due to mislocalization of tight-junction proteins. The re-introduction of wt AP1S1 restored proper localization of the tight-junction proteins ZO-1 (Fig. 3B) and claudin 3 (Fig. 4B). It also restored the ability to properly form a spheroid cyst with a central lumen in 3D culture (Fig. 5A). Finally, the observed epithelial barrier defects (trans-epithelial electrical resistance and permeability to dextran) were restored to wt levels (Fig. 5C, D). +The above experiments were also performed with AP1S1 expression constructs carrying patient missense variants. In each case, the results were indistinguishable from the AP1S1-KO, in spite of the fact that expression levels and subcellular localization were unaffected by the presence of these variants (Fig. 2B).",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b9559de4-1945-47fa-bea5-336d376eec0e-2022-06-10T160000.000Z,134,PubMed:32306098 +AP1S1 Cell Culture,Model Systems Cell culture model,"Klee KMC, et al., 2020, PMID: 32306098","Using a human enterocyte cell model, the authors investigated the role of AP1S1 in establishing and maintaining epithelial barrier integrity. They first generated an AP1S1-KO line using CRISPR/Cas9 (Fig. 2A). Confocal microscopy and IHC-staining demonstrated that overall polarity was not affected in cell monolayers (Fig. 2C-D, 3A). However, the tight-junction protein ZO-1 aberrantly accumulated a cell-cell contact sites, and was mislocalized basally (Fig. 3A). Similar results were obtained for the enterocyte-specific tight-junction marker claudin 3 (Fig. 4A-B). Steady-state expression levels were unaffected for both proteins (Fig. 4C). Trans-epithelial electrical resistance was measured with a patch-clamp electrode; this value was reduced in KO cells compared to controls, indicative of a free flow of ions between the apical and basal surface (Fig. 5C). Finally, they added fluorescently labeled dextran to the culture medium and scored for fluorescence in the basal compartment after ten hours exposure. KO cells showed significantly higher levels of fluorescence, a further indicator of epithelial barrier permeability. These phenotypes are consistent with the enteropathy and chronic, intractable diarrhea phenotypes observed in MEDNIK patients.",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b9559de4-1945-47fa-bea5-336d376eec0e-2022-06-10T160000.000Z,134,PubMed:32306098 +Rab5/Vps34 pathway protein interaction,Protein Interaction,"Candiello E, et al., 2016, PMID: 27411398","Formation of AP-1/σ1AArfGAP1- +Rabex-5 complexes is prevented by σ1B binding of Rabex-5 and the amount of endosomal +Rabex-5 is reduced. AP-1 complexes differentially regulate endosome maturation and coordinate +protein recycling and degradation, revealing a novel molecular mechanism by which they regulate +protein transport besides their established function in clathrin-coated-vesicle formation.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9caaaacd-e262-421c-826b-8433848721ff-2017-10-20T160000.000Z,135,PubMed:27411398 +Karampini_FA,Functional Alteration Non-patient cells,"Karampini E, et al., 2019, PMID: 30630984","AP-3 complex-dependent protein trafficking was studied in knock-out and patient-derived BOECs. CD63 was found to be mislocalized within round, endosome-like structures, and not contained in Weibel-Palade bodies (WPB) in AP-3-deficient cells experimentally generated and derived from patient, while in wild-type cells, about one-third of CD63 was found associated with WPB. CD63 surface expression was significantly increased in AP3-deficient cells. +Release of inflammatory and angiogenic mediators from storage and secretory compartment, WPBs, plays a significant role in hemostasis. CD63 is transferred to maturing WPBs through AP3-positive endosomes.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_00ce813c-9493-48f9-9351-b70defb71d75-2020-02-26T170000.000Z,137,PubMed:30630984 +Zebrafish-model,Model Systems Non-human model organism,"D'Amore A, et al., 2020, PMID: 32216065","Impaired CNS development, locomotor deficits, and abnormal neuronal excitability seen in AP4E1 knockout zebrafish is relevant to impaired motor development, spastic paraplegia, seizures and developmental delay seen in humans",Score,1 (2),Downgraded by 1 point because it is a non-mammalian model organism,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_652e2cbe-22aa-4cd4-ba41-5bacca69af13-2023-04-25T160000.000Z,140,PubMed:32216065 +Co-Immunoprecipitation,Protein Interaction,"Słabicki M, et al., 2010, PMID: 20613862","SPG11 and ZFYVE26, also known as spatacsin and spastizin, are encoded by two genes that +have been associated with hereditary spastic paraplegia",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_020a234e-180c-4d9f-8f04-bd79eac6046e-2022-09-19T160000.000Z,141,PubMed:20613862 +cation-selective ion permease activity in phospholipid vesic,Functional Alteration Non-patient cells,"Bruno J, et al., 2021, PMID: 33380423",There is a significant (approximately twofold) increase in the cation-selective ion permease activity of the two kidney-disease-associated variants compared with the reference protein.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_47d0f13d-5122-4762-82c9-08db3ba104d1-2021-09-28T023000.000Z,146,PubMed:33380423 +BAC transgenic animals exposed to high INFgamma state.,Model Systems Non-human model organism,"McCarthy GM, et al., 2021, PMID: 34350953","APOL1 risk variants (G1, G2) have been associated with high OR of developing HIVAN (glomerular disease in uncontrolled HIV infection) and in response to systemic interferon therapy. Risk appears to be associated with recessive model, such that 2 risk alleles are associated with very high risk compared to 1 or 0 in humans. +In the mice, 2 risk alleles (G1/G1, G2/G2 or G1/G2) did not induce renal disease at baseline. However, prolonged exposure to interferon gamma induced proteinuria, podocyte loss, segmental glomerulosclerosis and ultimately renal failure in homozygous G1/G1 or G2/G2 mice, and in G1/G2 mice, but not in G0/G0 mice or G2/G0 mice. This phenocopies the human disease closely.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_47d0f13d-5122-4762-82c9-08db3ba104d1-2021-09-28T023000.000Z,146,PubMed:34350953 +APOLD1 silencing in endothelial cells,Functional Alteration Non-patient cells,"Stritt S, et al., 2023, PMID: 35638551","APOLD1 silencing causes increase in cell size, altered shape, EC junction dismantling (reduction in the tight junction protein CLDN5 and PECAM1), markedly enhanced fibronectin fibrillogenesis and actin stress fiber formation, reminiscent of EC activation, and increased endothelial permeability to 40 kDa FITC-dextran",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3b8a1833-03a5-4e71-9f31-974fcd6443f6-2024-02-05T170000.000Z,147,PubMed:35638551 +APOLD1 is expressed in platelets and endothelial cells,Expression A,"Stritt S, et al., 2023, PMID: 35638551","APOLD1 localizes to cell-cell junctions and Weibel-Palade bodies in HDBEC , moreover it localizes in platelet alpha granules",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3b8a1833-03a5-4e71-9f31-974fcd6443f6-2024-02-05T170000.000Z,147,PubMed:35638551 +ischemic stroke model,Model Systems Non-human model organism,"Fan Z, et al., 2023, PMID: 36933174","Stroke volume was similar in Apold1−/− and WT mice +21 days after the stroke reduction in vascular area, branch numbers, and total length of the vascular network in Apold1 KO mice. One week after stroke Apold1−/− ECs within the ischemic border zone proliferate less. +This may be in line with the microvascular ischemic syndromes observed in the patients",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3b8a1833-03a5-4e71-9f31-974fcd6443f6-2024-02-05T170000.000Z,147,PubMed:36933174 +Immunolocalisation in tissue,Expression A,"Gräf S, et al., 2018, PMID: 29650961","Figure 9e & 9h: expression localised to pulmonary endothelium in healthy lung, also in plexiform lesions in PAH patients. +Figure 10: mRNA present in pulmonary artery smooth musle cells (PASMCs) and pulmonary artery endothelial cells (PAEs) and blood outgrowth cells",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_29eda804-13df-4fe9-bbb3-9494b11edc92-2021-01-11T145519.495Z,149,PubMed:29650961 +"Functional alteration, mouse analysis",Functional Alteration Non-patient cells,"Wang G, et al., 2021, PMID: 37118341","The ARF1-/- homozygous neuronal-specific knockouts (mice) had significant demyelination and neuronal degeneration compared to the heterozygous (+/-) mice. Neuronal number was markedly reduced in the homozygous knockout, as well as the levels of PSD95+SYP+. Both PSD95 & SYP are key for synaptic vesicle endocytosis/localization.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5b42038d-6fb1-40be-96c3-1e97eacd9092-2024-06-28T160000.000Z,151,PubMed:37118341 +Cell culture model rescue,Rescue Cell culture model,"Zhang KH, et al., 2024, PMID: 38014604",mRNA supplementation of ARF1 was able to partly recover function (normal mitotic spindle assembly),Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5b42038d-6fb1-40be-96c3-1e97eacd9092-2024-06-28T160000.000Z,151,PubMed:38014604 +"siRNA injection, functional alteration",Functional Alteration Non-patient cells,"Zhang KH, et al., 2024, PMID: 38014604",There was a substantial reduction in ARF1 protein concentrations in siRNA-injection oocytes (ARF1-knockdown) in comparison to the control. The knockdown of ARF1 significantly increased the proportions of abnormal protein kinases Aurora A and Plk1.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5b42038d-6fb1-40be-96c3-1e97eacd9092-2024-06-28T160000.000Z,151,PubMed:38014604 +GWAS in dog breeds with hereditary neuropathy,Model Systems Non-human model organism,"Ekenstedt KJ, et al., 2014, PMID: 25275565","Phenotype resembles human CMT, sural nerve biopsies showed a decreased number of myelinated nerve fibers as a result of axonal degeneration, tibial muscle biopsy showed neurogenic atrophy and fatty replacement of muscle fibers",Score,1.5 (2),The mode of in heritance (AR) and pathomechanism (LOF) are different in dogs than in humans.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b23121f9-57e1-48ac-a2bc-d5a293829530-2020-10-05T160423.090Z,153,PubMed:25275565 +protein-protein interactions by split-ubiquitin assay,Protein Interaction,"Di Gregorio SE, et al., 2020, PMID: 32764283",direct interaction as shown by split-ubiquitin assay in yeast,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ac27cecc-9749-4c69-88fa-fe83b2d49568-2024-03-28T190000.000Z,155,PubMed:32764283 +heterozygous knockout of Arid1b in mice,Model Systems Non-human model organism,"Jung EM, et al., 2017, PMID: 29184203",GABAergic interneurons play an important role in neural circuitry and in emotional and cognitive behaviors. The balance of excitatory and inhibitory neurotransmission is essential for controlling memory and emotional behaviors and is disrupted in ASD and intellectual disability. Reduction of inhibitory signaling is particularly involved in ASD-like behaviors in humans and in mouse models of ASD. Proper positioning and differentiation of interneurons during brain development are important for establishing anatomical and functional circuitry necessary for normal cognition.,Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d487e6c4-9727-4315-90a2-11338128a8e5-2019-12-04T200734.569Z,157,PubMed:29184203 +Structure of human chromatin-remodelling PBAF complex,Biochemical Function A,"Yuan J, et al., 2022, PMID: 35477757","The authors demonstrate that the structure of PBAF also includes the subunits SMARCA4, SMARCB1, SMARCC, and SMARCE1, which have also been reported to have a gene-disease association with Coffin-Siris Syndrome",Score,1 (0.5),"The SWI/SNF complex is divided into the two major subclasses: BAF and PBAF. Several genes in the BAF complex are associated with Coffin-Siris syndrome: ARID1A, ARID1B, DPF2, SOX11, and SOX4. Several genes in the PBAF complex also cause Coffin-Siris syndrome: SMARCA4, SMARCB1, SMARCC2, and SMARCE1.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ae1a697f-8dcd-4edf-a25b-e5e0593e7e61-2022-12-07T170000.000Z,158,PubMed:35477757 +Chlamydomonas Model,Model Systems Non-human model organism,", , PMID: 34982025","Chlamydomonous armc2 mutants were immotile (swimming velocity of 0 micrometers/s). Furthermore, the armc2 mutants were unable to develop radial spokes at the distal end of the cilia. The observations of immotiility and the morphological abnormality due to radial spoke deficiency are consistent with the phenotypes seen in humans with spermatogenic failure 38 (infertility, immotile sperm, sperm morphological abnormalities).",Score,0.5 (2),This model was downscored due to the inability of the chlamydomonas model to demonstrate male infertility,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_aef0ad23-4568-4ef7-94e9-557981bfbe6c-2023-05-10T160000.000Z,161,PubMed:34982025 +Chlamydomonas rescue,Rescue Non-human model organism,", , PMID: 34982025","motility restored to 100% WT, localization of radial spokes restored along length of cilia.",Score,0.5 (2),Rescue downscored due to inability to test infertility phenotype,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_aef0ad23-4568-4ef7-94e9-557981bfbe6c-2023-05-10T160000.000Z,161,PubMed:34982025 +ARMC2 enriched in growing flagella,Biochemical Function B,", , PMID: 34982025",The enrichment of ARMC2 in growing flagella is consistent with this gene having a prominent role in the assembly of flagellar structure. It follows that dysfunction in ARMC2 would result in spermatogenic failure.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_aef0ad23-4568-4ef7-94e9-557981bfbe6c-2023-05-10T160000.000Z,161,PubMed:34982025 +Kahr_FA,Functional Alteration Non-patient cells,"Kahr WH, et al., 2017, PMID: 28368018","Immunoblotting confirmed absence of APC1B protein and showed increased ARPC1A expression in KO cells relative to wild-type cells. ARPC1B knockout cells formed proplatelets much less frequently than wild-type cells when induced with thrombopoietin to form proplatelet-like extensions in culture. While wild-type cells formed proplatelets containing tubulin and branched actin filaments, ARPC1B-null cells did not.",Score,0 (0.5),The evidence is awarded no points as it is not clear how the loss of ARPC1B leads to the associated phenotype.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_13909f11-a592-41cc-ade9-c77a5b49b253-2020-07-22T160000.000Z,163,PubMed:28368018 +Function of arylsulfatase A,Biochemical Function B,"Shaimardanova AA, et al., 2020, PMID: 33195324","This publication provides a detailed review of various aspects of MLD, including the biochemical function of arylsulfatase A. Arylsulfatase A (encoded by ARSA) s a homo-octamer composed of a tetramer of dimers. It belongs to the family of sulfatases, enzymes that hydrolyze the sulfate ester bonds of various compounds. ARSA-mediated hydrolysis of substrates has been shown to be a multi-step mechanism involving nucleophile activation, nucleophilic attack, and S-O bond cleavage. pecifically, ARSA is involved in the degradation of sulfatides in the lysosomes. SapB is involved in the presentation of sulfatide to the active site of ARSA. ARSA then hydrolyzes sulfatide to galactosylceramide by cleaving the sulfate group (see Fig 1). +When ARSA activity is lacking, sulfatides accumulate in body tissues and urine, as observed in human patients with metachromatic leukodystrophy.",Score,2 (0.5),"The score is increased because the function of arylsulfatase A is well understood, with many publications over decades, and is consistent with the biochemical features observed in hundreds of patients.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a8d351d5-5158-4cc2-b4dd-d3179b53e2a4-2023-06-15T160000.000Z,164,PubMed:33195324 +Lentiviral haematopoietic stem-cell gene therapy,Rescue Human,"Fumagalli F, et al., 2022, PMID: 35065785","In this prospective, non-randomised, phase 1/2 clinical study, 29 pediatric patients with pre-symptomatic or early-symptomatic early-onset MLD were treated with ""arsa-cel"" a haematopoietic stem and progenitor cell population transduced ex vivo with a lentiviral vector encoding human arylsulfatase A (ARSA) cDNA. The subjects were compared with an untreated natural history cohort of 31 patients with early-onset MLD, matched by age and disease subtype. +After median follow-up of ~3 years, 26 of 29 patients were still alive (2 died during the study due to disease progression and one from an apparently unrelated event). +Treated patients showed sustained multilineage engraftment of genetically modified HSPCs. After 2 years of treatment, ARSA activity in PBMCs was significantly increased a by a mean of 18·7-fold (95% CI 8·3–42·2; p<0·0001) in patients with the late-infantile variant and 5·7-fold (2·6–12·4; p<0·0001) in patients with the early-juvenile variant. +There were significant improvement in gross motor function in treated patients when compared to age-matched and disease subtype-matched untreated natural history patients 2 years after treatment. Most treated patients progressively acquired motor skills or their motor skills stabilized (e.g. maintained the ability to walk). Most subjects had normal cognitive development and prevention or delay of central and peripheral demyelination and brain atrophy; treatment benefits were particularly apparent in patients treated before symptom onset.",Score,4 (2),"The score is increased because this is a gene therapy clinical trial in human subjects, showing improvement/stabilization of symptoms in a relatively large group of subjects.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a8d351d5-5158-4cc2-b4dd-d3179b53e2a4-2023-06-15T160000.000Z,164,PubMed:35065785 +ASB enzyme function,Biochemical Function B,"Valayannopoulos V, et al., 2010, PMID: 20385007",Accumulation of GAGs due to ASB deficiency results in mucopolysacchariduria.,Score,2 (0.5),"Per Aminoacidopthy GCEP SOP, well-established associations are scored 2 points (see below): +'Some of the gene products will have a well-established function in a metabolic pathway, supported by multiple studies over many years, and discussed in review papers. In that case, it is appropriate to cite the review and any figure(s) representing the role of the gene product in a metabolic pathway, and score 2 points. It is also recommended to score one or more primary research articles in addition to the review.'",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_2a850717-e21b-495d-8542-de4fdb142647-2022-04-17T160000.000Z,165,PubMed:20385007 +Arx knock-in mouse model,Model Systems Non-human model organism,"Dubos A, et al., 2018, PMID: 29659809",The model system recapitulates phenotypes observed in patients carrying the c.441_464dup variant in ARX.,Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ccf3ab49-ee8f-4980-aa04-ca13c21c124a-2020-12-01T170000.000Z,166,PubMed:29659809 +Alayoubi_Lentiviral vector encoding ACDase,Rescue Non-human model organism,"Alayoubi AM, et al., 2013, PMID: 23681708","Physiologically, Asah1P361R/P361R mice treated with LV/ACDase manifested intermediate phenotypes. Their growth was comparable to mice from the heterozygous and WT groups until 5 weeks of age, after which they started to lose weight similar to control-treated mice, but their body weights remained significantly higher than untreated mice. All control-treated Asah1P361R/P361R mice died by 11 weeks of age, while 7 out of 9 LV/ACDase-treated mice lived beyond 11 weeks. Ceramide levels were strikingly reduced in the spleen and liver of LV/ACDase treated mice. Total ceramide as well as ceramide/DAG ratios were reduced in the spleen and liver while ceramide levels in the brain remained elevated. Microscopic examinations demonstrated reduction in macrophage infiltrations in the liver and spleen, with mild reductions in infiltrations in the brain. Infiltrations were still observed in the spinal cord, sciatic nerve, thymus, lymph nodes, bone marrow, lung, and skin in treated Asah1P361R/P361R mice, however.",Score,1 (2),Score is reduced due to limited rescue of phenotypes associated with disease in the mouse model.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d7d25555-4d27-4fd4-8619-cdf78b50701a-2023-10-04T160000.000Z,167,PubMed:23681708 +Alayoubi_Knock-in mouse,Model Systems Non-human model organism,"Alayoubi AM, et al., 2013, PMID: 23681708","Asah1-P361R/P361R mice manifest growth retardation in comparison to their heterozygous and WT littermates as early as 3 weeks of age with death at approximately 7-13 weeks. Homozygous mice manifested lethargy, general dystrophy, and a weak forelimb grasp, which worsened with advancing age. Penile prolapse was also observed in male and smaller ovaries covered with less fat in female mice were noted compared WT animals. Visceral examination revealed remarkably enlarged spleens, thymuses, and lymph nodes. In contrast, heterozygotes appeared phenotypically normal, showed growth patterns and unremarkable visceral examination similar to their WT littermates. In the spleen, brain, heart, liver, lungs, and kidneys of Asah1P361R/P361R mice, total ceramide levels were dramatically elevated compared to WT mice; heterozygous animals displayed no increases in ceramide accumulation. ACDase protein expression levels in tissues from Asah1P361R/P361R mice were similar to that from heterozygous and WT mice, while ACDase activities were significantly reduced in Asah1P361R/P361R mice compared to those derived from WT animals.",Score,2 (2),"Authors introduce a variant identified in human patients with severe Farber lipogranulomatosis into mice and recapitulate several features of the human disease. Increased score was not considered because, while the homozyggous knock-in mice recapitulate features of Farber lipogranulomatosis, they do not show the classic signs such as hoarseness, arthritis or subcutaneous nodules.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d7d25555-4d27-4fd4-8619-cdf78b50701a-2023-10-04T160000.000Z,167,PubMed:23681708 +ASB10 co-immunoprecipitates with HDAC6,Protein Interaction,"Keller KE, et al., 2013, PMID: 23901248","ASB10 has been shown to co-immunoprecipitate with HSP70 and a subunit of the 20S proteasome (Figure 6C) and to co-localize with HDAC6 (Figures 4B, 6B), possibly in the context of a ubiquitin- and proteasome-mediated degradation pathway. While the interaction with HDAC6 has not been proven to be physical / direct, the HDAC6 gene has been associated with the potentially related phenotype of microphthalmia (PMID: 16001442).",Score,0 (0.5),"ASB10 has not been proven to directly interact with HDAC6, and variants in the HDAC6 gene have been associated with microphthalmia, not glaucoma exactly.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ac9aa333-15d1-404d-85e1-a3d6e759dc0b-2023-03-16T160000.000Z,168,PubMed:23901248 +ASB10 interacts with ubiquitin-mediated degradation complex,Biochemical Function B,"Keller KE, et al., 2013, PMID: 23901248","Figure 7K from this same paper shows that proteosomal inhibition by MG132 can recapitulate the tendency for ASB10-deficient anterior segments to show reduced fluid outflow, consistent with the high ocular hypertension observed in most patients.",Score,0 (0.5),This evidence has been down-scored for the relative lack of data definitively linking the ubiquitin / proteasome system to the prevention of increased intraocular pressure or glaucoma in general.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ac9aa333-15d1-404d-85e1-a3d6e759dc0b-2023-03-16T160000.000Z,168,PubMed:23901248 +Gao Mouse Model,Model Systems Non-human model organism,"Gao Y, et al., 2021, PMID: 34145365",The mice displayed repetitive behaviors similar to those with autism spectrum disorder commonly seen in probands with ASH1L variants.,Score,0 (2),The GCEP decided that the mouse model did not sufficiently recapitulate the disease phenotype and therefore the model was not scored.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_41052ba5-878d-4e64-8ef2-ed65887a1345-2023-02-23T070000.000Z,169,PubMed:34145365 +Deaf14 mouse,Model Systems Non-human model organism,"Carpinelli MR, et al., 2014, PMID: 24682784","In humans, Canavan disease is a leukodystrophy characterized by spongiform encephalopathy of the brain, progressive intellectual impairment, motor deficit, and death in childhood. Additional clinical symptoms include hearing and visual impairment and seizures. +Deaf14 mice were generated by ethyl-nitrosonurea screen and have a nonsense variant, c.516T>A (p.Tyr172Ter) variant in Aspa, which results in lack of gene product, These mice had a reduced startle response, due to an abnormal auditory brainstem response. The brain of deaf14 mice was grossly abnormal, with widely distributed spongiform encephalopathy and extensive vacuolation (Fig. 5). They developed a Parkinson’s disease-like tremor (by 280 days of life), had a shorter latency to fall off a rotating rod than wild type mice, indicating impaired motor coordination. In the open-field test, deaf14 mice made more moves but covered less distance than wild-type mice, suggesting ataxia. +Similarities between the deaf14 mouse model and human patients with Canavan disease include: biallelic of function variants in the ASPA gene, spongiform encephalopathy and extensive vacuolation within the brain, hearing impairment, impaired motor coordination, ataxia, and shortened life span.",Score,3 (2),"The score is increased because the mice are homozygous for a loss of function variant, as is observed in human cases, and several key features of Canavan disease are present. The biochemical features, such as increased NAA, were not reported.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_66306eff-659f-4508-a41b-1820e47e0e1d-2020-10-08T161701.633Z,170,PubMed:24682784 +Cell type specific ASPA-KO mice,Biochemical Function B,"von Jonquieres G, et al., 2018, PMID: 29116375","While these studies were carried out on cell-type specific ASPA-knock out mice, the results are relevant to the function of ASPA and the relevance of that function to the disease process in Canavan disease. Hence, these results are included here, under Biochemical Evidence. +The authors showed that ASPA is exclusively expressed in oligodendrocytes and that these cells are at the root of Canavan disease pathology. Transgenic mice with extra copies of the Nat8l gene (involved in NAA synthesis), under the neuronal Thy-1 promoter and in the Aspa WT background (ThyNAT mice), did not show signs of neurotoxicity even though they had higher NAA levels in the cortex than ASPA knock out mice. In these mice, NAA accumulation does not occur in oligodendrocytes due to normal ASPA function. Therefore, elevated NAA in the brain alone does not appear to be responsible for disease pathology. Rather, NAA toxicity appears to depend on the lack of its degradation in oligodendocytes. This indicated that the normal ASPA activity in the oligodendrocytes of ThyNAT mice was able to keep oligodendrocyte NAA at normal concentrations, preventing disease. +Deletion of the Aspa gene exclusively in oligodendrocytes triggered a Canavan disease-like pathology, with delayed progression and partially attenuated late-stage severity. The authors conclude that deficiency of ASPA, which causes a detrimental increase NAA in oligodendrocytes, is the root cause for Canavan disease pathology.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_66306eff-659f-4508-a41b-1820e47e0e1d-2020-10-08T161701.633Z,170,PubMed:29116375 +Oligodendrocyte gene therapy in ASPA KO mouse,Rescue Non-human model organism,"von Jonquieres G, et al., 2018, PMID: 29116375","The authors present data showing that ASPA activity in the oligodendocytes protects against NAA toxicity in the CNS. They chose to treat mice at p30, the age at which supra-physiological levels of NAA and other metabolites, brain vacuolization and hypomyelination manifest in knock out mice. +In AAV vectors, the mouse myelin basic protein promoter (Mbp) was used to drive oligodendrocyte expression of either ASPA or GFP. Knockout mice were treated by direct multi-site intracranial injections. Immunoblotting and qRT-PCR showed stable and abundant expression of transgenic ASPA in the CNS of treated mice. Five months after intracranial Mbp-ASPA gene therapy, T2-weighted MRI revealed that key aspects of the CD histopathology were reverted in AKO-GT mice. In vivo 1H-MR spectroscopy in the thalamus showed normalization of the metabolic profile. Brain volume and excessive ventricle dilation was normalized in treated mice. There was normalization of NAA and NAAG concentrations, as well as other metabolites and replenishment of the glutamate and GABA neurotransmitter pools. Neurochemical restoration in GT mice was supported by attenuation of brain damage. Compared to AAV-GFP controls, in ASPA-KO mice mice treated with AAV-ASPA, numbers of neurons and oligodendrocytes were restored in the thalamus. Immunohistochemistry studies showed absence of reactive astrogliosis and microgliosis in AAV-ASPA treated mice, as well as improved myelination. There were longterm improvements in locomotor behavior, as shown by hanging wire, dowel and rotarod tests.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_66306eff-659f-4508-a41b-1820e47e0e1d-2020-10-08T161701.633Z,170,PubMed:29116375 +Katoh 2013 Review,Biochemical Function A,"Katoh M, 2013, PMID: 23736028","The ASXL gene family (ASXL1, ASXL2, and ASXL3) encodes proteins involved in transcriptional regulation and participates in body patterning during embryogenesis. +Germline de novo truncating variants in ASXL2 have been implicated in Shashi-Pena (PMID: 27693232). ASXL3 has been implicated in Bainbridge-Ropers syndrome (PMIDs: 23383720). Both have overlapping features of intellectual disability and dysmorphic features.",Score,1 (0.5),"Based on expert review, the gene family biochemical evidence was felt to be stronger and was upgraded to 1 point.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_31e0ce4d-aeb7-4983-9ec2-85178d7f40f0-2021-07-30T160000.000Z,171,PubMed:23736028 +Katoh et al.,Biochemical Function A,"Katoh M, 2013, PMID: 23736028","The ASXL gene family (ASXL1, ASXL2, and ASXL3) encodes proteins involved in transcriptional regulation and participates in body patterning during embryogenesis. Germline de novo truncating variants in ASXL2 have been implicated in Shashi-Pena (PMID: 27693232). ASXL3 has been implicated in Bainbridge-Ropers syndrome (PMIDs: 23383720). Both have overlapping features of intellectual disability and dysmorphic features.",Score,1 (0.5),"Based on expert review, the gene family biochemical evidence was felt to be stronger and was upgraded to 1 point.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_cedd313e-b43b-4212-840b-7d4172258b16-2021-09-28T115443.696Z,172,PubMed:23736028 +Katoh 2013 Review,Biochemical Function A,"Katoh M, 2013, PMID: 23736028","The ASXL gene family (ASXL1, ASXL2, and ASXL3) encodes proteins involved in transcriptional regulation and participates in body patterning during embryogenesis. Germline de novo truncating variants in ASXL2 have been implicated in Shashi-Pena (PMID: 27693232). ASXL1 has been implicated in Bohring-Opitz syndrome (PMID:21706002). Both have overlapping features of intellectual disability and dysmorphic features.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_947933aa-f0f8-4909-abd8-2984dd11dcb8-2021-10-06T040000.000Z,173,PubMed:23736028 +Modeling Bainbridge-Ropers Syndrome in Xenopus laevis Embryo,Model Systems Non-human model organism,"Lichtig H, et al., 2020, PMID: 32132929",These results suggest that ASXL3 is crucial for specifying neural cell fates. The disrupted neural cell fate specification aligns with the neurological phenotypes we see in patients.,Score,0.5 (2),This non-human model organizem been downgraded to 0.5 because it is a non mammalian model and because the knockdown in Xenopus may not model the disease mechanism in most human cases.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_947933aa-f0f8-4909-abd8-2984dd11dcb8-2021-10-06T040000.000Z,173,PubMed:32132929 +Localization of mutant protein in COS cells,Functional Alteration Non-patient cells,"Ansar M, et al., 2015, PMID: 26063662",Confocal imaging of the tagged WT ATF6 revealed expression throughout the cytoplasm and localization to the ER. Mutant ATF6 (p.Glu119Glyfs*8; identified in affected members of family) had significantly reduced localization in the cytoplasm and was mainly confined to the nucleus.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_649d690a-8457-4c95-8d27-978daf4ac877-2021-10-07T160000.000Z,175,PubMed:26063662 +"RT-PCR, Western, and immunolocalization",Expression A,"Ansar M, et al., 2015, PMID: 26063662","RT-PCR performed on commercially obtained RNA samples showed expression of three known ATF6 isoforms in human eye, particularly in the RPE cells. Western blot analysis using anti-ATF6 antibodies on protein extract from adult C57BL/6J mouse retina (Fig S3e). Immunofluorescent staining of CD1 mouse retinae revealed that ATF6 immunoreactivity is most prominent in the retinal ganglion cells. Staining was also observed in the retinal pigment epitheleum, outer and inner segments of photoreceptor cells, inner and outer plexiform layers, as well as in the inner nuclear layer of neuronal retina (Fig 2 - top, p946, S5).",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_649d690a-8457-4c95-8d27-978daf4ac877-2021-10-07T160000.000Z,175,PubMed:26063662 +ATG5 encodes autophagy 5 protein,Biochemical Function B,"Mizushima N, et al., 2001, PMID: 11266458","ATG5 variants in SCAR25 patients result in reduced ATG5 protein function, as reflected by the fact that patients’ lymphoblastoid cells show decreased ability to bind ATG12 and reduced autophagy activity, as indexed by reduced formation of LC3-II, a product of the ATG12–ATG5-ATG16L1 complex (PMID: 26812546) +Thus the ATG5 gene’s function (as a protein involved in autophagy) is consistent with SCAR25 patients’ phenotype (of reduced autophagy due to damaging variation in ATG5)",Score,2 (0.5),"Per ClinGen LD GCEP guidelines, gene products that have a well-established function in a metabolic pathway are scored 2 points",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b47796b8-3811-4411-b0f0-5b703755f08b-2022-07-21T160000.000Z,176,PubMed:11266458 +ATG5 transgene rescue,Rescue Non-human model organism,"Kim M, et al., 2016, PMID: 26812546","in ATG5 knockout Drosophila model, reexpression of ATG5 transgene rescues the ataxia phenotype (seen in the knockout), as indexed by climbing assay",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b47796b8-3811-4411-b0f0-5b703755f08b-2022-07-21T160000.000Z,176,PubMed:26812546 +ATG5 knockout Drosophila,Model Systems Non-human model organism,"Kim M, et al., 2016, PMID: 26812546","ATG5 knockout flies show ataxia and reduced cellular autophagy (as indexed by reduced levels of Ref(2)P [p62], an autophagy substrate), recapitulating phenotype seen in the human patients reported",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b47796b8-3811-4411-b0f0-5b703755f08b-2022-07-21T160000.000Z,176,PubMed:26812546 +Cells transfected with Atlastin defective mutants,Biochemical Function A,"Wang S, et al., 2016, PMID: 27619977",ATL1 is important for ER tabulation. ATL3 mutations leads to disrupted ER structure,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_132d0be7-2003-43ed-a934-1cf60cf45773-2021-07-13T160000.000Z,179,PubMed:27619977 +Evaluation of mitochondrial distribution and dynamics,Functional Alteration Patient cells,"Krols M, et al., 2019, PMID: 30339187",Increased ER-mitochondrila contact sites and decreased mitochondrial trafficking in patients fibroblasts.,Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_132d0be7-2003-43ed-a934-1cf60cf45773-2021-07-13T160000.000Z,179,PubMed:30339187 +Zebrafish knowckdown study,Rescue Non-human model organism,"Spataro R, et al., 2019, PMID: 30992063","co-injection of embryos with WT ATP13A2 rescued the cerebellum formation defects and the motor neuron extension defects +co-injection of embryos with with the ATP13A2:p.Glu613* or ATP13A2:p.Gly504Arg constructs did not rescue the phenotype",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0ba5cb4f-3f7f-44dc-b2a5-0a2d62e510d4-2022-04-14T160000.000Z,181,PubMed:30992063 +ATP13A3 knockdown,Functional Alteration Non-patient cells,"Gräf S, et al., 2018, PMID: 29650961","ATP13A3 knockdown by siRNA in BOEC showed a decreased in proliferation (d) +In conditioned medium, BOECs transfected with siRNA of ATP13A3 showed an increased on apoptosis, quantified by Annexin-V+/PT-. (e) +BOEC apoptosis after siRNA of ATP13A3 transfection was also measured by caspase assay showing an increase in apoptosis compare to the BOEC control",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5024e74a-fe6e-4eb2-89df-d07ff18e439c-2021-11-09T173936.225Z,182,PubMed:29650961 +Immunohistochemistry,Expression A,"Gräf S, et al., 2018, PMID: 29650961","Immunohistochemistry showed that ATP13A3 is expressed in primary human PASMCs, ECs and BOECs of patients +Immunohistochemistry showed that ATP13A3 is also expressed in primary human PASMCs, ECs and BOECs of controls +It is endothelial predominantly expressed +ATP13A3 is expressed in human PASMCs, PAEC and BOEC.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5024e74a-fe6e-4eb2-89df-d07ff18e439c-2021-11-09T173936.225Z,182,PubMed:29650961 +gene expression in tissues,Expression A,"GTEx Consortium, et al., 2017, PMID: 29022597",gene expression in tissues,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_2a572fef-35c5-46dd-8a69-af436b3ecdcc-2022-05-22T063513.942Z,184,PubMed:29022597 +Altered mitochondrial cristae in patient fibroblasts,Functional Alteration Patient cells,"Siegmund SE, et al., 2018, PMID: 30240627","Mitochondria isolated from patient fibroblasts from a proband (P2) in Barca et al(2018) were used in In Situ Cryoelectron Tomography analysis. Despite the normal appearance of mitochondria with mitotracker staining and confocal microscopy, the additional analysis, compared to controls revealed: +1)Abnormal Crista Membrane Architecture (Fig 1) +2)Increased Width and Blunted Apex Curvature of the cristae(fig2) +3)Diminished Total Cristae Volume(fig3)",Score,1 (1),"The altered structure of cristae is consistent with the loss of the Vm super complex associated with the patient variant, Vd is thought to help helps shape mitochondrial cristae to optimize proton flow.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ff19a86d-404a-464e-8da6-8824ce45ed20-2020-08-27T164252.070Z,185,PubMed:30240627 +IMPC KO mouse International Mouse Phenotyping Consortium,Model Systems Non-human model organism,"Cacheiro P, et al., 2019, PMID: 31127358","Some overlap of phenotypes which may be relevant to Leigh syndrome such as neurological abnormalities abnormal gait, decreased grip strength.",Score,0.5 (2),"Limited phenotype overlap described but abnormal gait, decreased grip strength suggestive of mitochondrial disease",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ff19a86d-404a-464e-8da6-8824ce45ed20-2020-08-27T164252.070Z,185,PubMed:31127358 +Knockdown in mushroom body in Drosophila.,Model Systems Non-human model organism,"Dubos A, et al., 2015, PMID: 26376863","ATP6AP2 knockdown in fly leads to memory deficits, mimicking aspects of the neuropathology associated with ATP6AP2 mutations in humans. The results identify ATP6AP2 as an essential gene for the nervous system.",Score,1 (2),This is a knockdown experiment in non-mammalian model organism.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ac33652a-dd98-46f4-ba4e-d3d5a482a22e-2020-09-14T160000.000Z,186,PubMed:26376863 +Conditional knockout in glutamatergic neurons in mice.,Model Systems Non-human model organism,"Dubos A, et al., 2015, PMID: 26376863","The conditional KO in glutamatergic neurons in mouse leads to cognitive impairment and neurodegeneration, mimicking aspects of the neuropathology associated with ATP6AP2 mutations in humans. The results identify ATP6AP2 as an essential gene for the nervous system.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ac33652a-dd98-46f4-ba4e-d3d5a482a22e-2020-09-14T160000.000Z,186,PubMed:26376863 +ATPV0A2 in cellular senescence and glycosylation,Biochemical Function B,"Udono M, et al., 2015, PMID: 26611489","Glycosylation occurs as proteins travel through the Golgi. Therefore, alterations in Golgi structure or pH could impact this process. In this study, by comparison of young and old TIG-1 cells (human fibroblast cell line established from fetal lung), and young cells with siRNA knockdown of ATP6V0A2 and expression of the ATP6V0A2 in old cells, the authors show that ATP6V0A2 is involved in cellular senescence, maintaining normal Golgi structure, and in maintaining normal levels of glycosylation. +ATP6V0A2-related cutis laxa is also a congenital disorder of glycosylation, as evidenced by the abnormal N- and 0-glycosylation observed in serum from patients. Therefore, this study provides a link between the biochemical function of the protein and observations in patients.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_67eb6244-012c-48c0-a409-874636825d85-2024-04-03T160000.000Z,187,PubMed:26611489 +a2 subunit N-terminus binds PI(4)P,Biochemical Function B,"Chu A, et al., 2024, PMID: 38396846","Neutralization of the intracellular pH has been shown to impair glycosylation by a disturbance of the location of glycosyltransferases in the secretory route (PMID: 11479274). This indicates the importance of V-ATPase localized in the Golgi membrane, functioning to pump H+ ions into the Golgi lumen and maintain pH. Based on the results of this study, the a2 subunit of V-ATPase (encoded by ATP6V0A2) is important in correct localization of V-ATPase within the Golgi membrane. Failure of this function could result in abnormal glycosylation, as noted in patients with biallelic variants in ATP6V0A2.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_67eb6244-012c-48c0-a409-874636825d85-2024-04-03T160000.000Z,187,PubMed:38396846 +atp6v1e1b-deficient Zebrafish models,Model Systems Non-human model organism,"Pottie L, et al., 2021, PMID: 34143769","Two zebrafish models with deficient expression of one of the zebrafish ohnologs of ATP6V1E1, atp6v1e1b share similar features with one another and also recapitulate many of the findings in human patients including dermal defects, vascular anomalies (cardiomyopathy, structural heart defects), glycosylation defects, and Golgi abnormalities. +The molecular mechanism is the same in the zebrafish model and human cases - loss of funciton.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d86dbf9e-ebed-446b-8291-e5838e37fd06-2024-05-01T160000.000Z,190,PubMed:34143769 +siRNA treated HepG2 cells,Functional Alteration Non-patient cells,"Gu S, et al., 2013, PMID: 23843956",Knockdown cells were exposed to copper sulfate for 24 hours and reduced cell viability by 53.3% compared to control treated cells and by 44% compared to ATP7B siRNA treatment alone (p<0.05) and was dose dependent.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_f0ac0a41-d7d5-4377-a622-1ee9bc4ed9f3-2019-03-27T160000.000Z,193,PubMed:23843956 +Complex V assembly factor,Biochemical Function A,"Garone C, et al., 2022, PMID: 35330152","ATPAF2 is an assembly factor for the F1 component of Complex V composed of 5 subunits (alpha, beta, gamma, delta, and epsilon).",Score,1 (0.5),This gene product shares function with 2-5 other gene products associated with mitochondrial disease.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_cfb2ce05-0eb4-4b98-95e5-e01cac3131ac-2022-04-04T040000.000Z,194,PubMed:35330152 +ATXN2 repeat expansion alleles interaction with TDP-43,Functional Alteration Non-patient cells,"Elden AC, et al., 2010, PMID: 20740007","TDP-43-YFP, but not YFP alone, immunoprecipitated endogenous Ataxin-2. Additionally, Ataxin-2 repeat expansion length led to a stronger interatction with TDP-43. For example, 39Qs immunoprecipitated with TDP-43-YFP more robustly than Ataxin-2 with 22Qs. TDP-43 is major disease associated protein in ALS, often found in cytoplasmic incursion bodies in the motor neurons in patients with ALS.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a5f9701f-a9a7-4689-9aec-27b3cbb06129-2024-02-13T170000.000Z,197,PubMed:20740007 +Brain specific AUTS2 KO in mice,Model Systems Non-human model organism,"Gao Z, et al., 2014, PMID: 25519132","In this study, mice with brain specific KO of AUTS2 are small for gestational and exhibit delay in multiple developmental phenotypes. Additionally in a different heterozygote mouse model of AUTS2 behavioral and neurocognitive defects have been reported (PMID: 26717414). these phenotypes described in the mice are similar and related to the clinical presentations in affected humans.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_582999f6-b3b4-46de-90a0-8f44e22df469-2020-09-01T160000.000Z,198,PubMed:25519132 +humanized AVPR1A mice,Model Systems Non-human model organism,"Charles R, et al., 2014, PMID: 24924430",Memory can be measured with experiments such as novel object recognition and spatial recognition.,Score,0 (2),"The experiment cannot be scored because there is no genetic level evidence. Also, this experiment does not compare AVPR1A knockout mice with the wild-type mice. They compare the knockout mice and wild type mice with mice with the human AVPR1A locus.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_8ea232de-063f-489a-b00a-8c5d11dbe43a-2022-03-01T050000.000Z,199,PubMed:24924430 +Morpholino knockdown,Model Systems Non-human model organism,"Buysse K, et al., 2013, PMID: 23359570",Little or no glycosylated αDG was observed in extracts from b3gnt1 morphants compared to wild-type. These results demonstrate that loss of function of B3gnt1 results in hypoglycosylation and verifies the efficacy of the morpholino.,Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5fdad7b1-d881-4d7c-a9ab-34812a92ae24-2023-03-28T160000.000Z,203,PubMed:23359570 +Flow cytometry analysis of glycosylation,Functional Alteration Non-patient cells,"Buysse K, et al., 2013, PMID: 23359570",Transfection with single mutants and the double mutant did not cause an increase of IIH6-positive cells. Normalization of the results as percentage of IIH6-positive cells in relation to the empty vector control showed a statistically significant difference in αDG glycosylation between wild-type and mutant constructs. These results indicate that the identified mutations impair the glycosyltransferase function of B3GNT1.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5fdad7b1-d881-4d7c-a9ab-34812a92ae24-2023-03-28T160000.000Z,203,PubMed:23359570 +Expression evidence C. Elegans,Expression A,"Williams CL, et al., 2011, PMID: 21422230","In C. Elegans, the conserved B9-Domain (containing MKS-1, B9D1, B9D2), TMEM67 (MKS3), MKS5, MKS6 (CC2D2A), NPHP1, and NPHP4 have necessary, cumulative functionality at the transition zone (TZ) at the base of all cilia. The B9 Domain and NPHP proteins form basal body/ TZ membrane connections before or during intraflagellar transport-contingent axoneme lengthening and limit buildup of non-ciliary substances in the ciliary region. Inhibition of MKS1, B9D1, or B9D2 and NPHP-4 leads to transition zone membrane problems. In contrast to wild-type animals or NPHP-4 single mutants, the double mutants have serious ciliary issues. The double mutants had absent, improperly located, or shortened axonomes, and sometimes absent TFs (transition fibers).",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ebe1140c-09cc-4d05-8886-5a78267afe65-2023-06-12T160000.000Z,205,PubMed:21422230 +MKS/MKSR NPHP interaction evidence,Protein Interaction,"Williams CL, et al., 2011, PMID: 21422230","This study was done in C. elegans sensory neurons. By fluorescently tagging proteins, it was evident that MKS/MKSR and NPHP proteins localize to the ciliary transition zone. This is the case for MKS1, B9D1, MKS3, B9D2, NPHP1, and NPHP4. B9D1 is definitive for autosomal recessive ciliopathy, and NPHP1 and NPHP4 are definitive for autosomal recessive nephronophthisis 1 and autosomal recessive nephronophthisis 4, respectively. In C. Elegans, the conserved B9-Domain (containing MKS-1, B9D1, B9D2), TMEM67 (MKS3), MKS5, MKS6 (CC2D2A), NPHP1, and NPHP4 have necessary, cumulative functionality at the transition zone (TZ) at the base of all cilia. The B9 Domain and NPHP proteins form basal body/ TZ membrane connections before or during intraflagellar transport-contingent axoneme lengthening and limit buildup of non-ciliary substances in the ciliary region. Inhibition of MKS1, B9D1, or B9D2 and NPHP-4 leads to transition zone membrane problems. In contrast to wild-type animals or NPHP-4 single mutants, the double mutants have serious ciliary issues. The double mutants had absent, improperly located, or shortened axonomes, and sometimes absent TFs (transition fibers).",Score,1 (0.5),B9D1 interacts with a number of proteins associated with autosomal recessive ciliopathy/kidney-related conditions.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ebe1140c-09cc-4d05-8886-5a78267afe65-2023-06-12T160000.000Z,205,PubMed:21422230 +Bach2 is required for efficient formation of Treg cells,Biochemical Function B,"Roychoudhuri R, et al., 2013, PMID: 23728300",Impaired regulatory T cell function are evident in BACH2 mutant patients compared with healthy controls and also with patients with classical IBD,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_2473560a-6e5c-4342-a6e2-c89e37f4cc71-2023-02-21T180000.000Z,206,PubMed:23728300 +Bach2 haploinsufficient mice have abnormal B cell activity,Model Systems Non-human model organism,"Afzali B, et al., 2017, PMID: 28530713",Bach2 haploinsufficient mice have abnormal B cell differentiation and Treg cell numbersand impaired lymphocyte development.,Score,1.5 (2),"The model system recapitulated the immune phenotype detected in the reported patients. However, more points would be allocated for recapitulating both clinical and immune phenotype.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_2473560a-6e5c-4342-a6e2-c89e37f4cc71-2023-02-21T180000.000Z,206,PubMed:28530713 +Protein expression in BACH2 mutant cells,Model Systems Cell culture model,"Afzali B, et al., 2017, PMID: 28530713","BACH2 protein expression +by flow cytometry was also +reduced in patient CD4+, CD8+ and +B lymphocytes despite normal mRNA +expression",Score,0.5 (1),"The experiment revealed defective protein expression in BACH2 mutant culture cells, with no reference to how this affects immune function.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_2473560a-6e5c-4342-a6e2-c89e37f4cc71-2023-02-21T180000.000Z,206,PubMed:28530713 +Reduced T cell activation and proliferation,Functional Alteration Patient cells,"Afzali B, et al., 2017, PMID: 28530713","Proliferation (Cell Trace Violet (CTV) dilution) of primary patient CD4+ T cells in response to anti-CD3 and anti-CD28 revealed several immune defects including: compromised Treg cells, enhanced TH1 differentiation, impaired proliferation and defective B cell maturation and Ig class switching.",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_2473560a-6e5c-4342-a6e2-c89e37f4cc71-2023-02-21T180000.000Z,206,PubMed:28530713 +Silencing BACH2 in control T cells and B cells,Biochemical Function B,"Afzali B, et al., 2017, PMID: 28530713",Impaired B cell class switching and T cell proliferation are consistent with the phenotype described in the reported probands of hypogammaglobulinaemia and defective T cell function,Score,1 (0.5),"Two experiments revealed a crucial role of BACH2 in T cell proliferation and B cell class switching. Silencing BACH2 in control CD4+ T cells led to a significant rise in PRDM1 mRNA and resulted in reduced proliferation of CD4+ T cells +silencing BACH2 in healthy control B cells, significantly suppressed in vitro class switch recombination towards the IgG and IgA isotypes",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_2473560a-6e5c-4342-a6e2-c89e37f4cc71-2023-02-21T180000.000Z,206,PubMed:28530713 +Reduced BAG3 Protein levels,Expression B,"Toro R, et al., 2016, PMID: 27391596",BAG3 protein levels were reduced in heart tissue samples from individuals with the p.H243Tfr*64 variant compared to WT controls.,Score,0 (0.5),Not scored as evidence used as part of genetic scoring for family.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1bec07e1-0186-4f45-bd8e-7d8a0f2547a9-2020-10-09T160000.000Z,207,PubMed:27391596 +BAG3 Mouse Rescue,Rescue Non-human model organism,"Knezevic T, et al., 2016, PMID: 28164169","Retro-orbital injection of an adeno-associated virus serotype 9 expressing BAG3 (rAAV9-BAG3) significantly (p < 0.0001) improved left ventricular ejection fraction, fractional shortening, and stroke volume 9 days post-injection in mice with cardiac dysfunction secondary to a myocardial infarction. Furthermore, myocytes isolated from mice 3 weeks after injection showed improved cell shortening, enhanced systolic [Ca2þ]i and increased [Ca2þ]i transient amplitudes, and increased maximal L-type Ca2þ current amplitude.",Score,1 (2),Reduced score as DCM phenotype induced by MI rather than genetic alteration.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1bec07e1-0186-4f45-bd8e-7d8a0f2547a9-2020-10-09T160000.000Z,207,PubMed:28164169 +DNA pyruvate kinase/DNA repair activity,Biochemical Function B,"Burgess JT, et al., 2021, PMID: 33660778","Abnormality of DNA repair is linked to aging, which is the main phenotype of NGPS.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_2e2059e5-b7a5-42fe-93b7-182982608431-2024-04-03T160000.000Z,208,PubMed:33660778 +Interaction with lamin,Protein Interaction,"Janssen A, et al., 2022, PMID: 36039758","Interaction with lamin A/C is inhibited by the p.Ala12Thr mutation, compared to the control, but this interaction can be restored via over-expression of wild-type BAF.",Score,0.5 (0.5),"Lamin A/C has not been curated for this specific condition (NGPS), but is associated with aging, which is the main phenotype of NGPS.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_2e2059e5-b7a5-42fe-93b7-182982608431-2024-04-03T160000.000Z,208,PubMed:36039758 +Re-expression of BAP1 in BAP1-deficient mesothelioma cells,Rescue Cell culture model,"Testa JR, et al., 2011, PMID: 21874000",Re-expression of BAP1 in BAP1-deficient mesothelioma cells markedly decreased colony-forming ability (Supplementary Fig. 5b).,Score,1 (1),"Re-expression of BAP1 in two mesothelioma cell lines lacking detectable endogenous +expression of BAP1 resulted in decreased colony-forming ability.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d70c33af-2e4f-4489-9c29-797655015b1d-2019-03-21T175713.803Z,209,PubMed:21874000 +Immunohistochemistry on mesotheliomas from L and W families,Expression B,"Testa JR, et al., 2011, PMID: 21874000","Immunohistochemistry on mesotheliomas from L and W families reveals lack of BAP1 nuclear expression and only weak, focal cytoplasmic BAP1 staining.",Score,0.5 (0.5),Immunohistochemistry on mesotheliomas from L and W families revealed lack of BAP1 nuclear expression (Fig. 3).,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d70c33af-2e4f-4489-9c29-797655015b1d-2019-03-21T175713.803Z,209,PubMed:21874000 +BAP1 FISH and IHC show loss of nuclear staining,Expression B,"Wiesner T, et al., 2011, PMID: 21874003","Fluorescence in-situ hybridization shows loss of BAP1 in the area with large epithelioid melanocytes, but no loss in the region of the common nevus. BAP1 immunohistochemistry at the transition area between common nevus and epithelioid cell area shows a strong nuclear staining in the common nevus component and loss of nuclear staining in the epithelioid component.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d70c33af-2e4f-4489-9c29-797655015b1d-2019-03-21T175713.803Z,209,PubMed:21874003 +BBS10 KO Mice,Model Systems Non-human model organism,"Cognard N, et al., 2015, PMID: 26273430","Mice exhibit severe retinal degeneration, which is the human phenotype. 3-month-old Bbs10 −/− mice showed retinal thinning observed in the Optical Coherence Tomography (OCT)",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_f9eb490e-1977-426e-ac7a-c507bbc38490-2023-08-03T160000.000Z,213,PubMed:26273430 +Patient Fibroblasts ciliogenesis,Model Systems Cell culture model,"Hey CAB, et al., 2021, PMID: 33572860",the frequency of ciliated cells was significantly lower in BBS10−/−(A) (89.16%) and BBS10−/−(B) (85.78%) cells compared to the pool of the control cells (92.60%),Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_f9eb490e-1977-426e-ac7a-c507bbc38490-2023-08-03T160000.000Z,213,PubMed:33572860 +mouse knockdown,Model Systems Non-human model organism,"Mayer SK, et al., 2022, PMID: 36125046","Cone electrical activity is absent from the earliest age tested [postnatal day (P)30]; although rod function is present initially, it is less robust than in controls and diminishes further over time. This differs from most types of retinitis pigmentosa (RP), in which rod loss precedes cone loss. The Bbs10−/− mouse recapitulates the ‘cone-simultaneous-with-rod or cone-before-rod’ retinal phenotype reported in some BBS10 patients",Score,0.5 (2),downscored as this is the same mouse from the previous publication but further characterized,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_f9eb490e-1977-426e-ac7a-c507bbc38490-2023-08-03T160000.000Z,213,PubMed:36125046 +Bbs9 knockdown causes developmental defects in zebrafish,Model Systems Non-human model organism,"Veleri S, et al., 2012, PMID: 22479622","bbs9-spMO morphants displayed developmental defects in eye and brain, and often with hydrocephaly. These are reminiscent of the clinical features reported in BBS patients. Histological analysis of the morphants’ eyes revealed a dose dependent effect of bbs9-spMO on photoreceptors compared to uninjected or the control-MO injected embryos. Bbs9-spMO caused altered retinal layer stratification apparently forming an amalgam. The photoreceptor layer was indistinguishable from RPE, which often displayed denudation from the inner retinal +layer due to lack of photoreceptor outer segments. The morphants did not develop a full size eye as in the controls. +BBS9 is required for the assembly of the BBSome, which in turn is needed for targeting membrane proteins to the cilium. Hence, loss of (or severely reduced) function of BBS9 could affect the integrity of the BBSome complex and compromise cilia function. data demonstrate that like many other BBS genes, Bbs9 is required for cilia development. The retinal degeneration in zebrafish, exhibited by bbs9-spMO morphants, is a further indication of cilia dysgenesis similar to the phenotype produced by Rpgr knockdown, which causes abnormal ciliary transport.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3fc68f9f-ed7c-453e-8c41-179a9ccad0ca-2023-08-03T160000.000Z,214,PubMed:22479622 +Human BBS9 mRNA rescues bbs9 knockdown phenotype in the zebr,Rescue Non-human model organism,"Veleri S, et al., 2012, PMID: 22479622","Co-injection of 0.3 ng bbs9-spMO along with wild type human BBS9 mRNA rescued the morphant phenotype in a dose-dependent manner. Co-injection of bbs9-spMO with 100 pg of wild-type human mRNA significantly improved the eye size. Analysis of RNA from the rescued zebrafish revealed an effective splice blocking of zebrafish bbs9 transcript, suggesting that the phenotypic rescue was indeed by the human mRNA.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3fc68f9f-ed7c-453e-8c41-179a9ccad0ca-2023-08-03T160000.000Z,214,PubMed:22479622 +Biochemical Function Review,Biochemical Function B,"Blackburn PR, et al., 2017, PMID: 28919799","MSUD is caused by decreased function of the BCKAD complex, which includes BCKDHA. Variants in any of the subunits decrease its activity, thereby increasing BCAA levels, leading to toxicity in the skeletal muscle and brain.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5c89a6c7-751a-4a99-8a32-97cc33c5df7c-2018-09-14T160000.000Z,217,PubMed:28919799 +BCKD Complex,Biochemical Function A,"Blackburn PR, et al., 2017, PMID: 28919799","Pathogenic variants in the subunits of the BCKD complex decrease its activity, thereby increasing BCAA levels leading to toxicity in the skeletal muscle and brain tissue.",Score,0.5 (0.5),"The second major step in catabolism of branched-chain amino acids is catalyzed by the branched-chain alpha-keto acid dehydrogenase complex that consists of 3 subunits- E1a, E1b and E2. Variants in BCKDHA are well-known to cause MSUD type 1a.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0b0d314c-7355-441c-a357-72ba3e566c57-2019-02-08T170000.000Z,218,PubMed:28919799 +BCL11A structural and behavioral abnormalities in mice,Model Systems Non-human model organism,"Dias C, et al., 2016, PMID: 27453576","Mouse model showed alterations in cognition and brain morphology similar to that described in Dias-Logan syndrome patients. Using a number of different behavioral paradigms, Bcl11a haploinsufficient mice were found to have impaired cognition, abnormal social behavior, and microcephaly, in line with intellectual disability, autistic features, and microcephaly observed in human cases. +Note that the authors also used HEK293 cell to confirm the pathogenicity of the three missense variants observed (Subjects 1-3).",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9630f9a3-3f90-49c6-ae8b-6313c950b1b2-2020-09-13T171807.228Z,220,PubMed:27453576 +BCS1L knock in model,Model Systems Non-human model organism,"Tegelberg S, et al., 2017, PMID: 28427446","Immunohistochemical analysis showed general mild astrogliosis throughout the brain. In contrast to that, substantial astroglial activation was found highly localized to the primary somatosensory cortex which was reminiscent of patient’s with BCS1L mutations. No signs of neurodegeneration were detected in the Bcs1l c.232A>G mouse brain. The volume of cerebral cortex and cerebellum was unchanged as was the thickness and the amount of neurons in the individual layers. (neuronal preservation in the cortex). This mouse demonstrated neuropathological findings similar to those associated with Leigh spectrum syndrome in humans",Score,0.5 (2),"As per Leigh Working group model scoring rubric, BCS1L knock in mouse received 0.5 pts for neuropathological evidence.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3b50d7db-1144-4187-a60c-72b45adb80bd-2019-09-19T155315.896Z,224,PubMed:28427446 +Tegelberg Patient Cells,Functional Alteration Patient cells,"Tegelberg S, et al., 2017, PMID: 28427446",The quantity of fully assembled CIII was investigated using antibodies directed against two CIII subunits (RISP and CORE1). There was an almost complete lack of fully as-sembled CIII and BCS1L (both oligomer and monomer) in patient cells.,Score,0.5 (1),This is the second patient derived cell culture model demonstrating mitochondrial dysfunction.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3b50d7db-1144-4187-a60c-72b45adb80bd-2019-09-19T155315.896Z,224,PubMed:28427446 +Ji_Rescue,Rescue Patient cells,"Ji C, et al., 2019, PMID: 31836750","BV: Ca2+-dependent Cl− current measured at 1.2 μM [Ca2+]i by whole-cell patch clamp significantly increased from 24 to 48 hours, and in a dose-dependent manner at 48 hours post infection (Fig. 5b–e). A complete rescue of the Cl− current at peak [Ca2+]i was observed at 48 hours post infection with a minimum MOI of 100 (Fig. 5c–e, and Supplementary Fig. S5), +where Ca2+-dependent Cl− currents in a full range of [Ca2+]is were also fully restored (Fig. 5d). Consistently, Ca2+-dependent Cl− currents in the other five patient-derived iPSC-RPEs were all rescued to a similar level under the same conditions (Fig. 5f–k), regardless of the type or level of deficiency in the endogenous BEST1 function. Immunoblotting results showed that the exogenous BEST1 expression level is comparable to that of the endogenous +BEST1 (Supplementary Fig. S4). Taken together, we concluded that the defect of Ca2+-dependent Cl− conductance caused by BEST1 loss-of-function mutations, either dominant or recessive, is rescuable by BV-mediated supplementation of the WT BEST1 gene with the same dosage and time course. +AAV: Consistent with the results from BV-mediated augmentation, Ca2+-dependent Cl− currents were restored after AAV infection in iPSC-RPEs bearing either a dominant or recessive BEST1 mutation (Fig. 5i), providing a proof-of-concept for curing BEST1-associated retinal degenerative diseases in both dominant and recessive cases by AAV-mediated gene augmentation.",Score,1.5 (1),Increased score due to multiple rescue methods (BV and AAV) and inclusion of HEK-293 and subcellular localization experiments demonstrating functional impact of mutations.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_487a42cc-7dd0-4991-ac9d-1346f59073c0-2023-08-03T160000.000Z,226,PubMed:31836750 +Amphiphysin II (BIN1) Expression in Human Skeletal Muscle,Expression A,"Butler MH, et al., 1997, PMID: 9182667",Northern blot analysis of multiple diverse human tissues demonstrated marked enrichment of Amphiphysin II (BIN1) mRNA in skeletal muscle. Immunofluorescence light microscopy and electron microscopy immunocytochemistry localization of Amphiphysin II (BIN1) protein in skeletal muscle suggest the protein localizes around the plasmalemma of T tubules.,Score,0.5 (0.5),The Northern blot and in situ localization experiments in human tissue are in agreement with the enriched expression in skeletal muscle reported by HPA and GTEx.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_8bb963a9-ec8a-4966-93bb-4f8ef6f8f8a1-2024-06-10T160000.000Z,227,PubMed:9182667 +Heterologous overexpression of N-terminal FLAG-tagged human,Functional Alteration Non-patient cells,"Puffenberger EG, et al., 2012, PMID: 22279524",Mutant BRAT1 does not localize and forms puncate aggregations in cytoplasm.,Score,0 (0.5),Score as variant level evidence.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_698a4cb3-df52-432b-9d3e-d3d76111db25-2022-09-13T170000.000Z,244,PubMed:22279524 +Heterologous overexpression of N-terminal FLAG-tagged human,Functional Alteration Non-patient cells,"Puffenberger EG, et al., 2012, PMID: 22279524",Mutant BRAT1 does not localize and forms puncate aggregations in cytoplasm.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_93a7b6f1-75e5-4f97-be9d-62fb5770b8cb-2022-09-06T170000.000Z,245,PubMed:22279524 +Western Blot of BRAT1 in Patient Derived Cell Lines,Expression B,"Mahjoub A, et al., 2019, PMID: 31742228","""Markedly reduced level of BRAT1 protein in patient derived cell lines. Indeed, although we could not restore normal levels of BRAT1 protein in the patient cells by incubation with the proteasome inhibitor MG132(figure 2B), incubation with cycloheximide to prevent nascent protein synthesis revealed that the half-life of the mutant protein was much shorter than the parental BRAT1""",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_93a7b6f1-75e5-4f97-be9d-62fb5770b8cb-2022-09-06T170000.000Z,245,PubMed:31742228 +Mouse Model,Model Systems Non-human model organism,"Korb E, et al., 2015, PMID: 26301327",Both humans and mice have neurodevelopmental abnormality.,Score,0.75 (2),There are other mouse models.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_8b28cda3-bce6-4a8f-b359-0ab398a1111d-2022-04-20T160000.000Z,249,PubMed:26301327 +ChIP-seq in Drosophila,Protein Interaction,"Pherson M, et al., 2019, PMID: 30796039",NIPBL is associated with Cornelia de Lange syndrome with overlapping phenotype,Score,0.25 (0.5),Multiple evidence in this category,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_8b28cda3-bce6-4a8f-b359-0ab398a1111d-2022-04-20T160000.000Z,249,PubMed:30796039 +Mouse Model,Model Systems Non-human model organism,"Penas C, et al., 2019, PMID: 31292434",Both humans and mice have neurodevelopmental abnormality.,Score,0.75 (2),There are other mouse models,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_8b28cda3-bce6-4a8f-b359-0ab398a1111d-2022-04-20T160000.000Z,249,PubMed:31292434 +Yeast two-hybrid,Protein Interaction,"Luna-Peláez N, et al., 2019, PMID: 31320616",NIPBL is associated with Cornelia de Lange syndrome with overlapping phenotype.,Score,0.25 (0.5),Multiple evidence in this category,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_8b28cda3-bce6-4a8f-b359-0ab398a1111d-2022-04-20T160000.000Z,249,PubMed:31320616 +Fancj helicase-deficient mice,Model Systems Non-human model organism,"Matsuzaki K, et al., 2015, PMID: 26637282","Fancj-null mice exhibit subfertility, germ cell attrition, epithelial tumor predisposition, +and exquisite sensitivity to ICL-inducing agents, which phenocopy other mouse models of FA; enhanced predisposition to lymphomas",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_40aae4ea-8c9b-42a7-9d02-0f52a184712f-2019-08-18T160442.255Z,250,PubMed:26637282 +Model 1,Model Systems Non-human model organism,"Daino K, et al., 2013, PMID: 24040146",The model system does not recapitulate human phenotype with only a knock-down model.,Score,0.25 (2),"While the knock-down model in the cell line showed alterations as noted: ""We observed that the acini formed by BRIP1-knockdown cells were significantly larger than the control acini after 4 days of culture (Fig. 1B and C). Additionally, BRIP1-knockdown cells formed irregular-shaped acinar structures after 8 days of culture (Fig. 1B). In 20 days, the control cells developed into organized acini with hollow lumens (Fig. 2C and D). In contrast, the BRIP1-knockdown cells formed large irregular-shaped aggregates with filled lumens and were also characterized by increased cell size, filopodia formation, loss of cellular polarity, nuclear atypia, and nuclear stratification (Fig. 2A, B, E and F). BRIP1-knockdown cells also had a 3-fold higher rate of proliferation fraction than the control cells as assessed by Ki-67 immunohistochemistry, even after the control cells formed growth-arrested acini by day 20 (Fig. 2G)."" +The knockdown did not generate tumors in the nude mice or recapitulate features seen in breast cancer patients.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_87aa8181-721b-4583-98cf-0dead1827e27-2023-12-21T180000.000Z,251,PubMed:24040146 +BRWD1 mutated mice are infertile,Model Systems Non-human model organism,"Pattabiraman S, et al., 2015, PMID: 25547156",Male mice show asthenozoospermia and Multiple Morphological abnormalities of the flagella (MMAF) like observed in male patients with BRWD1 mutations.,Score,0 (2),"Infertile patients with BRWD1 variants have shown structural defects of cilia and sperm flagella. However in mice the infertility is caused by defects in spermatogenesis (defect in the postmeiotic sperm differentiation). Also, no respiratory signs were reported in the mutated mice.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9f74ee87-e640-4604-9bb7-e7617907f92c-2022-11-10T110000.000Z,254,PubMed:25547156 +BRWD1 mutated mice have hypogammaglobulinemia,Model Systems Non-human model organism,"Mandal M, et al., 2015, PMID: 26301565",BRWD1 mutated mice show decreased levels of circulating antibodies like observed in human patients.,Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a44471f3-0951-4456-955d-916b691e59f5-2022-12-08T170000.000Z,255,PubMed:26301565 +Confocal microscopy shows the nuclear localization of BRWD1,Biochemical Function B,"Mandal M, et al., 2015, PMID: 26301565","BRWD1 binds (through its bromodomains) to chromatin in B cell progenitors to regulate the Igk chain recombination. +The alteration of this function leads to the decrease in circulating antibody level.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a44471f3-0951-4456-955d-916b691e59f5-2022-12-08T170000.000Z,255,PubMed:26301565 +TgMT (double mutant N88S/S90L) mice,Model Systems Non-human model organism,"Guo J, et al., 2013, PMID: 23470542",The neuron-specific overexpression of N88S/S90L mutant Seipin leads to slowly progressive upper and lower motor neuron pathologies reminiscent of phenotypes in seipinopathy patients.,Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_02472719-c26d-40ff-8ad4-897ef7a6800a-2022-09-23T160000.000Z,257,PubMed:23470542 +Autophagy is activated in motor neurons of tgMT mice,Functional Alteration Non-patient cells,"Guo J, et al., 2013, PMID: 23470542","Increased formation of autophagosome structures was only seen in the spinal cord of tgMT, but not in tgWT mice. Motor neurons show accumulation of autophagy marker LC3II together with a fragmented Golgi apparatus phenotype. Overstimulation of autophagy by mutant seipin leads to signs of degeneration.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_02472719-c26d-40ff-8ad4-897ef7a6800a-2022-09-23T160000.000Z,257,PubMed:23470542 +Mutant Seipin forms aggregates in the CNS and spinal cord,Functional Alteration Non-patient cells,"Guo J, et al., 2013, PMID: 23470542","Seipin aggregates were found only in the CNS of tgMT mice, but not in tgWT mice. Approximately 20% cortical and 40% spinal neurons of tgMT mice were found to contain Seipin aggregates, while none in non-transgenic control or tgWT mice.",Score,0.5 (0.5),"Aggregates were also detected in teh N88S Tg mice (Yagi et al, 2011, PMID: 21750110).",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_02472719-c26d-40ff-8ad4-897ef7a6800a-2022-09-23T160000.000Z,257,PubMed:23470542 +Leigh map,Biochemical Function A,"Rahman J, et al., 2017, PMID: 27977873",BTD- and SLC19A3-related disease respond to biotin treatment.,Score,0.5 (0.5),Shares biochemical function with one other gene product (SLC19A3).,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_74599afe-02f9-4225-9e50-63306f04a552-2021-06-14T140327.018Z,260,PubMed:27977873 +BUB1 Hypomorphic Mice_Jeganathan 2007,Model Systems Non-human model organism,"Jeganathan K, et al., 2007, PMID: 17938250",increase in segregation errors and incidence of cancer,Score,0 (2),Decreased to 0 points because mice did not get colon/intestinal cancers.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_018019f0-2a13-42e7-9a03-b7eac3a4c483-2023-12-20T180000.000Z,263,PubMed:17938250 +Bub1 Functional Splice Mutation,Functional Alteration Patient cells,"Mur P, et al., 2018, PMID: 29448935",mRNA expression and segregation counts,Score,0 (1),"Not scored - already 1 paper scored that supports BUB1 role in chromosomal stability (Cahill, et al)",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_018019f0-2a13-42e7-9a03-b7eac3a4c483-2023-12-20T180000.000Z,263,PubMed:29448935 +Downregulate expression in Drosophila orthologs of C19orf12,Model Systems Non-human model organism,"Iuso A, et al., 2014, PMID: 24586779","Double RNAi and Double heterozygous Deletion Flies showed defective climbing that suggested a neuromuscular phenotype in double RNAi and double heterozygous deletion flies. +There was high number of vacuoles with an area up to 30 um2 was found in the brain and in the optical lobe of all investigated down-regulated double RNAi flies in comparison to control flies The presence of vacuoles suggested neurodegenerative process. +Often, a compromised mitochondrial metabolism generates bang sensitive mutants which respond to the mechanical boost with a temporary paralysis. It was noted that Double RNAi flies failed to recover a correct body position promptly even if no signs of paralysis or failure of movements were present with mechanical stress. Double heterozygous deletion flies restored upright position instantly but ceased moving. +The findings of the impaired climbing activity, bang sensitivity and presence of vacuoles in the brain could possibly similar to certain phenotype seen in humans (locomotor defect and possible neurodegeneration)",Score,0.5 (2),"The phenotype of reduced locomotor function (defective climbing) in the double RNAi and Double heterozygous deletion flies may mimick the phenotype seen in human (pyramidal symptoms). There was absence of iron deposition in brain in the double RNAi flies. The presence of vacuoles in brain is not a main feature seen in human with C19orf12-related NBIA. +Hence score downgraded to 1 as phenotypes seen in the double RNAi and double heterozygous deletion flies in this study are not exactly similar to the human phenotype.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_20b64ab8-0b48-40d4-8ef5-b3d251e4bec0-2023-02-28T170000.000Z,265,PubMed:24586779 +Mitochondrial Ca2+ Homeostasis Analysis,Functional Alteration Patient cells,"Venco P, et al., 2015, PMID: 26136767","Using mitochondrial-targeted aequorin probe in the measurement of mitochondrial Ca2+, it was found that high levels of mitochondrial Ca2+ in patient fibroblasts as compared to control, suggesting the mutation altering the intracellular distribution of C19orf12 is detrimental for proper mitochondrial function and Ca2+ homeostasis and may cause pateint derived fibroblast more sensitive to Ca2+ dependent stimuli like H2O2 induced death as compared to fibroblast. (figure 7)",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_20b64ab8-0b48-40d4-8ef5-b3d251e4bec0-2023-02-28T170000.000Z,265,PubMed:26136767 +Rescue phenotype in iPLA2-VIA-deficient flies using C19orf12,Biochemical Function A,"Mori A, et al., 2019, PMID: 31548400",PLA2G6 - see above,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_20b64ab8-0b48-40d4-8ef5-b3d251e4bec0-2023-02-28T170000.000Z,265,PubMed:31548400 +Zebrafish embryos as model for c19orf12a,Model Systems Non-human model organism,"Mignani L, et al., 2020, PMID: 33425903","The authors have demonstrated that with knock down of gene a (ortholog) in zebrafish embryo, the large majority of them (171/206, 83.0%) showed perturbed brain morphology with smaller brain size and eyes, reduced yolk extension along with a curved and thinner tail, and defected somite development (mild category). A small number of embryos (15/206, 7.3%) were characterized by a dramatic alteration of the structure, with severe perturbation of the antero-posterior axis, cardiac edema and compromised somite development (evere category) and the remaining embryos (20/206) showed a normal phenotype. +Besides that, the authors have also analysed neuronal development, musculature development and locomotor behaviours of the the zebrafish with mild phenotype using different methods. +i) Using transgenic lines expressing EGFP under neurogenin1 (neurog1) or neuronal +differentiation 1 (neurod1) promoters, there is suggestion that there were reduced signals in the midbrain-hindbrain boundary, particularly at the level of optic tectum and retina. The analysis of the transgenic lines suggests that downregulation of gene a may affect the early stages of development in neurons in trunk, or cells located in retina, tectum opticum and the midbrain-hindbrain boundary. +ii) The ATG-morphants showed an overall reduction in birefringence pattern (bright birefringence indicative of highly organized skeletal muscle) that was suggestive of a disorganized skeletal muscle structure. +iii) Objective motor function measurement was obtained through calculation of spontaenous tail coil movement at 24 hpf, touch-evoked swimming movement test at 48 hpf, and the downregulation of gene a expression is associated with significant loss of motor performance of embryos in injected embryo compared to control embryo. +The zebrafish model system phenotype shows that gene a which is ortholog to c19orf12 is involved in the development of selected brain areas, especially retina, that is a key feature seen in individuals with C19orf12-related NBIA.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_20b64ab8-0b48-40d4-8ef5-b3d251e4bec0-2023-02-28T170000.000Z,265,PubMed:33425903 +Rescue abnormal phenotype in ATG-morphants with C19orf12mRNA,Rescue Non-human model organism,"Mignani L, et al., 2020, PMID: 33425903","The expression of the human WT mRNA significantly increased the number of embryos showing a normal phenotype, which were about 55% of the alive embryos (167/305) vs. 8.3% (n D 24/290) observed in ATG-MO-injected embryos. About 43% (n D 132/305) of the co-injected embryos still showed a mild phenotype, but less than 2% (n D 6/305) a severe one (Figure 3C). +On the contrary, the type and percentage distribution of the morphological features observed upon the co-injection of ATGMO and MUT-mRNA were similar to those observed when +ATG-MO alone was injected (Figure 3C). Normal embryos represented 9.4% (14/127) of the survived embryos, while embryos with mild or severe abnormalities were 79.5% (101/127) +and 11% (12/127), respectively. +The differences in the percentage of embryos with normal and mild phenotype observed between +ATG-MO-WT-mRNA co-injected embryos, and ATG-MOinjected embryos was statistically significant (p < 0.001). This suggests that the WT human mRNA was able to overcome the +deficiency of c19orf12a mRNA, by significantly increasing the number of embryos with normal phenotypic development a compared to that observed in the ATG-MO-injected group. On +the contrary, the injection of the MUT-mRNA did not affect the aberrant development. This result further confirms the specific relationship between the knock-down of gene a mRNA and the +perturbed development observed in ATG-morphants.",Score,1 (2),"The phenotype abnormality seen in Zebrafish using a translation-inhibiting morpholino (ATG-MO) that is complementary to the -17/+5 region of gene a mRNA affects brain formulation and somite development - not completely translatable to human disease manifestation of NBIA. +Eventhough there was a statistically significant difference in the percentage of embryos with normal and mild phenotype observed between ATG-MO-WT-mRNA co-injected embryos, and ATG-MO-injected embryos, the rescue of the phenotype was not complete with 43% of co-injected embryos with human WT mRNA showing mild phenotype and <2% with a severe phenotype.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_20b64ab8-0b48-40d4-8ef5-b3d251e4bec0-2023-02-28T170000.000Z,265,PubMed:33425903 +Downregulate expression in Drosophila orthologs of C19orf12,Model Systems Non-human model organism,"Iuso A, et al., 2014, PMID: 24586779","Double RNAi and Double heterozygous Deletion Flies showed defective climbing that suggested a neuromuscular phenotype in double RNAi and double heterozygous deletion flies. There was high number of vacuoles with an area up to 30 um2 was found in the brain and in the optical lobe of all investigated down-regulated double RNAi flies in comparison to control flies The presence of vacuoles suggested neurodegenerative process. Often, a compromised mitochondrial metabolism generates bang sensitive mutants which respond to the mechanical boost with a temporary paralysis. It was noted that Double RNAi flies failed to recover a correct body position promptly even if no signs of paralysis or failure of movements were present with mechanical stress. Double heterozygous deletion flies restored upright position instantly but ceased moving. The findings of the impaired climbing activity, bang sensitivity and presence of vacuoles in the brain could possibly similar to certain phenotype seen in humans (locomotor defect and possible neurodegeneration)",Score,0.5 (2),The phenotype of reduced locomotor function (defective climbing) in the double RNAi and Double heterozygous deletion flies may mimick the phenotype seen in human (pyramidal symptoms). There was absence of iron deposition in brain in the double RNAi flies. The presence of vacuoles in brain is not a main feature seen in human with C19orf12-related NBIA. Hence score downgraded to 1 as phenotypes seen in the double RNAi and double heterozygous deletion flies in this study are not exactly similar to the human phenotype.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c78e8a8a-49db-40f5-96a3-d126a3834976-2023-02-28T170000.000Z,266,PubMed:24586779 +Mitochondrial Ca2+ Homeostasis Analysis,Functional Alteration Patient cells,"Venco P, et al., 2015, PMID: 26136767","Using mitochondrial-targeted aequorin probe in the measurement of mitochondrial Ca2+, it was found that high levels of mitochondrial Ca2+ in patient fibroblasts as compared to control, suggesting the mutation altering the intracellular distribution of C19orf12 is detrimental for proper mitochondrial function and Ca2+ homeostasis and may cause pateint derived fibroblast more sensitive to Ca2+ dependent stimuli like H2O2 induced death as compared to fibroblast. (figure 7)",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c78e8a8a-49db-40f5-96a3-d126a3834976-2023-02-28T170000.000Z,266,PubMed:26136767 +Rescue phenotype in iPLA2-VIA-deficient flies using C19orf12,Biochemical Function A,"Mori A, et al., 2019, PMID: 31548400",PLA2G6 - see above,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c78e8a8a-49db-40f5-96a3-d126a3834976-2023-02-28T170000.000Z,266,PubMed:31548400 +Zebrafish embryos as model for c19orf12a,Model Systems Non-human model organism,"Mignani L, et al., 2020, PMID: 33425903","The authors have demonstrated that with knock down of gene a (ortholog) in zebrafish embryo, the large majority of them (171/206, 83.0%) showed perturbed brain morphology with smaller brain size and eyes, reduced yolk extension along with a curved and thinner tail, and defected somite development (mild category). A small number of embryos (15/206, 7.3%) were characterized by a dramatic alteration of the structure, with severe perturbation of the antero-posterior axis, cardiac edema and compromised somite development (evere category) and the remaining embryos (20/206) showed a normal phenotype. Besides that, the authors have also analysed neuronal development, musculature development and locomotor behaviours of the the zebrafish with mild phenotype using different methods. i) Using transgenic lines expressing EGFP under neurogenin1 (neurog1) or neuronal differentiation 1 (neurod1) promoters, there is suggestion that there were reduced signals in the midbrain-hindbrain boundary, particularly at the level of optic tectum and retina. The analysis of the transgenic lines suggests that downregulation of gene a may affect the early stages of development in neurons in trunk, or cells located in retina, tectum opticum and the midbrain-hindbrain boundary. ii) The ATG-morphants showed an overall reduction in birefringence pattern (bright birefringence indicative of highly organized skeletal muscle) that was suggestive of a disorganized skeletal muscle structure. iii) Objective motor function measurement was obtained through calculation of spontaenous tail coil movement at 24 hpf, touch-evoked swimming movement test at 48 hpf, and the downregulation of gene a expression is associated with significant loss of motor performance of embryos in injected embryo compared to control embryo. The zebrafish model system phenotype shows that gene a which is ortholog to c19orf12 is involved in the development of selected brain areas, especially retina, that is a key feature seen in individuals with C19orf12-related NBIA.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c78e8a8a-49db-40f5-96a3-d126a3834976-2023-02-28T170000.000Z,266,PubMed:33425903 +Rescue abnormal phenotype in ATG-morphants with C19orf12mRNA,Rescue Non-human model organism,"Mignani L, et al., 2020, PMID: 33425903","The expression of the human WT mRNA significantly increased the number of embryos showing a normal phenotype, which were about 55% of the alive embryos (167/305) vs. 8.3% (n D 24/290) observed in ATG-MO-injected embryos. About 43% (n D 132/305) of the co-injected embryos still showed a mild phenotype, but less than 2% (n D 6/305) a severe one (Figure 3C). On the contrary, the type and percentage distribution of the morphological features observed upon the co-injection of ATGMO and MUT-mRNA were similar to those observed when ATG-MO alone was injected (Figure 3C). Normal embryos represented 9.4% (14/127) of the survived embryos, while embryos with mild or severe abnormalities were 79.5% (101/127) and 11% (12/127), respectively. The differences in the percentage of embryos with normal and mild phenotype observed between ATG-MO-WT-mRNA co-injected embryos, and ATG-MOinjected embryos was statistically significant (p < 0.001). This suggests that the WT human mRNA was able to overcome the deficiency of c19orf12a mRNA, by significantly increasing the number of embryos with normal phenotypic development a compared to that observed in the ATG-MO-injected group. On the contrary, the injection of the MUT-mRNA did not affect the aberrant development. This result further confirms the specific relationship between the knock-down of gene a mRNA and the perturbed development observed in ATG-morphants.",Score,1 (2),"The phenotype abnormality seen in Zebrafish using a translation-inhibiting morpholino (ATG-MO) that is complementary to the -17/+5 region of gene a mRNA affects brain formulation and somite development - not completely translatable to human disease manifestation of NBIA. Eventhough there was a statistically significant difference in the percentage of embryos with normal and mild phenotype observed between ATG-MO-WT-mRNA co-injected embryos, and ATG-MO-injected embryos, the rescue of the phenotype was not complete with 43% of co-injected embryos with human WT mRNA showing mild phenotype and <2% with a severe phenotype.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c78e8a8a-49db-40f5-96a3-d126a3834976-2023-02-28T170000.000Z,266,PubMed:33425903 +Yagi_KO mouse/MEFs,Model Systems Cell culture model,"Yagi M, et al., 2012, PMID: 22904065","KO of the orthologous C1qbp in MEFs caused impaired mitochondrial respiration associated +with reduced levels of respiratory-chain complexes I, III, and IV.",Score,1 (1),KO mice embryonic lethal (0.5); MEFs showed RC deficiencies (0.5),https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_8e98e3a8-77f2-4011-96cb-6bcc54f36a8b-2022-08-15T160000.000Z,267,PubMed:22904065 +neural-specific mouse model,Model Systems Non-human model organism,"Yagi M, et al., 2017, PMID: 29123152","Severe depletion of the mtDNA encoded proteins, mt-CoxI, CoxIII and of nuclear encoded Ndufa9 and CoxVα present in p32cKO nerves compared with controls; significantly reduced activities of complexes I and IV in p32cKO brain mitochondria, while the activities of complex II and III were unchanged (Fig. 2f).",Score,0.5 (2),"Mice lacking p32 in the central nervous system (p32cKO mice) showed white matter degeneration accompanied by progressive oligodendrocyte loss, axon degeneration and vacuolation in the mid brain and brain stem regions. Furthermore, p32cKO mice died within 8 weeks of birth. We also found that p32-deficient oligodendrocytes and neurons showed reduced oligodendrocyte differentiation and axon degeneration in primary culture. We show that mitochondrial disruption activates an adaptive program known as the integrated stress response (ISR) (0.5 for early death/weight loss/biochemical deficiency)",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_8e98e3a8-77f2-4011-96cb-6bcc54f36a8b-2022-08-15T160000.000Z,267,PubMed:29123152 +Wang_iPSCs-CMs,Functional Alteration Patient cells,"Wang J, et al., 2022, PMID: 35310974","The C1QBP-L275F-iPSC-CMs showed a cardiomyocyte hypertrophy phenotype in common with our patient. The cross-sectional area of iPSC-CMs derived from the proband was significantly increased compared to the mothers’. The C1QBP protein was distributed in the mitochondria. Electron microscopy showed that these were disordered in their morphology, number and size",Score,0.5 (1),Phenotype recapitulation in iPCS-CMs,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_8e98e3a8-77f2-4011-96cb-6bcc54f36a8b-2022-08-15T160000.000Z,267,PubMed:35310974 +Protein Interaction,Protein Interaction,"Thauvin-Robinet C, et al., 2014, PMID: 24997988","Ofd1 was previously shown to also localize near the distal end of centrioles. +Using antibodies raised against the endogenous proteins, C2CD3 and OFD1 were found to +co-immunoprecipitate out of human RPE cells. GST fusions of Ofd1 fragments were expressed in bacteria, immobilized on beads and used to capture GFP-C2cd3 expressed in HEK cells. The central fragment of Ofd1, which is also responsible for homo-dimerization, was found to specifically interact with GFP-C2cd3.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ca993ab8-029f-46f6-9fc5-ffc1f54cb120-2023-05-24T160000.000Z,269,PubMed:24997988 +Animal Model Chick,Model Systems Non-human model organism,"Chang CF, et al., 2014, PMID: 25053433",The talpid2 craniofacial and limb phenotype was consistent with C2CD3 expression in patients,Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ca993ab8-029f-46f6-9fc5-ffc1f54cb120-2023-05-24T160000.000Z,269,PubMed:25053433 +Functional Alteration(Patient Cells),Functional Alteration Patient cells,"Cortés CR, et al., 2016, PMID: 27094867",The cell’s ability to ciliate revealed that ciliogenesis and IFT protein (IFT88) recruitment at the centrioles was impaired in fibroblasts isolated from G3P1,Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ca993ab8-029f-46f6-9fc5-ffc1f54cb120-2023-05-24T160000.000Z,269,PubMed:27094867 +Mouse Model,Model Systems Non-human model organism,"Smith-Jackson K, et al., 2019, PMID: 30714990","When transferred to mice, an aHUS-associated gain-of-function change (D1115N) to the complement-activation protein C3 results in aHUS. Homozygous C3 p.D1115N (C3KI) mice developed spontaneous chronic thrombotic microangiopathy together with hematuria, thrombocytopenia, elevated creatinine, and evidence of hemolysis. Mice with active disease had reduced plasma C3 with C3 fragment and C9 deposition within the kidney. This data provide in vivo modeling evidence that gain-of-function changes in complement C3 drive aHUS.",Score,3 (2),This model was upgraded due to phenotypic specificity caused by a variant observed in human patients.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_78a4d83e-8fb0-4b47-9dfc-5dfe618e1aa3-2023-09-29T160000.000Z,271,PubMed:30714990 +qRT-PCR,Expression B,"Belzil VV, et al., 2013, PMID: 24166615","Obtained brain tissue samples from ten ALS and FTD C9orf72 repeat carriers (C9orf72+), nine ALS and FTD patients carrying a non-pathogenic C9orf72 repeat (C9orf72−), and nine C9orf72− disease controls. Found that the C9orf72+ group exhibited decreased mRNA expression across all assays, as compared to normal repeat length carriers and disease control participants. Expression was significantly reduced in the frontal cortex and cerebellum, and there was a trend toward reduced expression in the hippocampus and spinal cord.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_afd5a267-72c8-4a04-8404-4c819efe61c5-2021-09-21T030209.665Z,272,PubMed:24166615 +Immunofluorescence of endogenous p62,Functional Alteration Non-patient cells,"Webster CP, et al., 2016, PMID: 27334615",p62-positive puncta accumulated in both HeLa and primary neurons depleted of C9orf72 when compared to non-targeting control. This accumulation was directly caused by loss of C9orf72 because reintroducing C9orf72 by transduction with human C9orf72 reduced the number of p62 puncta back to control level in C9orf72 miRNA knockdown rat cortical neurons.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_afd5a267-72c8-4a04-8404-4c819efe61c5-2021-09-21T030209.665Z,272,PubMed:27334615 +Alternative splicing of DRG CA8-204,Expression B,"Upadhyay U, et al., 2019, PMID: 31199789","CA8-204G transcript expression occurred predominantly in non-neuronal cells (HEK293), while CA8-204C expression was restricted to neuronal derived cells (NBL) in vitro. CA8-204G produced a stable truncated transcript in HEK293 cells that was barely detectable in NBL cells.",Review,0 (0.5),"In vitro studies show the “G” allele (CA8-204G) produces a stable peptide that inhibits ITPR1 activation and Ca++ release in non-neuronal cells, but not in neuronal cells. This experiment is NOT relevant to function being discussed in the realm of this disease.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a0800c48-e3b1-4cb2-bbd1-4d649e506ebd-2024-01-16T170000.000Z,274,PubMed:31199789 +Yang Expression,Expression A,"Yang T, et al., 2016, PMID: 26809054","CABP2 was shown to be expressed in mouse cochlea by qRT-PCR. Transcript levels were not significantly different between P7 and P21. The three CABP2 splice variants were differentially expressed. CaBP2-alt expression was ~15-22 times higher than CaBP2-L, while CaBP2-S was barely detected. In situ hybridization and immunofluorescent labelling showed similar results, and additionally showed localization to inner hair cells at P7 and to inner and outer hair cells at P21.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_20de88d2-6681-4522-9e11-26cdf66a2c15-2020-02-06T170000.000Z,275,PubMed:26809054 +CRISPR/Cas9 CAD KO,Functional Alteration Non-patient cells,"Del Caño-Ochoa F, et al., 2020, PMID: 32461667","CAD-KO cells are unable to grow in the absence of uridine. In order to confirm that CAD is needed for de novo pyrimidine synthesis and cell growth in the absence of uridine, the authors measure proliferation of CAD-KO cells transfected with GFP-CAD with variants found in patients. Overall, 16 of the 34 variants tested have a deleterious effet on CAD activity.",Score,1 (0.5),"Uridine supplementation is a known treatment for individuals with this condition. Follow up study in PMID: 37540500 showed that p.G58S, p.R238C, p.R1475Q, p.K1482M, p.S1538L, p.W1581R, p.R1617Q, p.H1687R, p.R1722W, and p.R1785H did not rescue the growth in media without uridine.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e4a828c0-e00b-4756-aec7-b83e529ec8e4-2024-04-03T160000.000Z,286,PubMed:32461667 +Electrophysiology studies of CALM1 D130G & F142L mutation,Functional Alteration Non-patient cells,"Yin G, et al., 2014, PMID: 24958779",CALM1 mutants (D130G and F142L) impaired the Ca2+-dependent inactivation of L-type Ca2+ current.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_4a150cd9-e16b-4992-8cc7-5ccec44b4d6b-2018-09-25T160000.000Z,288,PubMed:24958779 +Whole-cell patch clamp,Functional Alteration Non-patient cells,"Yin G, et al., 2014, PMID: 24958779",Impaired Ca-dependent inactivation,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_86e4b783-3b60-4a1d-ab34-e61d27751ca6-2018-09-25T160000.000Z,290,PubMed:24958779 +Function,Expression A,"Proietti Onori M, et al., 2018, PMID: 30184290",CAMK2G is expressed in the hippocampus during gestation and is the dominant isoform during the first trimester when the nervous system starts developing and contributes substantially in the second and third trimester (Fig 1A). Human Protein Atlas reports protein expression is most adundant in neuronal cells.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_525f1ddb-a662-4baf-b877-45fc26e07b71-2021-07-30T130229.547Z,293,PubMed:30184290 +CAMK2G knock-down,Model Systems Cell culture model,"Proietti Onori M, et al., 2018, PMID: 30184290","There was also a substantial alteration of neuronal morphology with an increase in the complexity of the neurite tree compared to control (Fig 1C). There was a 38% increase in total neurite length and 55% increase of arborization compared to control (Fig 1B and D). Co-transfected human CAMK2G (lacking NLS), the isoform CAMK2G-NLS, CAMK2A, or CAMK2B together with shRNA against mouse Camk2g. Co-transfection with CAMK2A and CAMK2B had no effect on total neurite length (Supp fig S4B and C). Co-transfection of CAMK2G or CAMK2G-NLS with Camk2g shRNA borth resulted in the complete rescue of the neuronal morphology phenotype caused by the down-regulation of CAMK2G (Fig 1B-D and Supp Fig S4B and C).",Score,0.5 (1),Changes in neuronal morphology,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_525f1ddb-a662-4baf-b877-45fc26e07b71-2021-07-30T130229.547Z,293,PubMed:30184290 +Variant effect on neurons,Functional Alteration Non-patient cells,"Proietti Onori M, et al., 2018, PMID: 30184290",Neurons transfected with Arg292Pro had increased levels of CAMK2G. The cells with Arg292Pro also had reduced total neurite length and reduced arborization while cells expressing WT had no morphological changes.,Score,0 (0.5),scored as variant level evidence,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_525f1ddb-a662-4baf-b877-45fc26e07b71-2021-07-30T130229.547Z,293,PubMed:30184290 +Effect on subcellular localization,Functional Alteration Non-patient cells,"Proietti Onori M, et al., 2018, PMID: 30184290",The results show that localization was disrupted with the variant protein being found almost exclusively in the cytoplasm and WT found in the nucleus as well as the cytoplasm.,Score,0 (0.5),scored as variant level evidence,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_525f1ddb-a662-4baf-b877-45fc26e07b71-2021-07-30T130229.547Z,293,PubMed:30184290 +Protein stability,Functional Alteration Non-patient cells,"Proietti Onori M, et al., 2018, PMID: 30184290",Transfection of HEK-293T cells with CAMK2G p.Arg292Pro variant protein showed a 10-fold lower CAM2KG protein signal on Western blotting cf WT despite indicating the variant affects protein stability,Score,0 (0.5),scored as variant level evidence,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_525f1ddb-a662-4baf-b877-45fc26e07b71-2021-07-30T130229.547Z,293,PubMed:30184290 +Effect on phosphorylation,Functional Alteration Non-patient cells,"Proietti Onori M, et al., 2018, PMID: 30184290",There was a significant increase of Thr287 phosphorylation in cells with the variant when compared to WT,Score,0 (0.5),scored as variant level evidence,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_525f1ddb-a662-4baf-b877-45fc26e07b71-2021-07-30T130229.547Z,293,PubMed:30184290 +Effect on CaM binding,Functional Alteration Non-patient cells,"Proietti Onori M, et al., 2018, PMID: 30184290","Showed using CaM immunoprecipitation that CAMK2G-NLS Arg292Pro variant did not disrupt calmodulin binding, despite reduced protein levels, even suggesting the affinity of CAMK2G-NLS Arg292Pro for CaM in increased.",Score,0 (0.5),scored as variant level evidence,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_525f1ddb-a662-4baf-b877-45fc26e07b71-2021-07-30T130229.547Z,293,PubMed:30184290 +Effect on cell migration,Functional Alteration Non-patient cells,"Proietti Onori M, et al., 2018, PMID: 30184290","Cells expressing CAMK2G Arg292Pro exhibited a complete block of migration from the subventricular zone. In cells expressing CAMK2G WT, more than 80% migrated normally to layer 2/3 of the somatosensory cortex.",Score,0 (0.5),scored as variant level experimental evidence,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_525f1ddb-a662-4baf-b877-45fc26e07b71-2021-07-30T130229.547Z,293,PubMed:30184290 +RNA Sequencing and Immunohistochemistry,Expression A,"Mahajan VB, et al., 2012, PMID: 23055945","Bulk RNA sequencing from human donor retina samples showed the transcript at a level of 4.63 fragments per kilobase of exon per million. No significant splice variants were observed. Two antibodies against calpain-5 confirmed the expression in the photoreceptor cells of the donor human retinal tissue sections. No significant expression was observed in the nerve fiber layer, ganglion cell layer, inner nuclear layer, inner plexiform layer or RPE.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7d39e430-b1fc-43f1-957b-1c02eb66a69c-2021-08-05T160000.000Z,297,PubMed:23055945 +Multiple expression related experiments,Expression A,"Schaefer KA, et al., 2016, PMID: 27152965","In this study multiple expression related experiments were performed including mRNA analysis in human and mouse retina and in retinoblastoma cells. Immunohistochemistry in mouse retina, and western blots on neuronal cancer cells and fractionated central nervous tissue extracts. +It was observed that CAPN5 is moderately expressed in retina but highly expressed in other tissues. It was also observed that CAPN5 is expressed at photoreceptor synapse and with mitochondria.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7d39e430-b1fc-43f1-957b-1c02eb66a69c-2021-08-05T160000.000Z,297,PubMed:27152965 +NFkB activation in patient lymphocytes,Functional Alteration Patient cells,"Meitlis I, et al., 2020, PMID: 33202260","PBMCs isolated from healthy controls and patient, stimulated with PMA for 0, 5, and 10 min, and then Ikb-alpha and phospho-ERK was quantified by flow cytometry. Patient cells exhibited decreased stimulation-induced NF-kB signaling",Score,1 (1),Patient cells carrying CARD11 variant display defects in NFkB activation,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_603e8c98-82b7-41b5-8174-1fdbfc724a7d-2022-03-15T131220.080Z,300,PubMed:33202260 +RLTPR as scaffold bridging CD28 to the CARD11/CARMA1,Biochemical Function B,"Roncagalli R, et al., 2016, PMID: 27647348",CARMIL2 patient displayed impaired T cell signaling. RLTPR interactions with CD28 and CARMA1 following TCR stimulation are consistent with this.,Score,0.5 (0.5),RLTPR found to act as scaffold with CD28 and CARMA1,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0055cbc0-64df-4f38-9074-495f4ac74e1c-2024-03-12T160000.000Z,301,PubMed:27647348 +RLTPR-/- mice demonstrate T cell defects,Model Systems Non-human model organism,"Roncagalli R, et al., 2016, PMID: 27647348",T cells in the targeted RLTPR-/- mice were assessed. It was found the RLTPR-/- mice had decreased Treg and CD4+ effector-memory populations compared to WT. These RLTPR -/- cells also displayed decreased IL-2 production following CD3/CD28 stimulation and decreased differentiation into effector CD4+ T cell.,Score,1 (2),Downgraded score because this mouse model was only assessed for one small aspect of human disease. RLTPR-/- mouse T cells were found to display functional and differentiation impairment similarly to human patient cells.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0055cbc0-64df-4f38-9074-495f4ac74e1c-2024-03-12T160000.000Z,301,PubMed:27647348 +CARMIL2 protein expression in patient derived cells,Expression A,"Wang Y, et al., 2016, PMID: 27647349","Western blot of CARMIL2 protein in patient derived cells indicates CARMIL2 protein is expressed in B-cells, NK-cells, and CD4 and CD8 T cells (both naive and memory). Monocytes were not found to express CARMIL2 protein. +Flow cytometry indicates CARMIL2 expressed in memory B cells, NK cells, CD4 T cells (naive, central memory, effector memory, regulatory), CD8 T cells (naive, central memory, effector memory), monocytes (low levels), MAIT, delta gamma T cells, and iNKT cells and low levels of expression in monocytes",Score,0.5 (0.5),Western blot and flow cytometry indicates CARMIL2 is expressed in cells relevant to disease and that are affected in patients with a CARMIL2-related disorder.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0055cbc0-64df-4f38-9074-495f4ac74e1c-2024-03-12T160000.000Z,301,PubMed:27647349 +Defective cytokine production in patient CD4 T cells,Functional Alteration Patient cells,"Wang Y, et al., 2016, PMID: 27647349","T cells derived from healthy controls or patients were stimulated with a mixture of CD3, CD28 and PMA/Iono. Patient CD4+ T cells (but not CD8+ T cells) were found to have decreased TNF+, IFNg+ and IL-2+ production following CD3/CD28 stimulation compared to healthy T cells.",Score,1 (1),"CD4+ T cells isolated from multiple healthy controls and patients were demonstrated to have defects in cytokine production and NFkB activation downstream of CD28 stimulation, which is consistent with patient phenotypes.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0055cbc0-64df-4f38-9074-495f4ac74e1c-2024-03-12T160000.000Z,301,PubMed:27647349 +CARMIL2 has a role in CD28 signaling,Biochemical Function B,"Schober T, et al., 2017, PMID: 28112205",CD28 has an important role in T cell signaling-CARMIL2 has a role in facilitating this signaling and loss of this molecule impairs this.,Score,0.5 (0.5),"Role for CARMIL2 in NFkB activation downstream of CD28 signaling, which is consistent with impaired T cell responses in patients.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0055cbc0-64df-4f38-9074-495f4ac74e1c-2024-03-12T160000.000Z,301,PubMed:28112205 +Migration defects in patient T cells,Functional Alteration Patient cells,"Schober T, et al., 2017, PMID: 28112205",T lymphocytes derived from patients displayed migration that was less oriented with decreased directness and impaired CXCR4-mediated and CXCL12-guided chemotaxis compared to healthy controls.,Score,1 (1),"Patient T cells display migration defects consistent with CARMIL2 role in cytoskeleton, which could be related to primary immunodeficiency observed in patients.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0055cbc0-64df-4f38-9074-495f4ac74e1c-2024-03-12T160000.000Z,301,PubMed:28112205 +CARS2 Mice,Model Systems Non-human model organism,"Akaike T, et al., 2017, PMID: 29079736","Reduced persulfide production in heterozygote mice (Note heteroyzgote KOs did not show reduced MTCO1 on BNPAGE) +As expected, CysSSH derived from whole-cell proteins was decreased in Cars2+/– mice, but cysteine (CysSH) did not (Fig. 7). Specifically, formation of 20–30% of CysSSH in all cell proteins (polysulfidation) depended on CARS2 expression not only in the in vivo experiment using Cars2 KO mice (Fig. 7a) but also in the in vitro cell culture study (Fig. 7b), as identified by HPE-IAM labeling LC-MS/MS analysis with the whole cell and tissues proteins isolated.",Score,0.5 (2),"Awarded 0.5 points for embryonic lethality (early demise reported in humans but no reports of recurrent miscarriages, early infantile death) + 0 points for consistent abnormalities of persulfide biosynthesis in heterozygotes (per expert panel)",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a07aaa07-ad0d-4dac-8751-18242a3f36a9-2022-05-19T160000.000Z,302,PubMed:29079736 +HEK293T cells persulfide production and CARS2 activity,Model Systems Cell culture model,"Akaike T, et al., 2017, PMID: 29079736","mitochondrial translation defect shown in C78/257D mutant by absence of MT-CO1 similar to KO (other mutants did not show this, but showed persulfide production deficiencies)",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a07aaa07-ad0d-4dac-8751-18242a3f36a9-2022-05-19T160000.000Z,302,PubMed:29079736 +Review of mitochondrial translation disorders,Biochemical Function A,"Boczonadi V, et al., 2018, PMID: 29980628",All genes listed cause primary mitochondrial disease due to deficits in translation,Score,2 (0.5),>10+ genes with mitochondrial disease association implicated in mitochondrial translation,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a07aaa07-ad0d-4dac-8751-18242a3f36a9-2022-05-19T160000.000Z,302,PubMed:29980628 +CASK: non-cell autonomous reg. of postnatal brain growth,Model Systems Non-human model organism,"Srivastava S, et al., 2016, PMID: 27036546","CASK(+/-) mice have severe recurrent epileptic seizures and growth retardation, both of which are reliably observed in humans with heterozygous CASK mutations. Metabolic alterations, and their role in CASK phenotypes, are also an area being actively explored. The authors comment that ""the high metabolic demand of the growing neonatal brain could explain the lethality and postnatal onset of microcephaly and cerebellar hypoplasia in cases of CASK deficiency.""",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ca0e703c-3fe1-44a1-8632-036554b2f158-2019-07-09T160000.000Z,303,PubMed:27036546 +ONH in CASK(+/-) mice,Model Systems Non-human model organism,"Liang C, et al., 2017, PMID: 29067402","This model system very closely recapitulates the optic nerve anomalies that are observed in human patients with CASK variants. The overall phenotype in these animals is very similar to ONH in human (e.g. axonopathy, reduction in retinal ganglion cell numbers, etc.)",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ca0e703c-3fe1-44a1-8632-036554b2f158-2019-07-09T160000.000Z,303,PubMed:29067402 +Murata Rescue Experiment - Non Human Model Organism,Rescue Non-human model organism,"Murata T, et al., 2007, PMID: 17893196","Reexpression of CAV1 in endothelium rescued the vascular, cardiac, and pulmonary defects in the CAV1 knockout mice",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1f4c3d64-7993-4196-a002-6cc9904a4360-2022-11-23T170000.000Z,314,PubMed:17893196 +Marsboom Functional Alteration Experiment - Patient Cells,Functional Alteration Patient cells,"Marsboom G, et al., 2017, PMID: 28468941",Cav1* fibroblasts proliferated at a twofold higher rate than control fibroblasts. Collagen secretion was increased by 20% in Cav1* human fibroblasts compared with control fibroblasts. Treatment of cells with TGFβ increased collagen secretion by 30% in control fibroblasts but had minimal effect on Cav1* fibroblasts.,Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1f4c3d64-7993-4196-a002-6cc9904a4360-2022-11-23T170000.000Z,314,PubMed:28468941 +Copeland Functional Alteration Experiment - Patient Cells,Functional Alteration Patient cells,"Copeland CA, et al., 2017, PMID: 28904206",The density of caveolae and caveolar protein levels were reduced in patient fibroblasts expressing the c.474delA variant in CAV1,Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1f4c3d64-7993-4196-a002-6cc9904a4360-2022-11-23T170000.000Z,314,PubMed:28904206 +Bulk RNAseq from post-mortem brain tissue,Expression B,"Adey BN, et al., 2023, PMID: 36937187",Bulk RNAseq reveals higher expression of CAV1 and CAV2 in ALS patient tissue compared to controls,Score,0 (0.5),"The samples comprised of sporadic and familial ALS patients including C9orf72 and SOD1-associated ALS. Also, as the bulk RNA-seq analysis does not allow determination of the involved cell types responsible for observed changes in CAV1/2 expression. To address this, the authors analyzed gene expression in iPSC-derived MNs from ALS patients (n = 55) and neurologically normal controls (n = 15). No statistically significance in expression of both genes was detected when comparing ALS patients to controls. Not scored (not significant)",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_cab41529-d295-466c-8821-75a16bb12c38-2023-12-21T170000.000Z,315,PubMed:36937187 +IPSC-derived MNs,Expression B,"Adey BN, et al., 2023, PMID: 36937187",No statistically significance in expression of CAV1/2 gene was detected when comparing ALS patients to controls,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_cab41529-d295-466c-8821-75a16bb12c38-2023-12-21T170000.000Z,315,PubMed:36937187 +Bulk RNAseq from post-mortem brain tissue,Expression B,"Adey BN, et al., 2023, PMID: 36937187",Bulk RNAseq reveals higher expression of CAV1 and CAV2 in ALS patient tissue compared to controls,Score,0 (0.5),"The samples comprised of sporadic and familial ALS patients including C9orf72 and SOD1-associated ALS. Also, as the bulk RNA-seq analysis does not allow determination of the involved cell types responsible for observed changes in CAV1/2 expression. To address this, the authors analyzed gene expression in iPSC-derived MNs from ALS patients (n = 55) and neurologically normal controls (n = 15). No statistically significance in expression of both genes was detected when comparing ALS patients to controls. Not scored (not significant)",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_38faae4c-13ae-4c28-bea4-43e3ad15e178-2023-12-21T170000.000Z,316,PubMed:36937187 +IPSCs-derived Motor Neurons,Expression B,"Adey BN, et al., 2023, PMID: 36937187",No significant difference noted in expression of the the protein in ALS patients versus controls,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_38faae4c-13ae-4c28-bea4-43e3ad15e178-2023-12-21T170000.000Z,316,PubMed:36937187 +Dendritic complexity and synapse number reduction,Model Systems Non-human model organism,"Manzini MC, et al., 2014, PMID: 25066123","""Linked effects of Cc2d1a knock-down on dendritic arbor complexity, synaptic spine number, and synapse number show crucial roles in neuronal morphogenesis and circuit formation."" +""Analysis of primary neurons obtained from these lines has yielded either a reduction (Al-Tawashi et al., 2012) or no change in the dendritic arbor and defects in synaptic maturation (Zhao et al., 2011). These findings suggest that compensatory mechanisms may be in place leading to phenotypic variability as observed in the patients.""",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_63def86b-765e-4f12-93a3-94ef911c3190-2020-01-08T170000.000Z,320,PubMed:25066123 +Expression of CC2D1A in patient cells,Expression B,"Manzini MC, et al., 2014, PMID: 25066123","Expression in a heterozygous carrier was reduced. +CC2D1A was not expressed in the homozygous patient showing that the mutation is null.",Score,0 (0.5),Variant level evidence used to upgrade the genetic evidence associated with this variant .,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_63def86b-765e-4f12-93a3-94ef911c3190-2020-01-08T170000.000Z,320,PubMed:25066123 +Cc2d2a promotes ciliogenesis,Model Systems Non-human model organism,"Garcia-Gonzalo FR, et al., 2011, PMID: 21725307",Phenotypic features are consistent with a severe developmental ciliopathy presentation,Score,1 (2),Downgraded to 1 point due to limitations of phenotypic description,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0acbae16-a383-4345-978c-9d28dda80d02-2022-08-24T160000.000Z,321,PubMed:21725307 +Cc2d2a localizes to the connecting cilium in photoreceptors,Expression A,"Bachmann-Gagescu R, et al., 2011, PMID: 21816947",Cc2d2a localizes to the connecting cilium/transition zone of cilia in photoreceptors of zebrafish,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0acbae16-a383-4345-978c-9d28dda80d02-2022-08-24T160000.000Z,321,PubMed:21816947 +CC2D2A localizes to the sub-distal appendages,Biochemical Function B,"Veleri S, et al., 2014, PMID: 24947469",CC2D2A localizes to the sub-distal appendages of the transition zone. The transition zone is crucial for formation of the primary cilium. Defects in transition zone proteins are known to cause MKS and JSRD ciliopathies.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0acbae16-a383-4345-978c-9d28dda80d02-2022-08-24T160000.000Z,321,PubMed:24947469 +Cilia defects in mutant Cc2d2a mouse embryos,Model Systems Non-human model organism,"Veleri S, et al., 2014, PMID: 24947469","Cc2d2a-/- results in embryonic lethality and pleiotropic organogenesis defects comparable to MKS patients. Cilia are absent from the embryonic node, neural tube, and the perinatal kidney tubules. As a consequence, both motile and sensory cilia are defective and the Shh pathway is disrupted in the developing Cc2d2a-/- neural tube. +In both patients mice with loss of Cc2d2a, there are pleotropic effects involving the development of the brain, retina, skeletal system, kidney, and other organ systems.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0acbae16-a383-4345-978c-9d28dda80d02-2022-08-24T160000.000Z,321,PubMed:24947469 +Cc2d2a mutant MEFs display ciliary defects,Model Systems Cell culture model,"Veleri S, et al., 2014, PMID: 24947469","Primary cilium biogenesis defects observed in mutant mouse embryonic fibroblasts (MEFs) are consistent with the disease mechanism in humans, where loss and/or abnormal cilia morphology have been observed. In ciliopathy-causing genes, disruption to ciliary biogenesis is an established disease mechanism.",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0acbae16-a383-4345-978c-9d28dda80d02-2022-08-24T160000.000Z,321,PubMed:24947469 +HSVM of CCDC103 mutant cells,Functional Alteration Patient cells,"Panizzi JR, et al., 2012, PMID: 22581229","The effects of CCDC103 mutations were analysed by high-speed videomicroscopy of respiratory cells obtained by nasal brushing biopsy. Normal respiratory cell cilia beat vigorously and coordinately . Consistent with severe outer dynein arm defects observed by EM , patients carrying the homozygous p.Gly128fs25* mutation (OP-1193 II1) exhibited complete cilia paralysis . Patients carrying the homozygous p.His154Pro mutation exhibited either reduced cilia beat amplitude (patient OP-32II1;) or loss of beat coordination and cilia paralysis (patient OP-32II2; ), consistent with the variable reduction in EM ODA arm structure in these patients which ranged from apparently normal to complete ODA/IDA loss (patient UCL-143II1;).",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9974aaef-9082-4bcd-b05a-28869447b5de-2022-12-30T120000.000Z,322,PubMed:22581229 +TEM of CCDC103 mutant respiratory cilia,Functional Alteration Patient cells,"Panizzi JR, et al., 2012, PMID: 22581229","Transmission electron microscopy of respiratory cilia was performed, showing normal outer- and inner-dynein arms in epithelial cells from a healthy proband. Respiratory cilia of two affected siblings carrying both identical homozygous CCDC103 loss-of-function mutations display variable defects of outer dynein arms. Cilia from patient UCL-120II2 display severe defects of the outer- and inner-dynein arms, whereas in cilia from the other affected sibling (UCL-120II3) seems to have remnant outer dynein arms.",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9974aaef-9082-4bcd-b05a-28869447b5de-2022-12-30T120000.000Z,322,PubMed:22581229 +Rescuing cilia paralysis in schmalhans mutants,Rescue Non-human model organism,"Panizzi JR, et al., 2012, PMID: 22581229","Embryo injection of myc-tagged wild-type ccdc103 mRNA rescued axis curvature, left-right asymmetry defects, and kidney cyst phenotypes, and also restored cilia motility in smh mutants , confirming that ccdc103 was the schmalhans mutant gene. Mutant Ccdc103 mRNA carrying the Q27Stop smh mutation not only failed to rescue but also increased the frequency of axis curvature defects. Antisense morpholino knockdown of ccdc103 induced curved body axes, left-right asymmetry defects, hydrocephalus, and kidney cysts , and caused cilia paralysis.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9974aaef-9082-4bcd-b05a-28869447b5de-2022-12-30T120000.000Z,322,PubMed:22581229 +"Mislocalization of DNAH5, DNAI2 and DNAH9 in CCDC103 mutant",Biochemical Function A,"Panizzi JR, et al., 2012, PMID: 22581229","Immunofluorescence analyses of human respiratory epithelial cells using specific antibodies directed against the outer dynein arm heavy chains DNAH5 and DNAH9 as well as the outer dynein arm intermediate chain DNAI2. As control, axoneme specific antibodies against acetylated α-tubulin or α/β-tubulin were used. Nuclei were stained with Hoechst 33342 . In respiratory epithelial cells from healthy probands, DNAH5 localizes along the entire length of the axonemes. In respiratory epithelial cells from patient OP-1192 carrying the CCDC103 loss-of-function mutation, DNAH5 localization is restricted to the proximal part of the axoneme and shows mis-localization to subapical cytoplasm and the perinuclear region. DNAI2 is localized along the entire length of the axonemes of healthy probands. In contrast in respiratory cells of patient OP-1192 DNAI2 localizes solely to the proximal ciliary axonemes denotes cilia tips devoid of DNAI2 . DNAH9 localization is restricted to distal ciliary axonemes of respiratory epithelial cells from healthy probands, because it is only present in type2 ODA complexes. In the patient OP-1192 DNAH9 is completely missing , consistent with altered assembly of type-2 ODA complexes.",Score,0.5 (0.5),The experiment confirms the role of CCDC103 as a dynein arm assembly factor. Altered assembly of type-2 ODA complexes was evident using Immunofluorescence analyses of the CCDC103 mutant human respiratory epithelial cells.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9974aaef-9082-4bcd-b05a-28869447b5de-2022-12-30T120000.000Z,322,PubMed:22581229 +Ccdc103 homodimers assemble with dynein light chain 2,Biochemical Function B,"Panizzi JR, et al., 2012, PMID: 22581229","The experiment revealed function of Ccdc103 in dynein arm assembly. +The experiment examined the Chlamydomonas ccdc103 ortholog. Ccdc103, Pr46b protein was present in both flagella and cytoplasmic extracts and migrated as apparent monomers and dimers on SDS gels (figure 5B,C), similar to protein expressed in zebrafish embryos (figure 3G). In isolated flagella, Ccdc103/Pr46b was tightly associated with axonemes even after 0.6 M NaCl extraction (figure 5B). Fractionation of Chlamydomonas cytoplasm (Figure 5C) identified Ccdc103/Pr46b in high molecular weight complexes (440 KD - 2 MD) that co-purified with outer arm dynein light chain LC2, as well as in lower molecular weight complexes (<440,000 Da). Analysis of human CCDC103 expression in respiratory epithelial cells confirmed that CCDC103 is present as apparent monomers and dimers.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9974aaef-9082-4bcd-b05a-28869447b5de-2022-12-30T120000.000Z,322,PubMed:22581229 +CCDC22 mutant T17A leads to actin accumulation,Functional Alteration Patient cells,"Singla A, et al., 2019, PMID: 31537807","CCDC22 p.T17A in patient-derived fibroblast cells (Supplementary figure 3b), and depletion of the COMMD/CCDC22/CCDC93 (CCC) complex in mouse embryonic fibroblasts knockout cells, leads to elevated PI(3)P levels, enhanced recruitment and activation of WASH (an actin nucleation promoting factor), and excess endosomal F-actin (Fig 3a and b).",Score,1 (1),"The WASH complex is involved in the branched actin polymerization and needed for normal vesicle trafficking. Loss of CCC leads to increased WASH activity in the cells and excess endosomal F-actin accumulation, which can lead to mistrafficking of endosomal cargo recycling.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3d62f7f8-4a91-4e0c-86b2-3f1d5d38d54b-2023-06-07T160000.000Z,324,PubMed:31537807 +CCDC40 mutation causes short flagella and defective motility,Model Systems Non-human model organism,"Lin H, et al., 2015, PMID: 26348919","Mutations in fap172, the Chlamydomonas ortholog of CCDC40, cause short flagella and defective motility (Figure 1). Abnormalities in axonemal contents include absence of CCDC39, Tektin, DRC2, and DRC3 (Figure 3). This is consistent with other Chlamydomonas studies indicating that CCDC40 collaborates with CCDC39 to serve as docking sites for axonemal structures along the doublet microtubules (PMID: 25395538). These phenotypes partially recapitulate the ciliary dyskinesia and abnormal ciliary morphology observed in the affected human patients harboring pathogenic CCDC40 variants. Shorter respiratory cilia have been reported in at least one such patient (PMID: 21131974). Patient cilia also exhibit a characteristic mixed beating pattern, with some cilia beating with reduced amplitude (stiffness) and others showing no motility (PMID: 23255504).",Score,1.5 (2),"The model is a good match for the variant profile of the human patients in that it recapitulates motile cilia phenotypes at the cellular level and harbors a nonsense mutation (c.334G>A (p.Gln112Ter)) in the Chlamydomonas ortholog of human CCDC40. On the other hand, most of the organism-level phenotypes cannot be tested / recapitulated in a Chlamydomonas model. The origin of the model in a mutagenic screen rather than a targeted disruption of the gene of interest also introduces a small possibility of other linked contributions to the genetic basis of disease.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e9c192c6-9f74-4beb-85ba-a42199e9794a-2021-12-10T031508.185Z,326,PubMed:26348919 +CCDC40 expression restores flagellar length and motility.,Rescue Non-human model organism,"Lin H, et al., 2015, PMID: 26348919",Flagellar shortening was reversed to yield wild-type flagellar length (Figure 1A).,Score,1 (2),"Rescue transformation was performed with wild-type CCDC40 on a bacterial artificial chromosome, while the endogenous nonsense variant was c.334G>A (p.Gln112Ter). The experiment was conservatively scored because the experimental design did not include detail about the expression level of the exogenous CCDC40, or about the extent to which ciliary motility was restored.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e9c192c6-9f74-4beb-85ba-a42199e9794a-2021-12-10T031508.185Z,326,PubMed:26348919 +CCNO knock-out mouse model,Model Systems Non-human model organism,"Núnez-Ollé M, et al., 2017, PMID: 29245899","CCNO KO mouse model shows that deletion of CCNO leads to reduced numbers of multiple motile cilia and characteristic phenotypes of MCC dysfunction including severe hydrocephalus and mucociliary clearance deficits. Reduced cilia numbers are caused by compromised generation of centrioles at deuterosomes, which serve as major amplification platform for centrioles in MCCs. Ccno-deficient MCCs fail to sufficiently generate deuterosomes, and only reduced numbers of fully functional centrioles that undergo maturation to ciliary basal bodies are formed.",Score,0 (2),Not scoring as there is a stronger mouse model. Just adding this information.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_20a78ac7-91a7-44a6-b42e-22611de2d170-2022-08-19T160000.000Z,331,PubMed:29245899 +Crystal structure of holoTC,Biochemical Function B,"Alam A, et al., 2016, PMID: 27411955","CD320 encodes the transcobalamin receptor, which functions to transport cobalamin into mammalian cells. +The authors report the crystal structure of human holo-transcobalamin (TC) in complex with the extracellular domain of CD320, visualizing the structural basis of the TC-CD320 interaction. Their data explains the high affinity of CD320 for TC and lack of haptocorrin binding. . They also showed that the in vitro affinity of TC for CD320 is reduced at low pH, which supports the proposed ligand release during the endocytic pathway. +The function of the transcobalamin receptro (encoded by CD320) can explain the findgins in patients with CD320 deficiency. INtracellularly, methylCbl is a cofactor for methionine synthase (converts homocysteine to methionine) and 5′-deoxy-adenosylCbl is a cofactor for methylmalonyl CoA mutase (converts methylmalonyl CoA to succinyl CoA). Cbl deficiency, resulting from defect Cbl transport into cells, would be expected to result in homocysteinemia due to inhibition of the methionine synthase pathway and methylmalonic acidemia (MMA) due to inhibition of the mutase pathway. Both elevated homocysteine and elevated MMA have been observed in individuals with CD320 deficiency, although the findings, seen in the newborn period, seem to resolve over time.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d98515f5-4296-4d41-95a9-adac90c00349-2022-09-23T160000.000Z,336,PubMed:27411955 +Garcillán Functional Alteration in Jurkat Cells,Functional Alteration Non-patient cells,", , PMID: 34249896",The TCR complexes of knockdown cells do not incorporate CD247 or CD3E. (Figure 5) They also fail to reach the cell surface. (Figure 6),Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3d59cf46-9acb-42f7-92da-d17113d39b38-2022-05-10T185446.511Z,337,PubMed:34249896 +Vavassori mouse rescue,Rescue Non-human model organism,"Vavassori V, et al., 2021, PMID: 33475257","Adoptive transfer of wild-type T cells into conditioned HIGM1 mice rescued antigen-specific IgG responses (Fig. 5). It also protected mice from Pneumocystis murina, a disease-relevant pathogen, as determined by histopathological analysis of lung tissue after infection (Fig. 7, Table S2).",none,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_4184ad10-d95f-4027-b75d-e4e11127febf-2021-03-22T154242.503Z,341,PubMed:33475257 +Vavassori patient cell rescue,Rescue Patient cells,"Vavassori V, et al., 2021, PMID: 33475257","The variant c.334G>T (in exon 3) was rescued by inserting a 5'-truncated corrective cDNA, which included all downstream exons and the cognate 3'UTR within the first intron of CD40LG. CD40LG expression was at levels comparable to those of the edited healthy control after rescue. Corrected T cells promoted class switching at similar levels as controls.",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_4184ad10-d95f-4027-b75d-e4e11127febf-2021-03-22T154242.503Z,341,PubMed:33475257 +Human Cell Culture model,Model Systems Cell culture model,"Wieser M, et al., 2019, PMID: 30958843","CD46 is localized to glomeruli, but especially also to proximal tubular epithelial cells (RPTECs). +However, human cell culture models to assess CD46 function on RPTECs are still missing. +Gene editing of RPTEC/TERT1 cells generating a monoclonal CD46-/- cell line that did not show changes of the primary cell like characteristics. +Factor I and CD46-mediated cleavage of C4b into soluble C4c and membrane deposited C4d was clearly reduced in the knock-out cell line as compared to the maternal cells. +Human CD46-/- PTECs will be of interest to dissect the roles of the epithelium and the kidney in various complement activation mediated tubulointerstitial pathologies or in studying CD46 mediated uropathogenic internalization of bacteria. +Telomerized cells can be used in the generation of knock-out, knock-in or any kind of reporter cell lines without losing the primary cell characteristics of the maternal cells.",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_bddaec4f-9f57-41b7-81a4-2f6ff3fc5e7b-2024-06-27T160000.000Z,342,PubMed:30958843 +Mouse Knockout I,Model Systems Non-human model organism,"Maecker HT, et al., 1997, PMID: 9126932","CD81-knockout mice underwent normal thymic development, produce normal numbers of mature T cells, and undergo normal B cell development. CD81-null B cells were found to express lower levels of CD19 and show decreased early antibody production in response to a protein antigen. These mutants recover antibody production with time and with repeated antigen exposure.",Score,1 (2),"While the mutants show lower levels of B-cell CD19 expression and decreased early antibody production in response to a protein antigen, consistent with the phenotype observed in humans, mutants recover antibody production with time. They also display normal T cell and B cell development.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e2092b4c-a8ff-4b40-bc09-17fbe33aa3e7-2021-04-29T210806.386Z,345,PubMed:9126932 +Functional Characterization of 3 Mutations of the CDC73 Gene,Functional Alteration Non-patient cells,"Pazienza V, et al., 2013, PMID: 24340015","The WT vector limited the cell growth while mutated vectors induced higher cell proliferation rate, taking also into account the expression of the endogenous parafibromin. Four CDC73/HRPT2 gene mutations were used in the assay, three germline (c.679_680delAG, p.Val85_Val86del and p.Glu81_Pro84del), one somatic (p.Arg77Pro)",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a5bd498b-dc86-4f2d-a51b-48baf7017a02-2019-04-19T160000.000Z,349,PubMed:24340015 +CDC73 deficient mice develop parathyroid and uterine tumours,Model Systems Non-human model organism,"Walls GV, et al., 2017, PMID: 28288139","Cdc73+/− mice and the conditional Cdc73+/L/PTH- Cre and Cdc73L/L/PTH-Cre mice develop: parathyroid tumours in association with increased mean serum calcium concentrations and increased mean serum PTH concentrations, consistent with primary hyperparathyroidism; and uterine neoplasms, which comprised endometrial hyperplasia and cysts, adenofibroma and adeno- myoma.",Score,3 (2),"Increase points because (1) both conventional (Cdc73+/−) and conditional (Cdc73+/L/PTH-Cre and Cdc73L/L/PTH-Cre) knockout mice develop parathyroid tumours, (2) comprehensive comparison between phenotypes in mice and HPT-JT patients are described (Table 1 and in discussion).",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a5bd498b-dc86-4f2d-a51b-48baf7017a02-2019-04-19T160000.000Z,349,PubMed:28288139 +morpholino-mediated knockdown of cdca7 in zebrafish,Model Systems Non-human model organism,"Guiu J, et al., 2014, PMID: 25385755","This study found: + +expression of Cdca7 is restricted to the hematopoietic clusters of the aorta during embryonic hematopoietic development +Cdca7 is strongly up-regulated in the hemogenic population during human embryonic stem cell hematopoietic differentiation in a Notch dependent manner. +Down-regulation of Cdca7 mRNA in cultured AGM cells significantly +induces hematopoietic differentiation and loss of the progenitor population. +CDCA7 contributes to HSC emergence in vivo during embryonic development. + +However I don't think this contributes to the strength of the association with CDCA7 and ICF3.",Score,1 (2),Doesn't fully recapitulate phenotype in humans.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_357faf0e-a1db-4240-8268-bc9925a2c0ef-2023-04-20T170000.000Z,350,PubMed:25385755 +CpG methylation in wild-type mouse embryonic fibroblasts,Functional Alteration Non-patient cells,"Thijssen PE, et al., 2015, PMID: 26216346",Transient depletion of CDCA7 resulted in decreased CpG methylation at centromeric repeats in wild-type mouse embryonic fibroblasts,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_357faf0e-a1db-4240-8268-bc9925a2c0ef-2023-04-20T170000.000Z,350,PubMed:26216346 +IMPD database CDH11-/- mouse,Model Systems Non-human model organism,"Dickinson ME, et al., 2016, PMID: 27626380",Partially recapitulates human phenotype,Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_41cee7da-44c3-49fa-b174-80ae3da5d153-2024-05-17T160000.000Z,351,PubMed:27626380 +Dickinson IMPC db CDH11-/- Mouse Model,Model Systems Non-human model organism,"Dickinson ME, et al., 2016, PMID: 27626380",Partially recapitulates human phenotype including craniofacial and genitourinary defects,Score,0.5 (2),Inheritance mismatch between AR homozygous KO mouse and human het AD condition,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d159047f-2ee5-4406-8def-c5fe63b7ffe8-2024-05-17T160000.000Z,352,PubMed:27626380 +Hu Mouse Model,Model Systems Non-human model organism,"Hu J, et al., 2016, PMID: 27882946","erl mice start losing hearing ~P27 and are totally deaf by ~P100. In OHCs of these mice, some of the CDH23 proteins failed to reach the top of the hair bundles but remained in the OHC cytoplasm. The endoplastic reticulum stress marker BiP was up-regulated in the erl mice OHCS. There were also higher levels in spiral ganglion cells and stria vascularis at P6 and P12.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_f5799772-f233-4004-99a8-e6a0dddf0e8b-2018-05-22T040000.000Z,356,PubMed:27882946 +Shehata et al_variants,Functional Alteration Non-patient cells,"Shehata SN, et al., 2015, PMID: 26205494",Both variants showed lower cyclin Y expression and marginally detectable or absent binding to cyclin Y. The variants were also catalytically inactive.,Score,1 (0.5),Functional evidence showing altered cyclin Y binding and altered enzymatic activity,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_93557c1a-c141-4833-bcbb-83fccbd7d761-2021-10-28T160000.000Z,359,PubMed:26205494 +Shehata et al.,Protein Interaction,"Shehata SN, et al., 2015, PMID: 26205494","Their studies show that Pctaire 1 phosphorylates cyclin Y and that this influences their interaction and activity. They identified Ser336 as the Pctaire1 dependent phosphorylation site, however S336 phosphorylation does not have a significant activity or impact on the interaction between pctaire1 and cyclin Y. Further studies showed that phosphorylation of ser100 and ser326 residues play an important role in binding and activating pctaire 1 by promoting binding to other proteins.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_93557c1a-c141-4833-bcbb-83fccbd7d761-2021-10-28T160000.000Z,359,PubMed:26205494 +shRNA inhibition assay,Functional Alteration Non-patient cells,"Kollmann K, et al., 2019, PMID: 30858922","Knock-down of CDK4 or CDK6 results in reduced migration, decreases tumor growth, reduces subcutaneous tumor formation; reduces VEGF-A secretion/ production. The availability of CDK6 at the VEGF promoter depends on the presence of CDK4",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ca76579b-1432-4edc-84e8-b3332dce4ede-2020-01-13T194434.667Z,360,PubMed:30858922 +Electroporation of CDK5RAP2 in knockout brain organoid,Rescue Patient cells,"Lancaster MA, et al., 2013, PMID: 23995685","The extent of neuroepithelial differentiation and the number of radial glia, which were decreased in the patient's brain organoid, were increased after electroporation of wildtype CDK5RAP2. This differentiation and cellular developmental process are characterized in wild-type brain development.",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_70dace84-4d61-44f5-9de5-a81b5c70cad4-2022-01-25T170000.000Z,362,PubMed:23995685 +A cerebral organoid culture of loss-of-function in CDK5RAP2,Model Systems Cell culture model,"Lancaster MA, et al., 2013, PMID: 23995685","Control tissues displayed abundant, large neuroepithelial tissues composed of progenitors, patient-derived tissues displayed only occasional neuroepithelial regions (Extended Data Fig. 7e). Furthermore, these tissues displayed decreased RGs and increased neurons compared with control (Fig. 6f and Extended Data Fig. 7f), suggesting premature neural differentiation. To test this possibility, we performed BrdU pulse-chase experiments (Fig. 6g), which revealed a marked increase in the number of BrdU+/doublecortin (DCX)+cells in patient organoids, consistent with premature neurogenic non-proliferative divisions. +As a further independent approach, we performed RNAi knockdown of CDK5RAP2 by co-electroporating GFP with two independent shRNAs found to knock down endogenous CDK5RAP2 (Extended Data Fig. 8a). Both shRNAs led to a considerable loss of SOX2+ progenitors and an increase in DCX+ neurons (Fig. 6i and Extended Data Fig. 8b), reflecting a statistically significant increase in neuron production rather than progenitor maintenance (Extended Data Fig. 8c). These findings support the conclusion that loss of CDK5RAP2 leads to premature neural differentiation at the expense of progenitors.",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_70dace84-4d61-44f5-9de5-a81b5c70cad4-2022-01-25T170000.000Z,362,PubMed:23995685 +p27 expression in patients tissues,Expression B,"Molatore S, et al., 2010, PMID: 20824794",Parathyroid adenoma cells showed weak p27 nuclear staining in <1% of the tumor cells (interspersed normal endothelial cells served as controls) (Fig. 4C-D). A bronchial carcinoid of the P69L mutation-positive patient showed virtually no p27 staining when compared to a bronchial carcinoid of a mutation-negative individual (Fig. 4E-F).,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b07f8882-dd5e-4831-9926-f8b4c2a8c265-2018-12-21T154854.477Z,364,PubMed:20824794 +clonogenic assay using p27-negative GH3 cells,Functional Alteration Non-patient cells,"Molatore S, et al., 2010, PMID: 20824794",p27wt inhibits the growth of these cells while p27W76X does not. p27P69L was less efficient than p27wt at suppressing cell growth (Fig. 3B). Constitutive overexpression of p27W76X did not affect GH3 cell proliferation (Fig. 3C).,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b07f8882-dd5e-4831-9926-f8b4c2a8c265-2018-12-21T154854.477Z,364,PubMed:20824794 +Mutant expression in endocrinepancreatic tumor of patient,Expression B,"Occhi G, et al., 2013, PMID: 23555276",Endocrine pancreatic tumor of the patient having the c.-456_-453delCCTT mutation. Tumor cells show low expression of p27KIP1 in the nucleus but also expression in the cytoplasm. (Fig. 4).,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b07f8882-dd5e-4831-9926-f8b4c2a8c265-2018-12-21T154854.477Z,364,PubMed:23555276 +siRNA mediated CDT1 knockdown in control fibroblasts,Functional Alteration Non-patient cells,"Stiff T, et al., 2013, PMID: 23516378","impaired BrDU incorporation, impaired cilia formation, increased centrosome number, and aberrant chondroinduction phenotype. Similar alterations have been observed in ORC1-deficient patient cells, another gene implicated in pathogenesis of MGS",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_dfc9602f-fb88-419a-8955-6d7c00a52158-2023-03-03T170000.000Z,366,PubMed:23516378 +Origin licensing capacity asessment,Functional Alteration Patient cells,"Stiff T, et al., 2013, PMID: 23516378",MGS patient lymphoblastoid cell lines display impaired origin licensing capacity as shown through episome replication following transfection of EBV episomes with no impaired rate of S phase progression. Similar alteration is observed in other MGS-patient-derived LBL carrying variants in ORC complex genes.,Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_dfc9602f-fb88-419a-8955-6d7c00a52158-2023-03-03T170000.000Z,366,PubMed:23516378 +Review on Congenital Diseases of DNA Replication,Biochemical Function A,"Schmit M, et al., 2021, PMID: 33477564","several genes in the same pathway/replication complex as CDT1: ORC1, ORC2, ORC4, ORC5, ORC6, MCM5, CDC6, GMNN, CDC45",Score,1 (0.5),"since multiple genes from the same functional pathway forming a complex are implicated in the disorder with specific triad of features, upgraded to 1.0",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_dfc9602f-fb88-419a-8955-6d7c00a52158-2023-03-03T170000.000Z,366,PubMed:33477564 +Age-related hearing loss of Cheatham mouse,Model Systems Non-human model organism,"Goodyear RJ, et al., 2019, PMID: 31249509",The investigators followed the Cheatham mouse to a later age and demonstrated age-related hearing loss at 6-7 months of age.,Score,1 (2),This is further information on a previous mouse model from Cheatham et al 2014 (PMID: 31249509).,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_bcc9ab02-1df0-485a-a806-2651171120cd-2022-12-21T170000.000Z,367,PubMed:31249509 +Raeder Mouse Model,Model Systems Non-human model organism,"Ræder H, et al., 2013, PMID: 23565203","TgCEL mice had normal pancreatic exocrine function with normal pancreas morphology. The mice were normoglycemic (Fig. 2, table 1). +When fed a 60% high fat diet, TgCEL mice and WT mice gained weight comparatively, and normal pancreatic exocrine function and normal glucose tolerance remained (Fig. 3). +TgCEL mice exposed to cerulein were also glucose tolerant with no abnormalities of serum amylase, islet hormones, or pancreatic inflammation (Fig. 4,5, Table 2).",Score,0 (2),Scored as zero because human phenotype of CEL-MODY not recapitulated in mouse model.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_06571680-3730-4075-8e65-f6de7ddd3e62-2023-09-13T160000.000Z,369,PubMed:23565203 +Wolters Cell Culture Model,Model Systems Cell culture model,"Wolters-Eisfeld G, et al., 2018, PMID: 30305605","Human CEL recombinantly expressed in HEK293 WT and COSMIC-KO HEK293 cells - COSMIC-KO derived from Cosmc-knockout mouse model which displays symptoms of diabetes and exocrine pancreatic insufficiency: elevated fasting serum glucose and glycated hemoglobin, reduced fasting serum C-peptide, maldigestion, impaired zymogen granule release, decreased enzymatic elastase and lipase activity. +Cel is abundant and differentially O-glycosylated in murine exocrine pancreas (a Tn-modified pancreatic protein) - recombinant cells used to treat NT-3 cells (insulin producing neuroendorine tumor cell line) in presence of glucose. COSMIC-KO HEK293 cells (expressing non O-glycosulated CEL) caused reduced viability of NT-3 cells (Fig. 5g), and negatively regulated insulin secretion compared to HEK293 WT cells (expressing WT (O-glycosylated) human CEL) (Fig. 5h). - This suggests that loss of CEL O-glycosylation has effects similar to those caused by point mutations in MODY8-like diabetes.",Score,0 (1),"REVIEW: Model not directly showing genetic alteration of CEL, but showing that effects of O-glycosylation in the VNTR region of CEL can cause phenotypes similar to MODY in mouse model system.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_06571680-3730-4075-8e65-f6de7ddd3e62-2023-09-13T160000.000Z,369,PubMed:30305605 +Hosoya Expression,Expression A,"Hosoya M, et al., 2016, PMID: 27403418",This study looked at the expression of KIAA1199 in the cochlea of the marmoset. KIAA1199 was expressed in supporting cells in the inner and outer hair cells. KIAA1199 was also expressed in inner and outer sulcus cells.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_27d840d2-1f58-4d1c-9f6e-307db9f41b60-2018-07-17T160000.000Z,370,PubMed:27403418 +CENP-meta KO fruit fly,Model Systems Non-human model organism,"Yucel JK, et al., 2000, PMID: 10893249",embryonic tissue from CENP-meta KO fruit flies show disrupted mitosis and misaligned chromosomes comparable to observations in patient-derived LCLs(as characterized in PMID: 24748105),Score,0.5 (2),"fly KO model recapitulated disrupted mitochondrial alignment as seen in patient-derived LCLs, but does not assess brain malformation-related phenotypes in fly model, downgraded evidence to 0.5 point",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_830f266d-32bd-4d1f-9867-e97ffe6f2eae-2023-12-19T180000.000Z,371,PubMed:10893249 +Mouse Model Phenocopies Patients,Model Systems Non-human model organism,"McIntyre RE, et al., 2012, PMID: 23166506",McIntyre et al. (2012) concluded that dwarfism in CENPJ model mice was due to widespread DNA damage and apoptosis in embryos.,Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c10510c1-2c0e-466e-928a-77d896159d06-2022-05-21T104414.354Z,372,PubMed:23166506 +Silencing CENPJ in the CNS,Biochemical Function B,"Garcez PP, et al., 2015, PMID: 25753651",Abnormality of neuronal migration is likely the cause of most phenotypes related to the CNS in patients with disease.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c10510c1-2c0e-466e-928a-77d896159d06-2022-05-21T104414.354Z,372,PubMed:25753651 +In situ hybridization human embryonic tissue,Expression A,"Cheng YZ, et al., 2012, PMID: 23028714","Hybridisation with CEP290 antisense RNA probe shows CEP290 transcripts in developing retina, brain (especially choroid plexus, and kidney, especially mesonephros nd metanephros)",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ec24317e-70bc-48a0-999b-f960f951e8dd-2022-02-03T170000.000Z,374,PubMed:23028714 +Microtubule polymerization and co-sedimentation assays,Functional Alteration Non-patient cells,"Zhou H, et al., 2016, PMID: 26743940","RNAi (RNA interference) in HeLa cells depleted Cep57 in kinetochore. In Cep57-depleted cells, the time for mitosis arrest is reduced when unattached kinetochores occur in mitotic cells treated with nocodazole. The mitotic index was also decreased in Cep57-depleted cells after treatment with nocodazole and multiple small nuclei present.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c44921de-14cf-4907-8bef-1525329ee89c-2019-11-22T145303.972Z,375,PubMed:26743940 +RNA interference,Rescue Cell culture model,"Zhou H, et al., 2016, PMID: 26743940","siRNA resistant Cep57 wt (resCep57) with mutated siRNA targeted region is expressed in HeLa cells) rescued the phenotypes of reduced mitotic arrest during unattached kinetochore, reduce mitotic index with multiple small nuclei.",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c44921de-14cf-4907-8bef-1525329ee89c-2019-11-22T145303.972Z,375,PubMed:26743940 +TALEN-mediated knock-in strategy,Model Systems Non-human model organism,"Aziz K, et al., 2018, PMID: 30035751","Cep57T/T (homozygous truncating frameshift mutation, c.915_925dup11) mouse, Cep57 +/T (heterozygote) and fibroblasts from patient homozygous for the same truncating frameshift mutation are used. Cep57T/T mouse died shortly after birth with defective vertebral ossification. Newborn Cep57T/T mice have severe aneuploidies in a broad spectrum of tissues. Cep57+/T (heterozygous for the truncating frameshift mutation) mice had milder chromosomal instability phenotypes and were cancer prone. +Cep57 is undetectable in Cep57T/T MEFs and patient skin fibroblasts. Both Cep57 T/T MEF and patient fibroblasts had supernumerary centrioles, premature centriole disengagement, aberrant spindle that missegregate chromosomes, wide spread aneuploidies.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c44921de-14cf-4907-8bef-1525329ee89c-2019-11-22T145303.972Z,375,PubMed:30035751 +KO/KD mouse,Model Systems Non-human model organism,"Domènech EB, et al., 2020, PMID: 32658961","Physiological alterations are observed in mice at 18 months of age but not at 6–10 months, which mimics the relatively late-onset (second decade of life) but progressive degenerative disease observed in most patients bearing CERKL mutations. The mouse model mimics human CRD traits due to early cone loss and subsequent progressive degeneration of all photoreceptors. With age, the mouse model shows decreased number of cones, loss of photoreceptor nuclei, elongated OSs with mislocalized opsins, alterations in the RPE microvilli and phagocytosis, and stress-associated alterations.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a3003820-dc03-4eb1-921a-6eaee749fa9f-2022-09-01T160000.000Z,376,PubMed:32658961 +Chlamydomonas flagella,Model Systems Non-human model organism,"DiPetrillo CG, et al., 2010, PMID: 20421426","CFAP221 is the human orthologue of C. reinhardtii FAP221 gene. +Both FAP221 and mammalian CFAP221 bind calmodulin (CaM) in high [Ca2+] +CaM is a key axonemal Ca sensor. For all motile eukaryotic cilia and flagella, beating is regulated by changes in intraciliary calcium concentration. +Reduced expression of FAP221 in C. reinhardtii results in failure of the C1d central pair projection to assemble and significant impairment of motility including uncoordinated bends, severely reduced beat frequency, and altered waveforms. These combined results reveal that the central pair FAP221 complex is essential for control of ciliary motility.",Score,1 (2),Chlamydomonas models do not model lung issues or laterality defects.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c7c841e5-2973-4f23-8603-970e9e2cbc92-2023-08-10T160000.000Z,378,PubMed:20421426 +Expression and localisation of CFAP221 in control cells,Biochemical Function A,"Bustamante-Marin XM, et al., 2020, PMID: 31636325",FOXJ1 is a key gene driver for ciliogenesis.,Score,1 (0.5),"Discussed with Bill, and we think this is worth 1 point. Half a point for expression and half a point for localisation.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c7c841e5-2973-4f23-8603-970e9e2cbc92-2023-08-10T160000.000Z,378,PubMed:31636325 +RNA sequencing of total RNA from 20 human tissues,Expression A,"Duff MO, et al., 2015, PMID: 25970244",RNA sequencing of total RNA from 20 human tissues revealed biased expression in tissues lined with respiratory epithelium (trachea).,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6bcfa4e4-37a3-43a7-9b4d-60554bc7600c-2022-09-08T110000.000Z,380,PubMed:25970244 +CFAP410 Hyperphosphorylation,Functional Alteration Non-patient cells,"Watanabe Y, et al., 2020, PMID: 32891887","FBXO3 bound to C21ORF2(WT), whereas FBXO3 did not bind to C21ORF2(V58L) and the mutant protein was not ubiquitylated in HEK293T cells, suggesting that FBXO3 is the only ubiquitin ligase for C21ORF2 and that the ALS-related V58L mutation prevents the ubiquitylation of C21ORF2. Given that SCFFBXO3 targets C21ORF2 for proteasomal degradation, C21ORF2(V58L) might be expected to be more stable than the WT protein. The percentage amount of C21ORF2(V58L) remaining during the time course was significantly greater than that of C21ORF2(WT), indicating that C21ORF2(V58L) is indeed more stable than is C21ORF2(WT) as a result of not being a substrate of SCFFBXO3. +The measured average length of neurites formed by the GFP-positive cells for VLKI iMNs was significantly shorter than that for iMNs differentiated from the parental ESCs",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_bde7edf1-ccfa-443e-a917-cf3d2dd9cba6-2023-12-12T180000.000Z,381,PubMed:32891887 +VNTR CNS expression,Expression A,"Marshall JNG, et al., 2022, PMID: 36131690",RNA-seq data from tissues from the Target ALS cohort. Authors compared different isoforms of CFAP410 against healthy controls to see if there is a correlation in ALS and expressed VNTR isoforms.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_bde7edf1-ccfa-443e-a917-cf3d2dd9cba6-2023-12-12T180000.000Z,381,PubMed:36131690 +TbCFAP43 localizes to DMTs 5/6 and paraflagellar rod,Expression A,"Coutton C, et al., 2018, PMID: 29449551","Trypanosoma brucei, a flagellated protozoan, was used as a model organism to help characterize the possible role of human CFAP43 in the structure of the sperm flagellum. Immunoelectron and stimulated-emission depletion microscopy performed on epitope-tagged (Myc or TY1) TbCFAP43 shows that in Trypanosome, the CFAP43 ortholog localizes between the axonemal double microtubules 5 and 6 and the paraflagellar rod. The 5–6 bridge is a doublet-specific structure that links DMTs 5 and 6 in the axonemes of many animal cilia and flagella (PMID:31210147) This bridge limits the inter-doublet sliding against its neighbor, offering a firm plane that is vertical to the bending plane of the flagella. The absence of CFAP43 could destabilize this complex, producing both peri-axonemal and axonemal defects.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a5055c70-e22e-47e5-af3b-04f3f2a0ed34-2022-12-14T200000.000Z,383,PubMed:29449551 +T. Brucei CFAP43 ortholog required for axonemal organization,Model Systems Non-human model organism,"Coutton C, et al., 2018, PMID: 29449551","Mutations in CFAP43 cause male infertility associated with sperm axonemal central pair defects. The main defect based on human sperm EM cross sections appears to be the lack of central pair, although some completely disorganized axonemal and accessory structures are also observed. In some CFAP43 mutation patients, the missing central pair was accompanied by disorganized outer doublets. In other patients the central pair was mis-oriented when present. In the Trypanosome ciliate, TbCFAP43 is localized on the outer surface of the doublet microtubules. Based on this observation, humans CFAP43 is suggested to have a role in connecting specific doublet microtubules to periaxonemal structures in the human sperm tail. Ultrastructural defects and abnormal flagella beating seen in Trypanosome TbCFAP43 knockdown is consistent with abnormal sperm motility, abnormal sperm axoneme morphology, and central pair defects seen in patients with CFAP43 mutations.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a5055c70-e22e-47e5-af3b-04f3f2a0ed34-2022-12-14T200000.000Z,383,PubMed:29449551 +Murine CFAP43 ortholog expressed during spermatogenesis,Expression A,"Sironen A, et al., 2020, PMID: 31781811","RNAseq was conducted on mouse testis tissue collected at specific postnatal time points. The murine CFAP43 ortholog showed a pattern of increasing expression during the progression of spermatogenesis reaching a high level expression (98 FPKM, Fragments Per Kilobase Million) by PND (Post Natal Day) 28.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a5055c70-e22e-47e5-af3b-04f3f2a0ed34-2022-12-14T200000.000Z,383,PubMed:31781811 +Human CFAP43 expressed in ciliated tissues (lungs/brain),Expression A,"Duff MO, et al., 2015, PMID: 25970244","RNA sequencing of total RNA from 20 human tissues showed significant expression of CFAP43 in lung, trachea, and brain. The expression of CFAP43 in these tissues is consistent with a role for CFAP43 in the respiratory system and in the brain ventricular system.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_f2622390-3981-4f40-8c28-194fb13dd35a-2022-12-29T200000.000Z,384,PubMed:25970244 +FAP43 identified as component of T/TH complex activity,Biochemical Function B,"Fu G, et al., 2018, PMID: 29514928","CFAP43 is part of the T/TH complex that is structurally linked to to the IDA motor domains as well as other axonemal complexes. The T/TH complex is thought to regulate conformational changes in the IDAs (through a phosphorylation signaling cascade) that affect microtubule sliding motion, ultimately affecting ciliary beat. In humans, coordinated ciliary beating helps mucociliary clearance of the respiratory system and drives circulation of the cerebrospinal fluid in the brain ventricles. Loss or disfunction of cilia is associated with Primary Ciliary Dyskinesia (PMID: 32943623. An alteration in ciliary motility caused by disfunction of CFAP43 (change in beat frequency or beat amplitude) in respiratory and ependymal epithelial cells could plausibly result in respiratory symptoms and hydrocephalus.",Score,0.5 (0.5),"Morimoto et al 2019 (PMID: 31004071) did not provide any evidence of an alteration in human ciliary function in their patients. The Tetrahymena and Chlamydomonas studies elucidate the function of CFAP43 in cilia in general, adding plausibility to ciliary involvement in CFAP43 patients. More information on the mechanism that underlies the respiratory and hydrocephalus phenotypes seen in CFAP43 human patients is needed.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_f2622390-3981-4f40-8c28-194fb13dd35a-2022-12-29T200000.000Z,384,PubMed:29514928 +Tetrahymena FAP43 knockout reduces cilia beat amplitude,Model Systems Non-human model organism,"Urbanska P, et al., 2018, PMID: 29687140","In humans, coordinated ciliary beating helps drives mucociliary clearance of the airways, as well as circulation of the cerebrospinal fluid in the brain ventricles. Loss or disfunction of cilia in the respiratory system or brain ventricles has been associated with PCD (PMID: 32943623) as well as with hydrocephalus (PMID: 35903173). Knockout of FAP43 lowers cilia beat amplitude and swimming speed in Tetrahymena. It is plausible that a mutation in human CFAP43 could similarly impair ciliary motility, leading to a new primary ciliary dyskinesia subtype.",Score,1 (2),"Down-scored because Tetrahymena model cannot recapitulate important PCD phenotypes seen in humans such as respiratory defects, laterality defects, hydrocephalus. +The Tetrahymena knockout model does provide data on changes in ciliary motility in FAP43 mutants, confirming the plausibility of CFAP43 playing a role in human respiratory and ependymal ciliary motility.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_f2622390-3981-4f40-8c28-194fb13dd35a-2022-12-29T200000.000Z,384,PubMed:29687140 +Tetrahymena Fap43p expressed along length of cilia,Expression A,"Urbanska P, et al., 2018, PMID: 29687140","Immunofluorescent studies In Tetrahymena, show that when expressed under the control of the native promoter, Fap43p–3HA was exclusively targeted to cilia and was present along the entire length of the cilium, with the exception of the cilium tip. The expression of Fap43p along the cilium is consistent with a role for human CFAP43 in ciliary structure and/or activity.",Score,0.5 (0.5),"Morimoto et al 2019 (PMID: 31004071) were not able to provide definitive evidence that their CFAP43 patients carried ciliary defects. At least one patient showed the presence of compound respiratory cilia, but this phenotype is not indicative of respiratory or ependymal ciliary disfunction and can be seen in healthy patients.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_f2622390-3981-4f40-8c28-194fb13dd35a-2022-12-29T200000.000Z,384,PubMed:29687140 +Tetrahymena Fap43p interacts with ciliary protein Fap44p,Protein Interaction,"Urbanska P, et al., 2018, PMID: 29687140","Tetrahymena orthologs of human CFAP43 and CFAP44, Fap43p and Fap44p, were shown to be interacting proteins by two methods: Co-immunoprecipitation and a BirA* proximity labelling assay on cytoskeletal and/or ciliary fractions from cells (native or over-expressing Fap43p), followed by mass spectrometry. Some Dyh6p peptides were also identified as interacting with Fap43p and Fap44p. In Tetrahymena, Dyh6 is one of the dynein heavy chains of the two-headed inner dynein arm I1 (IDAI1). Urbanska et al suggest that Fap43p and Fap44p form a novel ciliary complex located near IDAI1. They show that loss of either protein results in altered waveform, beat stroke and swimming speed. They hypothesize that a Fap43p-Fap44p complex might regulate IDA I1 activity.",Score,0.25 (0.5),"Down-scored because CFAP44 has not been associated with human cases of Primary Ciliary Dyskinesia or in any human phenotypes involving ciliary disfunction. Like CFAP43, CFAP44 has been strongly associated with human cases of male infertility, specifically MMAF (PMID: 29449551) and defects in the sperm flagella structure and axoneme.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_f2622390-3981-4f40-8c28-194fb13dd35a-2022-12-29T200000.000Z,384,PubMed:29687140 +"Human CFAP43 expressed in ciliated tissues, including brain",Expression A,"Duff MO, et al., 2015, PMID: 25970244","RNA sequencing of total RNA from 20 human tissues showed significant expression of CFAP43 in lung, trachea, and brain. The expression of CFAP43 in brain tissue is consistent with a role for CFAP43 in the brain ventricular system.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ff67c788-1b69-4da8-84df-f37741c9913f-2022-12-13T200000.000Z,385,PubMed:25970244 +FAP43 identified as component of T/TH complex activity,Biochemical Function B,"Fu G, et al., 2018, PMID: 29514928","CFAP43 is part of the T/TH complex that is structurally linked to to the IDA motor domains as well as other axonemal complexes. The T/TH complex is thought to regulate conformational changes in the IDAs (through a phosphorylation signaling cascade) that affect microtubule sliding motion, ultimately affecting ciliary beat. In humans, coordinated ciliary beating helps drive circulation of the cerebrospinal fluid in the brain ventricles. Loss or disfunction of cilia in brain ventricles is associated with hydrocephalus (PMID: 35903173). An alteration in ciliary motility caused by disfunction of CFAP43 (change in beat frequency or beat amplitude) in brain ependymal cells could plausibly result in hydrocephalus as is seen in CFAP43 patients (Morimoto et al 2019; PMID: 31004071).",Score,0.5 (0.5),"Morimoto et al 2019 (PMID: 31004071) did not provide any evidence of an alteration in human ciliary function in their patients. The Tetrahymena and Chlamydomonas studies elucidate the function of CFAP43 in cilia in general, adding plausibility to ciliary involvement in CFAP43 patients. More information on the mechanism that underlies the respiratory and hydrocephalus phenotypes seen in CFAP43 human patients is needed.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ff67c788-1b69-4da8-84df-f37741c9913f-2022-12-13T200000.000Z,385,PubMed:29514928 +Tetrahymena Fap43p expressed along length of cilia,Expression A,"Urbanska P, et al., 2018, PMID: 29687140","Immunofluorescent studies In Tetrahymena, show that when expressed under the control of the native promoter, Fap43p–3HA was exclusively targeted to cilia and was present along the entire length of the cilium, with the exception of the cilium tip. The expression of Fap43p along the cilium is consistent with a role for human CFAP43 in ciliary structure and/or activity.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ff67c788-1b69-4da8-84df-f37741c9913f-2022-12-13T200000.000Z,385,PubMed:29687140 +Tetrahymena Fap43p interacts with ciliary protein Fap44p,Protein Interaction,"Urbanska P, et al., 2018, PMID: 29687140","Tetrahymena orthologs of human CFAP43 and CFAP44, Fap43p and Fap44p, were shown to be interacting proteins by two methods: Co-immunoprecipitation and a BirA* proximity labelling assay on cytoskeletal and/or ciliary fractions from cells (native or over-expressing Fap43p), followed by mass spectrometry. Some Dyh6p peptides were also identified as interacting with Fap43p and Fap44p. In Tetrahymena, Dyh6 is one of the dynein heavy chains of the two-headed inner dynein arm I1 (IDAI1). Urbanska et al suggest that Fap43p and Fap44p form a novel ciliary complex located near IDAI1. They show that loss of either protein results in altered waveform, beat stroke and swimming speed. They hypothesize that a Fap43p-Fap44p complex might regulate IDA I1 activity.",Score,0.25 (0.5),"Down-scored because CFAP44 has not been associated with human cases of Hydrocephalus. or in human phenotypes involving ciliary disfunction. Like CFAP43, CFAP44 has been strongly associated with human cases of male infertility, specifically MMAF (PMID: 29449551) and defects in the sperm flagella structure and axoneme.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ff67c788-1b69-4da8-84df-f37741c9913f-2022-12-13T200000.000Z,385,PubMed:29687140 +Tetrahymena FAP43 knockout reduces cilia beat amplitude,Model Systems Non-human model organism,"Urbanska P, et al., 2018, PMID: 29687140","In humans, coordinated ciliary beating helps drive circulation of the cerebrospinal fluid in the brain ventricles. Loss or disfunction of cilia in brain ventricles is associated with hydrocephalus (PMID: 35903173). Knockout of FAP43 lowers cilia beat amplitude and swimming speed in Tetrahymena. It is plausible that a mutation in human CFAP43 could similarly impair ciliary motility and affect cerebrospinal fluid movement by ependymal cilia, leading to hydrocephalus (Morimoto et al 2019; PMID: 31004071).",Score,1 (2),Down-scored because Tetrahymena model cannot recapitulate primary phenotype seen in human CFAP43 variant: Hydrocephalus. The Tetrahymena knockout model confirms the plausibility of CFAP43 playing a role in human ependymal ciliary motility,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ff67c788-1b69-4da8-84df-f37741c9913f-2022-12-13T200000.000Z,385,PubMed:29687140 +CFAP43 CRISPR-Cas9 knockout mouse,Model Systems Non-human model organism,"Morimoto Y, et al., 2019, PMID: 31004071","Mice homozygous for truncated CFAP43 developed hydrocephalus, abnormalities in ciliary protein composition in ventricle epithelia, ultrastructural defects in their tracheal cilia, sperm defects, and compound cilia in mouse tracheal epithelia. Morimoto et al. patients with a defective CFAP43 gene developed hydrocephalus and had some compound respiratory cilia. The respiratory symptoms and tracheal ciliary abnormalities in humans are not well enough characterized to be attributed to a defective CFAP43. The mouse model phenotype suggests that a mutant CFAP43 could lead to defective cilia and flagella. Hence, the implication is that in humans and mice, CFAP43 could play a role in in ependymal cilia, and a defect in this protein could lead to hydrocephalus.",Score,0.5 (2),"Down-scored due to autosomal recessive inheritance pattern of mouse model compared to autosomal dominant inheritance in human case. Human patients and mouse model indicate that a mutation in CFAP43 can produce hydrocephalus but the mechanism by which these alterations in CFAP43 affect ciliary structure or activity may be different in the different organisms. The presumed dominant-negative mode of action of the described human mutation needs to be confirmed and mechanistically evaluated. +Also down-scored because of lack of convincing data that there is brain ciliary dysfunction in this model. Data on respiratory ciliary dysfunction and sperm flagellar abnormalities could use further investigation.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ff67c788-1b69-4da8-84df-f37741c9913f-2022-12-13T200000.000Z,385,PubMed:31004071 +Silencing of CFAP57 in hTEC reduces ciliary motility,Functional Alteration Non-patient cells,"Bustamante-Marin XM, et al., 2020, PMID: 32764743",HSVMA shows a reduction in CBF and altered waveform.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_50ed292f-0044-4c82-9419-a040cbcaf205-2022-06-23T160000.000Z,387,PubMed:32764743 +Chlamyomonas flagella,Model Systems Non-human model organism,"Bustamante-Marin XM, et al., 2020, PMID: 32764743","CFAP57 is the human ortholog of C. reinhardtii BOP2/IDA8/FAP57/WDR65 gene. FAP57 forms an extended structure that interconnects multiple IDAs and regulatory complexes. TMT mass spectroscopy shows that FAP57 is missing, and the “g” inner dyneins (DHC7 and DHC3) and the “d” inner dynein (DHC2) are reduced, but the FAP57 paralog FBB7 is increased. Mutant fap57 Chlamydomonas strains show reduced swimming velocity and altered waveforms. Biallelic loss of CFAP57 causes a failure to assemble a subset of IDAs.",Score,1 (2),Chlamydomonas models do not model lung issues or laterality defects.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_50ed292f-0044-4c82-9419-a040cbcaf205-2022-06-23T160000.000Z,387,PubMed:32764743 +Localisation and expression of CFAP57 in control cells,Biochemical Function A,"Bustamante-Marin XM, et al., 2020, PMID: 32764743",FOXJ1 is a key gene driver for ciliogenesis.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_50ed292f-0044-4c82-9419-a040cbcaf205-2022-06-23T160000.000Z,387,PubMed:32764743 +Chlamydomonas flagella,Model Systems Non-human model organism,"DiPetrillo CG, et al., 2010, PMID: 20421426","CFAP74 is the human ortholog of C. reinhardtii FAP74 gene. FAP74 is a subunit of the C1d projection. FAP74 knockdown results in the loss of the C1d projection and abnormal beating patterns with reduced frequencies (CBF reduced to 30% of WT; flagella are uncoordinated, with defects in propagating bends and switching between effective and recovery strokes).",Score,1 (2),Chlamydomonas models do not model lung issues or laterality defects.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e5a065a6-73b9-46ba-89a2-afadedb4b82c-2023-10-12T160000.000Z,388,PubMed:20421426 +Significantly reduced expression compared to WT in vitro,Functional Alteration Non-patient cells,"de Jong S, et al., 2020, PMID: 32510551",Multiple variants demonstrated significantly reduced expression compared to WT in vitro often paired with low FI plasma level in HEK293T cells:,Score,1 (0.5),Upgraded for consistent effect for variants identified in patients with disease.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_943f6c06-e32b-4052-8628-4c28de20c838-2024-06-28T160000.000Z,394,PubMed:32510551 +Mouse model,Model Systems Non-human model organism,"Song H, et al., 2021, PMID: 34149444","The mice were all normal in either SPF (specific pathogen free) or regular environment. When treated with lipopolysaccharides (LPS), a bacterial endotoxin that mimics infection and sepsis, the mice developed albuminuria, kidney function impairment, and C3 glomerular deposition at levels comparable with the wild-type mice. +The mice with other genotypes concerning CFI D288G and P467S were also tested in parallel. Unexpectedly, the D288G homozygotes all developed severe mesangial deposition of C3 in the LPS model, indicating that CFI D288G variation was involved in the C3 deposition, a key feature of C3GN.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_943f6c06-e32b-4052-8628-4c28de20c838-2024-06-28T160000.000Z,394,PubMed:34149444 +TDP43 Interacts w/ CHCHD10,Protein Interaction,"Woo JA, et al., 2017, PMID: 28585542","TDP-43 forms a complex with CHCHD10 and promotes its nuclear localization +CHCHD10 depletion and FTD/ALS CHCHD10 mutations induce cytoplasmic TDP-43 mislocalization +FTD/ALS CHCHD10 mutations induce TDP-43 mislocalization frequently with mitochondria",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d154f67a-25ce-40d3-9de3-1f001753843a-2022-09-13T160000.000Z,398,PubMed:28585542 +Mutant CHCHD10 on TDP43 apoptosis and synaptic damange,Protein Interaction,"Woo JA, et al., 2017, PMID: 28585542",Wild-type CHCHD10 ameliorates and FTD/ALS CHCHD10 mutations potentiate TDP-43-induced apoptosis and synaptic impairment,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d154f67a-25ce-40d3-9de3-1f001753843a-2022-09-13T160000.000Z,398,PubMed:28585542 +C. Elegans,Model Systems Non-human model organism,"Woo JA, et al., 2017, PMID: 28585542",Abnormal locomotion and decreased lifespan are consistent with motor neuron disease,Score,0 (2),"Ortholog to CHCHD10 used with 41% identity in a non-mammalian model system. While decreased locomotion and decreased survival are seen with ALS, this does is not specific to the disease. The C. elegans ortholog shares 41% amino acid identity with CHCHD10 and +CHCHD2 therefore a phenotype arising due to KD or KO of the ortholog cannot be attributed to loss of either CHCHD10 or CHCHD2 specifically, due to their homology",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d154f67a-25ce-40d3-9de3-1f001753843a-2022-09-13T160000.000Z,398,PubMed:28585542 +Postmortem R15L,Expression B,"Keith JL, et al., 2020, PMID: 32042922","The CHCHD10 mutated ALS case showed a different pattern +of CHCHD10 labeling; in addition to the strong neuronal +cytoplasmic and axonal staining seen in the other cases, there +were also numerous aggregates of CHCHD10 within the +anterior horns, slightly more abundant at cervical levels +(figure 3, E–G, figure e-1, A–C, links.lww.com/NXG/A218). +These aggregates had a dense central core and a surrounding +halo of CHCHD10 immunopositivity (figure 3, H and I), and +they did not contain CHCHD2. Also present were rare +corkscrew-shaped CHCHD10 immunopositive inclusions +within all levels of the anterior horn (figure 3, F and J). The +frontal cortex of the CHCHD10 mutated case showed predominantly strong neuronal cytoplasmic and axonal labeling +with CHCHD10, but CHCHD10 aggregates and corkscrewshaped inclusions were also present focally in the superficial +cortical layers (figure e-1, D–F).",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d154f67a-25ce-40d3-9de3-1f001753843a-2022-09-13T160000.000Z,398,PubMed:32042922 +Drosophila,Model Systems Non-human model organism,"Baek M, et al., 2021, PMID: 33772006",Loss of motor neurons is characteristic for ALS,Score,0 (2),Not a strong model system. Ortholog created. Difficult to distinguish CHCHD10 and CHCHD2.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d154f67a-25ce-40d3-9de3-1f001753843a-2022-09-13T160000.000Z,398,PubMed:33772006 +TDP43 solubility and mitochondrial translocation,Functional Alteration Non-patient cells,"Baek M, et al., 2021, PMID: 33772006","Examined insoluble TDP-43 levels after CHCHD10WT and +CHCHD10S59L transfection. Strikingly, CHCHD10S59L expression +increased insoluble TDP-43, whereas CHCHD10WT expression +decreased insoluble TDP-43 (Fig. 4b). Co-expression of +CHCHD10WT with CHCHD10S59L suppressed CHCHD10S59Linduced insoluble TDP-43",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d154f67a-25ce-40d3-9de3-1f001753843a-2022-09-13T160000.000Z,398,PubMed:33772006 +Summary of yeast two-hybrid results,Protein Interaction,"Estruch SB, et al., 2016, PMID: 26867680","FOXP2 is a gene that has been shown to have a transcription factor that has been implicated in monogenic forms of CAS, accompanied by wide-ranging language problems, in multiple families and unrelated cases. In a yeast two hybrid assay, DNA was isolated from positive colonies, the cDNAs of the prey constructs were sequenced and BLAST searched was used to identify the proteins encoded by positive colonies. Proteins represented by two or more colonies were listed. CHD3 was found in 4 preys.",Score,1 (0.5),The score was updated since FOXP2 has been implicated in monogenic forms of childhood apraxia of speech. This gene has also been curated definitively for specific language disorder.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0e94c7c1-9c13-4189-8a9f-e9808916526f-2022-03-02T170000.000Z,399,PubMed:26867680 +Conditional Chd4 KO in granule neurons of mouse cerebellum,Model Systems Non-human model organism,"Goodman JV, et al., 2020, PMID: 32647123","Conditional knockout of Chd4 in granule neurons of the mouse cerebellum impacts genomic accessibility and results in increased promoter and enhancer accessibility during development, modulating genome architecture at a genome-wide level.",Score,1 (2),Score downgraded because the knockout only affected the granule neurons of the cerebellum and the analysis focused only on chromatin remodeling.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_f1795399-d5bc-456d-bc6b-be07d7ab6af6-2023-04-19T160000.000Z,400,PubMed:32647123 +Lysosomal and phagocytosis defects in CHM cells,Functional Alteration Patient cells,"Strunnikova NV, et al., 2009, PMID: 20027300","Using E. coli particles conjugated with a pH-dependent fluorescent dye, the authors showed that lysosomal pH was consistently increased in monocytes of CHM patients. Experiments with DQ-ovalbumin, a self-quenched substrate for proteases which becomes fluorescent after proteolytic cleavage further showed that rates of proteolytic degradation were slower in CHM monocytes than controls, presumably sue to the increased lysosomal pH. Phagocytosis in primary fibroblasts was tracked and quantified using collagen I coated FluoSpheres beads. The rate of uptake was significantly lower in fibroblasts from CHM patients compared to controls 1 h following feeding but then continued at a similar rate to controls, however the number of cells taking up particles was consistently less in primary cultures of CHM patients. Microarray analysis of gene expression revealed that some genes involved in the immune response, small GTPase regulation, transcription, cell adhesion and the regulation of exocytosis were significantly up and down regulated in cells from CHM patients compared to controls. CHM fibroblasts also secreted significantly lower levels of cytokine/growth factors, suggesting a secreation defect. +The RPE serves a number of vital functions in the eye including daily phagocytosis and degradation of shed photoreceptor outer segments; maintenance of the visual cycle by the uptake, processing, and transport of vitamin A; and the transport of nutrients between the choroid and the RPE. By extrapolation, dysfunctional lysosomal processing and transport functions in the RPE, as suggested by this study, could lead to the pathophysiological process causing choroideremia.",Score,0.5 (1),"The score is decreased because the studies were not performed in the cells type affected e.g. photoreceptor or RPE. Instead, due to the unavailability of these cells types, monocytes and fibroblasts were used. In addition, the link between the functional defects identified and the pathophysiological process of choroideremia is theoretical.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d84b01d6-8b3c-4a1e-bd25-68ee6962f374-2020-10-26T124704.094Z,404,PubMed:20027300 +Knock-in mouse,Model Systems Non-human model organism,"Xu J, et al., 2011, PMID: 20603624",Seizures and hyperexcitability as in human NFLE,Score,0 (2),Reduced to 0 because the mice do not have a robust epilepsy phenotype,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ed365ac2-8cfa-4ae9-8fef-323dd596a22f-2023-02-07T170000.000Z,412,PubMed:20603624 +Vallone Function,Functional Alteration Non-patient cells,"Vallone R, et al., 2018, PMID: 30174586",conclude that the p.E64D variant in CBI2 causes an inability of the CIB2 mutant to switch to its native Mg2+-bound conformation which is necessary for normal function,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_95709038-78a4-4043-a054-9cbe245d2588-2019-02-19T170000.000Z,415,PubMed:30174586 +Riazuddin Animal Model,Model Systems Non-human model organism,"Riazuddin S, et al., 2012, PMID: 23023331",MO-knockdown in zebrafish. Approximately 80% of 5-day old morphants did not respond to acoustic stimuli or were unable to remain upright while swimming. SEM showed decrease in number of neuromasts,Score,1 (2),Downgraded for animal model type.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d4187cb6-182f-43fc-aeec-d27297c36bdb-2018-02-20T170000.000Z,416,PubMed:23023331 +Riazuddin Protein Interaction,Protein Interaction,"Riazuddin S, et al., 2012, PMID: 23023331",CIB2 multimerized and interacted with whirlin and myosin VIIa using immunostaining.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d4187cb6-182f-43fc-aeec-d27297c36bdb-2018-02-20T170000.000Z,416,PubMed:23023331 +Riazuddin Expression,Expression A,"Riazuddin S, et al., 2012, PMID: 23023331","CIB2 was widely expressed in human and mouse inner ear and retina. In cytoplasm of adult supporting cells, in the IHC and OHC, and along lenth of stereocilia. Often more intense staining at shorter row stereocilia tips than in neighboring sterocilia of a longer row. Also in vestibular hair cell sterocilia.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d4187cb6-182f-43fc-aeec-d27297c36bdb-2018-02-20T170000.000Z,416,PubMed:23023331 +Giese Animal Model,Model Systems Non-human model organism,"Giese APJ, et al., 2017, PMID: 28663585","Two mouse models, one with a LoF and one with the p.F91S missense mutation, were deaf. No obvious indications of vestibular dysfunction. Morphological changes were characterized in OHCs and IHCs. Strong evidence (via SEM) of hair cell disorganization in both. Mechanotransduction currents were impaired in both models.",Score,4 (2),Upgraded for two distinct mouse models.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d4187cb6-182f-43fc-aeec-d27297c36bdb-2018-02-20T170000.000Z,416,PubMed:28663585 +Giese Protein Interaction,Protein Interaction,"Giese APJ, et al., 2017, PMID: 28663585","Cib2 interacted with TMC1 via yeast two-hybrid. Experiment also showed Cib2 forms dimers, but function of this is unknown. Three HL mutations, E64D, F91S, and C99W, affected interaction with TMC1",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d4187cb6-182f-43fc-aeec-d27297c36bdb-2018-02-20T170000.000Z,416,PubMed:28663585 +Hu Rescue 1,Rescue Cell culture model,"Hu H, et al., 2016, PMID: 25644381","""Introduction of ClC-4 protein in knock-down cells using RNAi-insensitive cDNA rescued both dendritic phenotypes to control levels, thus highlighting the specificity of the phenotype truly associated with the loss of ClC-4 protein (Figure 3a). Primary neurons derived from Clcn4− / − mice41 confirmed these findings (Figure 3b). Although the observed morphological changes were more subtle when compared with those obtained with the shRNAmediated knock-down, they were statistically significant.""",Score,0.5 (1),"Opting to score down to 0.5 points as this is a relatively non-specific phenotype (developmental delay in humans, dendritic branching in the cell model).",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_54fbcbc8-77d7-4496-8527-1171cdd7452c-2017-10-20T160000.000Z,419,PubMed:25644381 +Hu Functional Alteration,Functional Alteration Non-patient cells,"Hu H, et al., 2016, PMID: 25644381",Transfection of mouse hippocampal neurons with knock-down constructs targeting the gene showed reduced dendritic branching per cell (~30% compared to control). Reproduced finding with cells from knockout mice.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_54fbcbc8-77d7-4496-8527-1171cdd7452c-2017-10-20T160000.000Z,419,PubMed:25644381 +Electrophysiological characteristics of ClC-6,Biochemical Function B,"Zhang B, et al., 2023, PMID: 37831762",Abnormal brain MRI,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6226904f-234f-490b-8353-7d6c63bd8724-2024-06-07T160000.000Z,421,PubMed:37831762 +Clc-7 role in autophagy in mouse cardiomyocytes,Biochemical Function B,"Lin J, et al., 2021, PMID: 33495814","In this study, the authors shows that CLC-7 (Clcn7) is recruited to lysosomes during autophagy in cultured mouse cardiomyocytes, and suggest that CLC-7 promotes lysosomal acidification required fro autophagy. This is consistent with the findgins of lysosomal storage, as well as increased acidification of lysosomes in the two patients reported thus far with gain of function of CLCN-7.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0e47aa25-2107-4e36-8fa8-f9e81eb9de69-2023-12-05T170000.000Z,422,PubMed:33495814 +"CLCN7 inhibition by PI(3,5)P2",Biochemical Function B,"Leray X, et al., 2022, PMID: 35670560","The authors showed that PI(3,5)P2, a signaling lipid synthesized by the enzyme PIKfyve, negatively regulates the activity of CLCN7. Based on their results, the authors conclude that ClC-7 is involved in two mechanisms downstream of PIKfyve. This includes determination of lysosomal pH and regulation of lysosomal size and/or lysosomal trafficking.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0e47aa25-2107-4e36-8fa8-f9e81eb9de69-2023-12-05T170000.000Z,422,PubMed:35670560 +Cl as an activator of lysosomal hydrolases,Biochemical Function B,"Feng X, et al., 2023, PMID: 37191899","This commentary discusses two papers (Wu et al, 2023, PMID: 37010469; and Zhang et al, 2023, PMID: 37058288), both of which show that lysosomal Cl− regulates lysosomal degradation, and that the ClC-7/CLCN7 is responsible for generating and maintaining of a 2-4 fold trans-lysosomal concentration gradient of Cl− without affecting lysosomal acidification. In turn, the high intralysosomal Cl−, generated by CLC-7, is important in hydrolase activation, which is required for (phago)lysosome function and protecting lysosomal membrane integrity in vivo. This function is consistent with findings in the two patients reported thus far, both of whom have evidence of a lysosomal storage disorder, based on observation of cytoplasmic vacuoles (with some containing ""amorphous floccular material"") in various cell types. In cultured fibroblasts, some of the large vacuoles stained partially with Lamp1 and Rab7, suggesting that they have endolysosomal properties, but most did not appear to be functional lysosomes as measured by an assay for cathepsin B activity.",Score,1 (0.5),"Score incresed because the commentary discussed 2 papers, in different organisms, showing the importance of CLCN7 in lysosome function.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0e47aa25-2107-4e36-8fa8-f9e81eb9de69-2023-12-05T170000.000Z,422,PubMed:37191899 +Spontaneous Dog Model,Model Systems Non-human model organism,"Kolicheski A, et al., 2016, PMID: 27203721","The presence of visual impairment, seizures, and ataxia is clinically similar, plus the dogs also has similar brain pathology, including accumulation of autofluorescent lysosomal storage material.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a522b1d6-5ade-4749-94b8-d5426bbe5961-2021-09-08T023930.981Z,428,PubMed:27203721 +Cln6 nclf mouse,Model Systems Non-human model organism,"Morgan JP, et al., 2013, PMID: 24223841","Behavioral findings (impaired motor coordination, vision, learning/memory) and pathological changes (neuron loss/reduced brain size) align with phenotypes such as photosensitivity/retinal degradation, ataxia, dementia, and cerebellar atrophy in human patients diagnosed with NCL/Batten disease.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_09654b45-6649-4d11-b43e-aeb6d20fb86d-2020-12-01T170000.000Z,429,PubMed:24223841 +Gene therapy in Cln6 nclf mouse,Rescue Non-human model organism,"Cain JT, et al., 2019, PMID: 31331814","The treatment prevented accumulation of autofluorescent storage material and ATP synthetase subunit C, reactive gliosis, and loss of dendritic spines. Many of the motor, memory and learning, and survival deficits (65% increase) seen in untreated mice were also prevented (after a single treatment, some learning/memory deficits were seen at later time points).",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_09654b45-6649-4d11-b43e-aeb6d20fb86d-2020-12-01T170000.000Z,429,PubMed:31331814 +Mouse model studies,Model Systems Non-human model organism,"Kandaswamy S, et al., 2022, PMID: 36115851",The mice homozygous for p.Tyr509Cys were reported to show progressive retinal degeneration and photoreceptor loss from 8 weeks onwards. The variant p.Tyr509Cys corresponds to human p.Tyr513 which is present in the same protein domain as human p.Gly509Arg which was identified in the family with arRP. This shows that KO mouse model recapitulates the RP phenotype observed in human patients.,Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_bdf9374a-2ec6-4852-ac0b-ec1a3e638245-2022-10-06T160000.000Z,433,PubMed:36115851 +Intravitreal gene therapy of CNGA3-/- mouse,Rescue Non-human model organism,"Pavlou M, et al., 2021, PMID: 33616280","Confocal microscopy confirmed widespread transduction and successful wildtype-like expression of Cnga3 protein in PNA-positive cone photoreceptor outer segments through-out the retina. To further validate the protein expression profile, we compared Cnga3-/- -treated retina (Fig 6G) to wild-type (Fig 6H) and Cnga3-/--untreated retina (Fig 6I), thus confirming the correct CNGA3 localisation and distribution.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_39fe36b7-54c3-486b-a9f9-19bce71f096e-2022-02-03T170000.000Z,434,PubMed:33616280 +Immunohistochemistry in Papillon with PRA,Model Systems Non-human model organism,"Winkler PA, et al., 2013, PMID: 23977260","Progressive retinal atrophy (PRA) is the canine equivalent of retinitis pigmentosa, +Electroretinography (ERG) of affected Papillons showed markedly reduced or absent rod-mediated ERG responses from an early age with preservation of cone photoreceptor responses. +SD-OCT performed on PRA-affected Papillons (confirmed to have theCNG B1 mutation described in this paper) showed that affected dogs have a progressive thinning of the outer nuclear layer with age",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_664a3eaa-0139-4f5a-8f97-a4a7e00ddfd3-2022-09-01T160000.000Z,435,PubMed:23977260 +Dendrite phenotype Rescue,Rescue Cell culture model,"Zhang Y, et al., 2020, PMID: 33298018","Depletion of the Cnksr2 gene in mouse primary hippocampal neurons resulted in a severe reduction in the number of dendrite branches, loss of dendrite complexity due to loss of terminal dendrite branches, and decreased total length of neurites per neuron compared to controls. These defects could be rescued by expression of the wildtype protei.",Score,2 (1),Knockdown of gene in mouse neurons shows phenotype relevant to disease pathology which is rescued by wt protein.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_420ee599-c745-43b9-b9a9-c80dfd7f68a8-2020-12-16T170000.000Z,437,PubMed:33298018 +Zebrafish Model,Model Systems Non-human model organism,"Arjona FJ, et al., 2014, PMID: 24699222","Knockdown of CNNM2 orthologues in zebrafish results in impaired development of the brain, abnormal neurodevelopmental phenotypes manifested as altered locomotor and touch-evoke escape behaviours, and reduced body Mg content, indicative of impaired renal Mg2+ absorption. The zebrafish phenotype can be rescued by injection of mouse Cnnm2 cRNA.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_522bb617-c817-4536-a87b-01d4302d7bf0-2024-02-15T170000.000Z,438,PubMed:24699222 +Cellular Mg2+ uptake in HEK293 cells,Biochemical Function B,"Arjona FJ, et al., 2014, PMID: 24699222",Defective Mg2+ uptake can cause hypomagnesemia.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_522bb617-c817-4536-a87b-01d4302d7bf0-2024-02-15T170000.000Z,438,PubMed:24699222 +Mouse model,Model Systems Non-human model organism,"Franken GAC, et al., 2021, PMID: 33600043","Breeding Cnnm2+/− mice resulted in a Mendelian distribution at embryonic day 18. Nevertheless, only four Cnnm2−/− pups were born alive. The Cnnm2−/− pups had a significantly lower serum Mg2+ concentration compared to wildtype littermates and displayed exencephaly. Subsequently, adult Cnnm2+/− mice were fed with low, control, or high Mg2+ diets for two weeks. Adult Cnnm2+/− mice showed mild hypomagnesaemia compared to Cnnm2+/+ mice and increased serum Ca2+ levels, independent of dietary Mg2+ intake. Fecal analysis displayed increased Mg2+ and Ca2+ excretion in the Cnnm2+/− mice. Transcriptional profiling of Trpm6, Trpm7, and Slc41a1 in kidneys and colon did not reveal effects based on genotype. Microcomputed tomography analysis of the femurs demonstrated equal bone morphology and density.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_522bb617-c817-4536-a87b-01d4302d7bf0-2024-02-15T170000.000Z,438,PubMed:33600043 +Expression of CNNM4 in rat incisor,Expression A,"Parry DA, et al., 2009, PMID: 19200525",Paraffin-embedded sections of demineralized rat incisor was labeled with anti-CNNM4 antibody detected expression in ameloblasts during transition and maturation which is consistent with the tissue affected in Jalili syndrome.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e3cedd07-df9e-4838-8a6b-b24b2802f223-2021-08-06T154836.361Z,439,PubMed:19200525 +Mouse retinal expression,Expression A,"Parry DA, et al., 2009, PMID: 19200525","Immunofluorescence of mouse retina sections labeled with rabbit anti-cnnm4 antibody shows expression in photoreceptor inner segments, and predominantly localized to the outer plexiform layer (OPL), inner plexiform layer (IPL), and ganglion cell layer (GCL), containing the axons, dendrites, and synaptic terminals of the neuronal cells of the retina.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e3cedd07-df9e-4838-8a6b-b24b2802f223-2021-08-06T154836.361Z,439,PubMed:19200525 +Cnnm4-/- mouse model,Model Systems Non-human model organism,"Yamazaki D, et al., 2013, PMID: 24339795",Malabsorption of Mg2+ in mice knockouts result in defects in amelogenesis. Hypomineralization is seen in tooth enamel in knock out mice similar to defects in enamel formation in hypomaturation Amelogenesis imperfecta in patients with mutations in CNNM4.,Score,1 (2),"The phenotype of the mouse model recapitulated the AI, however no signs of CRD was seen in KO mice.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e3cedd07-df9e-4838-8a6b-b24b2802f223-2021-08-06T154836.361Z,439,PubMed:24339795 +HEK293 studies,Functional Alteration Non-patient cells,"Yamazaki D, et al., 2013, PMID: 24339795","Mg2+ extrusion assays were performed measuring the fluorescence intensity of transfected constructs over time (0-5min). Wild type relative intensity decreased rapidly after Mg2+ depletion began, while missense mutations display very weak, if any, Mg2+ extrusion activity similar to empty vector relative intensities.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e3cedd07-df9e-4838-8a6b-b24b2802f223-2021-08-06T154836.361Z,439,PubMed:24339795 +Oguro-Ando mouse model,Model Systems Non-human model organism,"Oguro-Ando A, et al., 2021, PMID: 33542194",Anxiety and stress are common symptoms of ASD.,Score,0.5 (2),Downgrading because the mouse model only recapitulates one aspect of the ASD phenotype.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_716109ea-60b6-48d9-8ab7-b3883063bae0-2022-04-14T180000.000Z,444,PubMed:33542194 +Melchionda_functional alteration,Functional Alteration Patient cells,"Melchionda L, et al., 2014, PMID: 25175347","Biochemistry: BNGE in S1 and S2 fibroblasts, amount of both COX holocomplex and cIII2þcIV supercomplex was clearly reduced in both mutant cells, more markedly in S2; other complexes similar to controls +Response to ROS: Expression of wild-type APOPT1 in mutant fibroblast cells led to an increase in the amount of COX and a reduction of ROS production to normal levels. However, shRNA-mediated stable downregulation of APOPT1 expression in human myoblasts or immortalized fibroblasts failed to either impair COX activity or increase ROS production, but was associated with markedly attenuated cell growth up to arrest of proliferation and cell degeneration. +Measured the production ROS using a dichlorofluorescein-based assay. +In basal conditions ROS levels were comparable between immortalized mutant S2 fibroblasts and control fibroblasts +After H2O2 incubation, ROS levels in mutant S2 were higher than in control fibroblasts +In S2 fibroblasts transduced with APOPT1-HA-expressing lentiviral vector, the amount of ROS was decreased with either treatment, being comparable to that found in control cells treated with the higher H2O2 concentration, suggesting a role for APOPT1 in mitochondrial response to ROS (APOPT1 was stabilized when cells were exposed to H2O2)",Score,2 (1),Biochemistry and response to ROS consistent with disease mechanism.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7b2b04f9-275d-45e9-acc6-ee86bf20c782-2023-07-11T160000.000Z,447,PubMed:25175347 +Signes_mouse,Model Systems Non-human model organism,"Signes A, et al., 2019, PMID: 30552096","Recapitulation of phenotype: impaired motor skills (decreased motor coordination and endurance evidenced by difficulty with treadmill and rotarod) +Biochemistry: Reduced COX activity in multiple tissues, low steady-state levels of structural subunits and defective assembly in all the tested tissues.",Score,3 (2),2 points: phenotype; 1 point: biochemistry,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7b2b04f9-275d-45e9-acc6-ee86bf20c782-2023-07-11T160000.000Z,447,PubMed:30552096 +Signes_functional alteration,Functional Alteration Patient cells,"Signes A, et al., 2019, PMID: 30552096","Biochemistry/rescue: Performed in cells from S2 and S6, first showed low steady-state levels of COX subunits, reduced levels of fully assembled COX, and decreased COX activity; both cell lines were transduced with APOPT1 and showed full recovery of COX assembly and COX enzymatic activity, which were around 50% of the control in the non-transduced (naıve) and GFP alone transduced cells. +Response to ROS: With increased ROS, APOPT1 is stabilized, increasing its mature intramitochondrial form and thereby protecting COX from oxidatively induced degradation.",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7b2b04f9-275d-45e9-acc6-ee86bf20c782-2023-07-11T160000.000Z,447,PubMed:30552096 +Brischigliaro_drosophila,Model Systems Non-human model organism,"Brischigliaro M, et al., 2019, PMID: 31555154","complex IV deficiency, neurologic impairment",Score,3 (2),2 points - phenotype recapitulation; 1 point - biochemistry,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7b2b04f9-275d-45e9-acc6-ee86bf20c782-2023-07-11T160000.000Z,447,PubMed:31555154 +Interaction of COG1 and other COGs,Protein Interaction,"Ungar D, et al., 2002, PMID: 11980916","The researchers employed coimmunoprecipitation, focusing on the COG proteins, namely Cog1, Cog2, Cog3, and Cog5. In their experiment, an antibody against Cog2 was used to pull out proteins from rat liver cells. The results demonstrated that all examined COG proteins (Cog1, Cog2, Cog3, and Cog5) co-precipitated together. Similarly, using an antibody against Cog1 in a sample from bovine brain cells yielded the same outcome. Furthermore, the researchers confirmed that Sec8, a protein from a different complex, did not co-precipitate with the COG proteins. +This experimental evidence supports the interaction among the COG proteins, specifically Cog1, Cog2, Cog3, and Cog5, as revealed by co-immunoprecipitation. (Default: 0.5 points)",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6607c8c3-e293-49df-904d-da27aa8e0232-2024-01-03T170000.000Z,449,PubMed:11980916 +Knockout of COG1,Functional Alteration Non-patient cells,"Bailey Blackburn J, et al., 2016, PMID: 27066481",The morphological changes in the Golgi structure observed in HEK293T KO cell lines appeared to be on par (or possibly even more severe) compared to previously described Cog1 and Cog2 deficient CHO cells.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6607c8c3-e293-49df-904d-da27aa8e0232-2024-01-03T170000.000Z,449,PubMed:27066481 +Interaction of COG2 and other COGs,Protein Interaction,"Ungar D, et al., 2002, PMID: 11980916","The researchers employed coimmunoprecipitation, focusing on the COG proteins, namely Cog1, Cog2, Cog3, and Cog5. In their experiment, an antibody against Cog2 was used to pull out proteins from rat liver cells. The results demonstrated that all examined COG proteins (Cog1, Cog2, Cog3, and Cog5) co-precipitated together. Similarly, using an antibody against Cog1 in a sample from bovine brain cells yielded the same outcome. Furthermore, the researchers confirmed that Sec8, a protein from a different complex, did not co-precipitate with the COG proteins. +This experimental evidence supports the interaction among the COG proteins, specifically Cog1, Cog2, Cog3, and Cog5, as revealed by co-immunoprecipitation. (Default: 0.5 points)",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_67d145eb-648f-4e00-b53f-9447d650cc3e-2024-02-07T170000.000Z,450,PubMed:11980916 +Reynders et al. Down Regulation of COG4 in HeLa cells,Functional Alteration Non-patient cells,"Reynders E, et al., 2009, PMID: 19494034","Knockdown of COG4 in HeLa cells recapitulated two phenotypes associated with the few COG4-CDG patients. First, both COG4 patient fibroblasts and COG4 knock down HeLa cells observed a significant decrease in COG4 protein levels (20% and 3% respectively). Next, both patient fibroblasts and COG4 knock down HeLa cells observed a significant delay in BFA-induced redistribution of Golgi remnants, suggesting COG4-CDG is associated with a retrograde transport delay from the Golgi to the ER.",Score,1 (0.5),"Upscored due to recapitulation of altered BFA-induced redistribution of Golgi remnants, which is one of the core molecular and specific phenotypes of COG-CDG.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6c9f2031-7487-45a5-abbe-ca2d27f1b09c-2023-05-17T180000.000Z,452,PubMed:19494034 +Function of the COG complex and relation to COG4-CDG,Biochemical Function B,"Blackburn JB, et al., 2019, PMID: 31381138","COG dysfunction (and knock out of COG and specific COG subunits) is associated with defects in glycosylation, including both N and O glycosylation defects. Additionally, variants in 7 out of the 8 COG subunits have been implicated and found in patients with CDGs. Knock down of specific COG subunits have resulted in the mislocalization of Golgi glycosylation enzymes. These critical glycosylation enzymes are likely misplaced by impaired intra-golgi retrograde trafficking that affects Golgi enzyme replacement.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6c9f2031-7487-45a5-abbe-ca2d27f1b09c-2023-05-17T180000.000Z,452,PubMed:31381138 +Mouse Model,Model Systems Non-human model organism,"Forouhan M, et al., 2018, PMID: 30010889","Both wt/m and m/m mice grew slower than their wt/wt littermates from birth. The differences between wt/wt and both wt/m and m/m mice body weights and endochondral bone growth rates were maintained over the time course of the experiment and were still apparent at 9 weeks of age. The lengths of femur and tibia bones as well as body weight in wt/m mice were intermediate between the wt/wt and m/m values. The inner canthal distance (ICD) between the eye sockets, a part of the skeleton formed by intramembranous ossification, was identical between all genotypes, indicating that the observed skeletal defects in wt/m and m/m mice are specifically related to defects in endochondral bone growth. +Het and hom mice displayed hip dysplasia. +Expansion of the cartilage growth plate HZ is the histological hallmark of MCDS. The HZs of tibial growth plates were significantly expanded by 3.5- and 5-fold in 3-week-old wt/m and m/m mice, respectively, compared with their wt/wt control littermates. Such marked expansions of HZ in both wt/m and m/m mice compared with wt/wt mice were also present at birth and were still apparent at 7 weeks of age despite marked reductions in the overall height of growth plates in all genotypes that occur naturally as the animals mature. +The MCDS phenotype was shown to be a direct result of increased ER stress caused by intracellular retention of mutated and misfolded collagen X protein within the HCs that disrupts HC differentiation. Immunohistochemical analysis of tibial growth plates in wt/wt mice revealed the expected secretion of collagen X into the extracellular matrix surrounding the HCs. The mutant protein in m/m mice was mainly retained intracellularly with a significantly delayed and reduced collagen X secretion in the lower half of the HZ. wt/m mice displayed an intermediate phenotype with less retention and more secretion particularly in the lower half of the HZ compared with the m/m mouse. Immunostaining for the ER stress-induced chaperones GRP78/BiP and Cysteine Rich with EGF Like Domains 2 (Creld2) was markedly induced in the HCs of wt/m and m/m animals compared with the wt/wt control.",Score,4 (2),Mice heterozygote (wt/m) and homozygote (m/m) for Col10a1 p.Y632X displayed a robust MCDS phenotype.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5529304a-e8aa-4e44-a544-6864b8afe78a-2024-06-28T160000.000Z,454,PubMed:30010889 +Calcification and Ossification of Growth Plate,Biochemical Function B,"Kamakura T, et al., 2023, PMID: 37197316",Leads to shortening of various skeletal structures and overall short stature.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5529304a-e8aa-4e44-a544-6864b8afe78a-2024-06-28T160000.000Z,454,PubMed:37197316 +COL1A1 expression in tendons and ligaments,Expression A,"Wang C, et al., 2017, PMID: 28206959",It is widely accepted that COL1A1 is expressed throughout tendon and ligament tissues.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_35866dc4-e7a2-42c8-801c-019214666e8f-2023-09-28T160000.000Z,458,PubMed:28206959 +Expression in tendons and ligaments,Expression A,"Wang C, et al., 2017, PMID: 28206959",COL1A1 is the predominant collagen comprising tendons and ligaments.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ac0eb1d7-5309-48a0-acd8-53de284f4e4b-2023-09-28T160000.000Z,461,PubMed:28206959 +COL1A1 expression in tendons and ligaments,Expression A,"Wang C, et al., 2017, PMID: 28206959",COL1A1 is the predominant collagen comprising tendons and ligaments.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d013cb4d-bb06-4db8-8efd-b3808f8f123c-2023-09-28T160000.000Z,463,PubMed:28206959 +Daley_OOA Mouse,Model Systems Non-human model organism,"Daley E, et al., 2010, PMID: 19594296","Consistent with the human pedigree, these mice had reduced body mass, BMD, and bone strength compared to wild-type mice",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_457065a1-4ed1-4d23-aa54-26fffa6f2853-2023-09-28T160000.000Z,466,PubMed:19594296 +Point mutation of Col4a4 resulting in mice model of Alport S,Model Systems Non-human model organism,"Falcone S, et al., 2019, PMID: 31892712","As part of ongoing phenotype driven screening programme, mutant mice exhibiting ESKD between 37 and 103 days of age were identified. Kidneys from affected mice were small and pale and histopathological analysis of these mice revealed extensive glomerulonephropathy.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c235830a-a6f5-4cf6-b015-902da62f1b2e-2021-08-24T023000.000Z,482,PubMed:31892712 +Gene Expression levels in mutant mice model,Expression A,"Falcone S, et al., 2019, PMID: 31892712","Gene expression levels in C3H-Col4a4G400X/G400X and B6-Col4a4G400X/G400X mice at 7 wks of age in whole kidney cDNA showed that podocalyxin (Podxl), nephrin (Nphs1) and podocin (Nphs2) significantly decreased and laminin a5 (lama5), agrin (Agrn), integrin a3 (itga3) and matrix metalloproteinase 12 (Mmp12) and tumour necrosis factor (Tnfa) expression levels significantly increased compared to wild type. Lama5 increased equally in homozygous mice on both backgrounds. There were significant differences between C3H-Col4a4G400X/G400X and B6-Col4a4G400X/ G400X mice in the expression of Agrn, Itga3, Tnfa, and Mmp12.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c235830a-a6f5-4cf6-b015-902da62f1b2e-2021-08-24T023000.000Z,482,PubMed:31892712 +Hashikami Mouse Model,Model Systems Non-human model organism,"Hashikami K, et al., 2019, PMID: 30582011","Resulting mice were fertile and crossed. Females were not examined in this study. By 26 weeks, mutant males started dying, with 72.2% dead by 30 weeks. Urinary ALB levels shows a tendency to increase, hematuria was observed after 22 weeks, mice had decreased TP and increased BUN and CRE levels with aging. 6 week old mutant male mice showed focal irregularity of GBM and occasional foot process effacement. At 22 weeks, mice showed marked thickening with matrix lamination in GBM and mesangial matrices were increased.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0407dc2e-1cab-4043-889d-4695b043d7b3-2019-03-19T160000.000Z,483,PubMed:30582011 +COL5A2 variant in Holstein cattle,Model Systems Non-human model organism,"Jacinto JGP, et al., 2020, PMID: 33143196","The Holstein calf and its dam, described in the paper, met one of the major clinical criterion for diagnosis of EDS in humans (skin hyperextensibility and atrophic scarring), and the calf also met a minor criterion (skin fragility/traumatic splitting). The calf and its dam did not meet the second major criterion for diagnosis of classic EDS in human - joint hypermobility. Whole exome sequencing revealed a heterozygous missense variant in COL5A2 (c.2366G>T; p.Gly789Val) that was present only in the calf and its dam. This variant alters a glycine in the triplet repeat sequence Gly-X-Y, which is critical to collagen triple helix folding and stability. Similar variants, altering a glycine residue in the triple helix domain, are commonly seen in various types of collagen in patients with connective tissue disorders, including in COL5A2. The inheritance pattern for COL5A2 variants in EDS in humans, and in this dam-calf, is autosomal dominant.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1901d495-d33f-4741-88fd-4b66ac43bbad-2021-03-24T184245.711Z,485,PubMed:33143196 +col6a1 zebrafish knockdown,Model Systems Non-human model organism,"Telfer WR, et al., 2010, PMID: 20338942","Injection of morpholino to zebrafish exon 9 of col6a1 resulted in an in-frame deletion in the N-terminal part of the triple helical domain, paralleling the dominant mutations in UCMD. As would be predicted, this morpholino caused a severe myopathy with early-onset development motor deficits and severe ultrastructural changes. Additionally, observed mitochondrial swelling and increased apoptosis, consistent with the changes observed in patients with UCMD. Antibody labeling of exon 9 morphant embryos, gave an abnormal pattern of staining which was diminished overall but found in small clumps scattered throughout the myofiber compartment. Such a pattern is consistent with staining previously reported for some UCMD patients with dominant mutations.",Score,3 (2),"In addition to strong zebrafish model of UCMD. Injection of morpholino to exon 13 resulted in an in-frame deletion in the C-terminal part of the triple helical domain, paralleling a typical dominant BM mutation. This morpholino resulted in a mild myopathy with late-onset motor deficits and obvious histopathologic abnormalities.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_95ee3b63-8083-49e2-9e20-a1006ac168dd-2022-09-26T160000.000Z,486,PubMed:20338942 +COL6A1 Spontaneous Canine Model,Model Systems Non-human model organism,"Steffen F, et al., 2015, PMID: 26438297","This naturally occurring model of Collagen VI-related myopathy is remarkably similar to the severe spectrum of disorder observed in human, the canines recapitulate the most important phenotypes observed in humans such as progressive muscle weakness, contractures, non-ambulation, and the muscular signs on biopsy including fiber size variation and degeneration, necrosis, and endomysial tissue infiltration into the muscle fibers.",Score,1 (2),"While a strong phenotypic recapitulation is observed, this biallelic null model is not consistent with the dominant negative mechanism observed in human dominant disease.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_95ee3b63-8083-49e2-9e20-a1006ac168dd-2022-09-26T160000.000Z,486,PubMed:26438297 +COL6A1 Hypomorphic Mice,Model Systems Non-human model organism,"Noguchi S, et al., 2017, PMID: 28043812","COL6A1 gt/gt mice were generated, becoming a hypomorphic model with very little viable COL6A1 mRNA or protein. The Col6a1GT/GT mice develop non-progressive weakness from younger age, accompanied by stunted muscle growth. There are several phenotypes that are recapitulated from the human disorder, including the histological phenotypes (fiber-size variation and skeletal muscle fibrosis) and general muscle weakness/decreased size due to reduced number of myofibers, resulting to an overall decrease in muscle size.",Score,1 (2),"Although these mice do recapitulate the core phenotypes observed in the human probands, including histological abnormalities and weakness/decreased muscle size, they do not display a comparably severe phenotype to those observed in human with biallelic null variants. Additionally, the dominant negative mechanism of disease observed in patients with dominant disease is not consistent with these mice. Mice heterozygous at the genomic level of the knockin allele were indistinguishable with wild type control.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_95ee3b63-8083-49e2-9e20-a1006ac168dd-2022-09-26T160000.000Z,486,PubMed:28043812 +altered stiffness,Functional Alteration Non-patient cells,"Urciuolo A, et al., 2013, PMID: 23743995","When investigated in WT murine muscle, Collagen VI was confirmed to be present in quiescent muscle satellite cells and decreased in activated cells. Collagen VI expression is markedly increased during the initial phases of regeneration when injured, suggesting a role in regeneration. COL6A1 -/- mice were also subject to injury with significantly decreased numbers of satellite cells observed correlating with decreased regeneration and defective self-renewal, indicating a role in SC function and maintenance. To verify the exact role of collagen VI in SCs, both in vitro and in vivo COL6A1 null cells were observed when exposed to purified Collagen VI. The survival and regeneration observed in both was significantly increased when the collagen VI was restored, indicating a reliance on this protein for proper activity. Mechanistically collagen VI is also important structurally via regulating muscle stiffness, as SCs grown in WT stiffness muscle were dramatically increased to those grown in the loose null muscle (<8% of the WT). To establish that the function could be restored if proper Collagen VI was provided, null mice were injected with fibroblasts from hindlimb muscle into TA muscle. After a few days of injection, fibroblasts were diffuse and the collagen VI localized in the endomysium. These muscles showed an increase in satellite cells production and and an improved response to injury when treated with the wild-type fibroblasts.",Score,0.5 (0.5),"Showed that the extracellular matrix protein collagen VI is a key component of the satellite cell niche. Lack of collagen VI in Col6a1–/– mice causes impaired muscle regeneration and reduced satellite cell self-renewal capability after injury. The findings indicate that i) Col6a1–/– muscles display a distinct increase of elasticity; and that ii) this lower stiffness is associated with a significant loss of in vitro and in vivo self-renewal capability of wild-type SCs, pointing to altered stiffness as one key mechanism underlying in vivo SC defects in collagen VI deficient muscles. When collagen VI is reinstated in vivo by grafting wild-type fibroblasts, the biomechanical properties of Col6a1–/– muscles are ameliorated and satellite cell defects rescued.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9de84294-8404-4bd0-a7c6-89a9a70eb408-2022-09-26T160000.000Z,487,PubMed:23743995 +COL6A1 Spontaneous Canine Model,Model Systems Non-human model organism,"Steffen F, et al., 2015, PMID: 26438297","This naturally occurring model of Collagen VI-related myopathy is remarkably similar to the severe spectrum of disorder observed in human, the canines recapitulate the most important phenotypes observed in humans such as progressive muscle weakness, contractures, non-ambulation, and the muscular signs on biopsy including fiber size variation and degeneration, necrosis, and endomysial tissue infiltration into the muscle fibers.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9de84294-8404-4bd0-a7c6-89a9a70eb408-2022-09-26T160000.000Z,487,PubMed:26438297 +COL6A1 Hypomorphic Mice,Model Systems Non-human model organism,"Noguchi S, et al., 2017, PMID: 28043812","COL6A1 gt/gt mice were generated, becoming a hypomorphic model with very little viable COL6A1 mRNA or protein. The Col6a1GT/GT mice develop non-progressive weakness from younger age, accompanied by stunted muscle growth. There are several phenotypes that are recapitulated from the human disorder, including the histological phenotypes (fiber-size variation and skeletal muscle fibrosis) and general muscle weakness/decreased size due to reduced number of myofibers, resulting to an overall decrease in muscle size.",Score,1.5 (2),"Although these mice do recapitulate the core phenotypes observed in the human probands, including histological abnormalities and weakness/decreased muscle size, they do not display a comparably severe phenotype to those observed in human with biallelic null variants.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9de84294-8404-4bd0-a7c6-89a9a70eb408-2022-09-26T160000.000Z,487,PubMed:28043812 +Col6A2 KO mouse,Model Systems Non-human model organism,"Meehan TF, et al., 2017, PMID: 28650483",Mice displayed decreased grip strength consistent with the muscle weakness observed in patients.,Score,0.25 (2),"Col6A KO mice were not well described, only a decreased grip strength was noted as such full recapitulation of human disease cannot be confirmed. Additionally, the mechanism of disease here (homozygous knockout) does not match the dominant negative mechanism being evaluated in this curation.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a7a4dad5-f179-44ac-adcb-c5e15c11a1ec-2022-06-27T160000.000Z,488,PubMed:28650483 +Col6A2 KO mouse,Model Systems Non-human model organism,"Meehan TF, et al., 2017, PMID: 28650483",Mice displayed decreased grip strength consistent with the muscle weakness observed in patients.,Score,1 (2),"Col6A KO mice were not well described, only a decreased grip strength was noted as such full recapitulation of human disease cannot be confirmed.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c523dbfa-e08e-4bdc-82d4-6bf43480697c-2022-06-27T160000.000Z,489,PubMed:28650483 +Zebrafish Model,Model Systems Non-human model organism,"Telfer WR, et al., 2010, PMID: 20338942","Demonstrated that the severe morpholino-dependent phenotypes are specific for alterations in collagen VI and not due to non-specific, off-target effects. Both zebrafish and humans exhibit motor deficiencies and myopathic changes. Morpholino knockdown of exon 9 in col6a3 caused a severe phenotype with both significant motor deficiencies and widespread morphologic changes (data not shown). The average number of spontaneous coils per 15 s for col6a3 morphants was 2.6 (+0.6, n ¼ 40) as compared to 7.9 (+1.2, n ¼ 21) for controls (P , 0.0001).",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_37d30e5c-61f5-4e4a-9ee7-573a2ed704b3-2022-06-27T160000.000Z,490,PubMed:20338942 +Mia3/TANGO1 KO mice,Model Systems Non-human model organism,"Wilson DG, et al., 2011, PMID: 21606205","The knockout of this protein causeddefects in several collagens including Col IX, however this cannot be scored as a knockout for COL9A2 because it is too far removed. COL9A2 is a subunit of Col IX.",Review,0 (2),"do not score this, Mia3 is too far removed from COL9A2 even if they are functionally connected.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_697ae26e-2b07-4f87-b42c-121684c89bc0-2019-02-19T170000.000Z,494,PubMed:21606205 +Zebrafish COL9A2 expression,Expression A,"Mitchell RE, et al., 2013, PMID: 23159952","The expression of COL9A2 in the otic capsule implicates its ability to cause hearing loss associated with Stickler syndrome. Additionally, it was expressed in the ventral jaw which implicates its association with the facial structural changes as well as the bone malformations also associated with Stickler syndrome. This study used in situ hybridization to identify expression.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_697ae26e-2b07-4f87-b42c-121684c89bc0-2019-02-19T170000.000Z,494,PubMed:23159952 +Mouse otic COL9A2 expression,Expression A,"Hartman BH, et al., 2015, PMID: 25852475","Using whole mount in-situ hybridization as well as immunohistochemistry, E10.5 otic vesicles were found to contain COL9A2 expression. This tissue is further developed into the ear and therefore can be counted as ear expression. Given the hearing loss phenotype in patients with Stickler syndrome, this can be counted as 0.5 for expression.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_697ae26e-2b07-4f87-b42c-121684c89bc0-2019-02-19T170000.000Z,494,PubMed:25852475 +Knockin D469del mouse,Model Systems Non-human model organism,"Suleman F, et al., 2012, PMID: 22006726",The heterozygous knock-in mutant mice recapitulated phenotypes seen in patients with pseudoachondroplasia including short-limbed dwarfism and skeletal abnormalities.,Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_630905e9-0f42-452b-81fa-7fad4eae08f9-2020-02-07T180000.000Z,496,PubMed:22006726 +THP-1 COPG1-deficiency experiment,Functional Alteration Non-patient cells,"Steiner A, et al., 2022, PMID: 35484149","Like COPA and COPD, cGAS/STING pathway is activated upon deletion of COPG1, inducing inflammatory signalling. +Supplementary Fig9 - COPG1-deficiency results in a break in cGAS signalling upon stimulation with HT-DNA and +poly (dA:dT), but IFNλ release following STING stimulation with c-di-AM(PS)2 remains comparable to control cells or higher - Further highlights the essential rolde of intact retrograde transport for functional cellular defence in response to foreign DNA. +Fig6a - Immunoblotting for confirmation of COPG1 deletion efficiency. COPG1 deletion also led to spontaneous phosphorylation of STAT1. +Fig6c - qRT-PCR analysis of baseline inflammatory cytokine transcripts in COPG1- and COPG2-depleted THP-1 cells. The COPG1-deficient cells showed a significant increase of inflammatory cytokines when compared to the parental cells.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7d3aaced-2415-425a-b2c7-b59c7a687a2c-2024-01-18T180000.000Z,497,PubMed:35484149 +HeLa COPG1-deficient cells,Model Systems Cell culture model,"Steiner A, et al., 2022, PMID: 35484149","As observed in patients, COPG1 is essential for retrograde trafficking between Golgi and the ER. There is an accumulation of KDEL in Golgi due to defective retrograde trafficking.",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7d3aaced-2415-425a-b2c7-b59c7a687a2c-2024-01-18T180000.000Z,497,PubMed:35484149 +Rescue in COQ2 patient cells,Rescue Patient cells,"Desbats MA, et al., 2015, PMID: 25564041","Complex II+III activity was assayed in fibroblasts from a patient homozygous for the p.Met132Arg variant and from an unaffected control. The activity of this complex is sensitive to CoQ10 availability, and was assayed as a proxy for CoQ10 synthesis rates. When normalized against citrate synthase activity, complex II+III activity was decreased by ~55% in patient fibroblasts (Fig. 2D). However, when wt COQ2 was re-introduced using a lentiviral vector, complex II+III activity was restored to wt levels. Further, two different isoforms were tested for their ability to rescue, each one using a different transcription start site (labeled ""ATG3"" and ""ATG4""; see Fig. 1). Both constructs were able to rescue with equivalent efficiency (Fig. 3D).",Score,0.5 (1),"The assay performed primarily measures secondary, downstream effects of loss of COQ2 function, and is not as thorough as it could be. Therefore, the score has been downgraded",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0b91e278-c030-40b2-b135-c558fcc49531-2023-01-30T170000.000Z,498,PubMed:25564041 +COQ2 Mitochondrial Expression,Expression A,"Desbats MA, et al., 2015, PMID: 25564041","5' RACE experiments using mRNA from human kidney, muscle, and fibroblasts detected COQ2 transcripts. Further, GFP-tagged COQ2 was expressed in HeLa cells, and was found to overlap completely with a mitochondrial marker (Fig. 1D). Finally, the results of a proteinase K protection assay were consistent with COQ2 being imported into the inner mitochondrial membrane. These experiments demonstrate the mitochondrial localization of this nuclearly-encoded protein",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0b91e278-c030-40b2-b135-c558fcc49531-2023-01-30T170000.000Z,498,PubMed:25564041 +homozygous KO mouse,Model Systems Non-human model organism,"Perez-Garcia V, et al., 2018, PMID: 29539633","Mice homozygous for a knock-out allele exhibit defects in chorion formation and placentation, abnormal trophoblast layer morphology, and complete lethality throughout fetal growth and development. Consistent with critical role of gene in early development.",Score,0.5 (2),"embryonic lethality is consistent with critical role of gene in early development, potentially lack of observations of biallelic null variants",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7d59cb98-0dd9-4707-8464-876eee053467-2023-01-30T170000.000Z,499,PubMed:29539633 +COQ9 mouse model Q95X,Model Systems Non-human model organism,"Luna-Sánchez M, et al., 2015, PMID: 25802402",Both the COQ9 Q95X mouse model and Leigh syndrome patients demonstrate OXPHOS dysfunction.,Score,0.5 (2),This mouse model recapitulates a biochemical abnormalities reported in Leigh syndrome. (Awarded 0.5 pts as per scoring rubric),https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_cebc5501-5d36-4767-98bc-edc4ddab3527-2021-04-09T140634.407Z,503,PubMed:25802402 +Ptcd mouse,Model Systems Non-human model organism,"Shiow LR, et al., 2008, PMID: 18836449","Irradiated wild-type mice that had been reconstituted with Ptcd bone marrow cells had an accumulation of mature thymocytes and low circulating T cells (Fig. 1b). +Transwell migration assays: +Ptcd mature CD4 SP thymocytes were less efficient at migrating towards S1P (despite S1P1 being expressed at normal amounts) than cells from control heterozygous littermates (Fig. 1d). +CD4+ T SP and DB T cells migrated less efficiently to chemokines CCL21 and CXCL12. Migration of Ptcd naïve splenic T cells was impaired in response to CCL21, while B cells migrated normally (Fig. 1f). +CONCLUSION: T cells in Ptcd mice have a general, cell-intrinsic migration defect that impairs S1P1 responsiveness and blocks thymic egress. +Fig2 a and b - Transfer of Ptcd and control T cells into WT mice. After one hour, accumulation of Ptcd in blood and low proportion in lymph nodes. After 24h, low proportion of Ptcd in lymph (higher proportion in lymph nodes) +CONCLUSION: Impaired trafficking through the lymph nodes. Also, slower migration rate. +Fig5 b - Annexin V staining (apoptosis) - comparing WT, KO and Ptcd - higher proportion of annexin V staining in mature and naive CD4+ thymocytes in KO mice. Ptcd only had higher proportion of annexin V in naive T cells. +Fig5 c - actin accumulation - KO mouse shows actin accumulation in mature and naive CD4 T cells and Ptcd shows accumulation of actin only in naive CD4 T cells. +Fig 6e - Ptcd mutation enhances Arp2/3 inhibition - co-immuniprecipitation with Arp2/3 is stronger with Ptcd protein than WT protein. +CONCLUSION: Highly conserved Glu26 residue in Coro1A is important for regulation of Arp2/3",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_f55fde93-1b6e-4d03-b737-ecad8aa89ecf-2022-06-03T160000.000Z,504,PubMed:18836449 +Viscomi 2011 ACTA-Cox15 -/- mouse,Model Systems Non-human model organism,"Viscomi C, et al., 2011, PMID: 21723506","ACTA-Cox15 -/- mice: muscle specific KO (human skeletal muscle-specific a-actin (ACTA1) promoter), trace COX15 in heart, mosaic . +Smaller than WT littermates at 30 days after birth +Significantly reduced motor performance (measured at 4, 6, 12 and 16 weeks) by a standard treadmill. +Histochemical analysis showed marked COX deficiency and compensatory proliferation of aberrant mitochondria (Fig 3) +PMID: 26039449: Civiletto G, et al., 2015",Score,1 (2),"Recapitulation of reduced lifespan, motor delay, muscle weakness and wasting, complex IV deficiency and abnormal mitochondrial morphology. Further characterization in PMID: 26039449: Civiletto G, et al., 2015, 2 pts for model shared across two PMIDs.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_2f825de2-a93c-4f96-b1e5-7b2843c668ee-2023-12-04T050000.000Z,508,PubMed:21723506 +Civiletto 2015 ACTA-Cox15 -/- mouse,Model Systems Non-human model organism,"Civiletto G, et al., 2015, PMID: 26039449","Further characteristaion of ACTA-Cox15 -/- mice: +Muscle weakness and reduced motor performance replicated (Fig2A). +Reduced lifespan (Fig 2B). +Histology staining showed hypotrophic and dystrophic muscle fibres (reduced muscle fibre area, Fig3A) +EM showed muscle mitochondria with disorganized cristae and vacuolar degeneration of the inner mitochondrial compartment (Fig4A). +Spectrophotometric assays confirmed significant decrease in complex IV activity, complex I-III comparable to controls (Fig 5B)",Score,1 (2),"Recapitulation of reduced lifespan, motor delay, muscle weakness and wasting, complexIV deficiency and abnormal mitochondrial morphology. Further characterisation of this model in PMID: 21723506: Viscomi C, et al., 2011. 2pts shared across two PMIDs.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_2f825de2-a93c-4f96-b1e5-7b2843c668ee-2023-12-04T050000.000Z,508,PubMed:26039449 +COX15 muscle specific knockout mouse,Model Systems Non-human model organism,"Viscomi C, et al., 2011, PMID: 21723506",Model system demonstrated biochemical abnormalities consistent with Leigh spectrum syndrome (reduced COX activity) along with developmental abnormalities (smaller than WT littermates and exercise induced fatigue).,Score,1.5 (2),"Utilized model scoring system developed for Leigh spectrum syndrome experimental evidence. (0.5/1 pts for biochemical abnormalities, 1/1 pts for neurocognitive/developmental differences)",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b5c8d1e1-24d0-4b88-8c04-023197db14f3-2019-05-20T183321.284Z,509,PubMed:21723506 +COX15 muscle specific knockout mouse (Civiletto),Model Systems Non-human model organism,"Civiletto G, et al., 2015, PMID: 26039449",Model system demonstrated biochemical abnormalities consistent with Leigh syndrome (reduced Complex IV holoenzyme). This models additional neurocognitive/developmental phenotype and additional biochemical findings consistent with Leigh spectrum syndrome were previously curated and scored under Viscomi et al.,Score,0.5 (2),Utilized model scoring system developed for Leigh spectrum syndrome experimental evidence. (0.5/1pt) for biochemical abnormalities. This models additional neurocognitive/developmental phenotype and additional biochemical findings consistent with Leigh spectrum syndrome were previously curated and scored under Viscomi et al.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b5c8d1e1-24d0-4b88-8c04-023197db14f3-2019-05-20T183321.284Z,509,PubMed:26039449 +Review of Complex IV,Protein Interaction,"Sinkler CA, et al., 2017, PMID: 28593021","The largest of the nuclear-encoded subunits, COX subunit IV, is located adjacent to the catalytic subunits, containing numerous contact sites with subunits I +and II . This location allows the subunit to play a major role in regulation of overall COX activity. +Responsible for modulating COX activity through allosteric regulation—ATP and ADP are capable of binding to COX through subunit IV, resulting in fine-tuned control of respiration.",Score,1.5 (0.5),"27977873: Rahman 2017 (LeighMa)p: COX8A, NDUFA4 complex IV subunits and SURF1, SCO2, COX10, COX15, PET100 complex IV assembly units are associated with LSS. +Scored according to rubric: 6-9 gene products",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d56c1fe4-7711-45f4-992c-7e9586b9efc6-2021-04-09T135824.042Z,511,PubMed:28593021 +IMPC KO mouse,Model Systems Non-human model organism,"Cacheiro P, et al., 2019, PMID: 31127358","Cox4i1tm1.1(KOMP)Vlcg: Reporter-tagged deletion allele (post Cre, with no selection cassette)(https://www.mousephenotype.org/data/genes/MGI:88473) +The homozygous mouse is noted to be embryonic lethal prior to organogenesis (E9.5). +The heterozygous KO mouse is noted to have abnormal midbrain and hindbrain development and abnormal neural closure.",Score,0.5 (2),0.5pts for embryonic lethality.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d56c1fe4-7711-45f4-992c-7e9586b9efc6-2021-04-09T135824.042Z,511,PubMed:31127358 +Rahman 1,Biochemical Function A,"Rahman J, et al., 2017, PMID: 27977873","COX8A is one of the four subunits of Complex IV. COX8A interacts two other gene products whose dysfunction is known to cause Leigh syndrome as part of the Compex IV subunit. +NDUFA4 and MT-CO3",Score,1 (0.5),Score increased in accordance with internal guidelines,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_70763eb9-40f7-4f71-a64b-ab0c6ad536b0-2021-04-09T135510.592Z,513,PubMed:27977873 +Cheong Expression Experiment,Expression A,"Cheong SS, et al., 2016, PMID: 27839872","Researchers analyzed the expression of the following two isoforms; CPAMD8-1a and CPAMD8-1b through RT-PCR. CPAMD8-1a expression was detected in the developing human lens and retina at week 9 of gestation; was expressed into the second trimester. Expression of CPAMD8-1a also detected in the iris and cornea at week 22 of gestation. Found differential temporal expression of CPAMD8-1a in the lens and retina, with increasing levels of expression in the lens from week 9 to week 22 of gestation and decreasing levels of expression in the retina. CPAMD8-1b showed the same expression pattern as CPAMD8-1a",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_bc4d2b2a-08d6-4869-a56e-55721fd4c9dc-2022-11-18T170000.000Z,516,PubMed:27839872 +Hollman Expression Experiment,Expression A,"Hollmann AK, et al., 2017, PMID: 28683140","Through the use of immunohistochemistry, the researchers detected CPAMD8 in the epithelium of the ciliary body in fetal and adult cattle +Interestingly, western blotting found that CPAMD8 was detectable in normal fetal and normal adult but not adult cataractous lenses",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_bc4d2b2a-08d6-4869-a56e-55721fd4c9dc-2022-11-18T170000.000Z,516,PubMed:28683140 +Xenopus KO Rescue,Rescue Non-human model organism,"Toriyama M, et al., 2016, PMID: 27158779","Full length WT-Jbts17 rescued the neural tube defects, ciliogenesis defects, and the loss of IFT-A basal body recruitment resulting from MO-based knockdown.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_954cdc22-7834-4876-a64e-27d56615c1ff-2022-05-20T114241.088Z,517,PubMed:27158779 +Mouse model with heterozygous disruption of Cpox,Model Systems Non-human model organism,"Conway AJ, et al., 2017, PMID: 28600349","Although the mice match the mode of inheritance from the human patients, the biochemical defect in the form of elevated urinary and fecal porphyrins (especially the ratio of coproporphyrinogen III to coproporphyrinogen I) was specifically observed in female mice but not in males. The human condition is similarly more likely to be symptomatic in females, with triggers including the menstrual cycle. The biochemical phenotype of urinary and fecal porphyrin accumulation (especially copropporphyrinogen III) is a very good match, although urinary porphobilinogen levels were normal (Figure 3), which does not match and suggested absence of a trigger. Phenobarbital treatment (but not starvation) is a shared trigger (of the biochemical phenotype) between mice and humans. Starvation did not work because Cpox expression in the mouse liver was adjusted to compensate (Figure 4). The mice have microcytic anemia as well (Table 1). Interestingly, the homozygous mice showed embryonic lethality.",Score,1.5 (2),"The metabolic phenotype is a good match, as well as the mode of inheritance, the greater severity of the biallelic phenotype, and the ability to be triggered by heme pathway-activating medication.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_f7cfd579-9ded-4e8a-b8be-c1a6e573e28b-2023-01-27T170000.000Z,518,PubMed:28600349 +Cradd Knockout Mice,Model Systems Non-human model organism,"Di Donato N, et al., 2016, PMID: 27773430",Phenotype observed in mice was consistent with thin-lissencephaly phenotype (megalencephaly and seizures without changes in cortical thickness or lamination),Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7f64ee7f-13a7-4a2d-b1a2-ad6c9e63cab3-2021-06-16T180000.000Z,525,PubMed:27773430 +Reduced Neuronal Apoptosis,Functional Alteration Non-patient cells,"Di Donato N, et al., 2016, PMID: 27773430","CRADD variants unable to activate caspase-2, resulting in reduced neuronal apoptosis",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7f64ee7f-13a7-4a2d-b1a2-ad6c9e63cab3-2021-06-16T180000.000Z,525,PubMed:27773430 +Redig knockout mouse,Model Systems Non-human model organism,"Redig JK, et al., 2014, PMID: 25328912","Knock-out CRELD1 mice presented fewer cells and less extracellular matrices in the atrioventricular endocardial cushions than wild-type mice. +Creld1 knockout mouse model combined with increased VEGFA showed abnormal morphogenic response to VEGFA in Creld1-deficient embryonic hearts, indicating that interaction between CRELD1 and VEGFA has the potential to alter atrioventricular canal morphogenesis  +Complete knockout of Creld1 resulted in embryonic lethality, while heterozygotes were phenotypically normal but displays biochemical abnormalities that predispose the developing heart to an aberrant response to increased VEGFA signaling. +CRELD1 plays a role in regulating VEGFA and that CRELD1 haploinsufficiency alone causes dysregulation of VEGFA",Score,1 (2),Genotype does not match human patients,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1aa67af6-c8df-4151-98ab-049b69fefd08-2023-09-05T160000.000Z,529,PubMed:25328912 +Yoshimura_Expression,Expression A,"Yoshimura H, et al., 2014, PMID: 24676347","Investigation of differential expression of many genes in the mouse cochlea between apical, middle, and basal turns revealed that CRYM expression was higher in the apex than in the base.",Score,0.25 (0.5),0.25 points given because no explanation of relevance to CRYM hearing loss is provided,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d15cf48a-3696-467a-b3c8-a45ef5a577bf-2021-09-21T160000.000Z,534,PubMed:24676347 +Hosoya_Expression,Expression A,"Hosoya M, et al., 2016, PMID: 26915689",CRYM expression was detected in the marmoset. Expression was broader than in mice- was detected in both inner and outer hair cells and supporting cells. This suggests that mice may not be a good model for CRYM deafness.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d15cf48a-3696-467a-b3c8-a45ef5a577bf-2021-09-21T160000.000Z,534,PubMed:26915689 +Disruption of Csde1 in Drosophila NMJ,Model Systems Non-human model organism,"Guo H, et al., 2019, PMID: 31579823","In the Drosophila model, we found that disruption of dUnr led to impaired NMJ synapse growth, as indicated by increased total synaptic and satellite bouton number. These morphological abnormalities were accompanied by defect synapse endocytosis and impairment in synaptic function. Presynaptic KD of dUnr mimicked these phenotypes, and synaptic overgrowth +could be suppressed by coexpression of dUnr and hCSDE1. Our results argue that dUnr and hCSDE1 play an important role in synapse development and function.",Score,1 (2),Downgraded for being a non-mammalian model.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7061e9de-d429-4d92-a8fa-e386016ab9db-2023-11-21T070000.000Z,535,PubMed:31579823 +Csde1 knockdown in primary mouse cortical neurons,Model Systems Cell culture model,"Guo H, et al., 2019, PMID: 31579823",Csde1 deficiency consistently suppresses excitatory and inhibitory synaptic transmission in cultured neurons.,Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7061e9de-d429-4d92-a8fa-e386016ab9db-2023-11-21T070000.000Z,535,PubMed:31579823 +Skin fibroblast alteration - non-patient cells,Functional Alteration Non-patient cells,"Dominguez I, et al., 2021, PMID: 33944995","CK2α mutant cells transfected with variants seen in patients (R47G, Y50F, F197I, E27K, P231R, R47Q, S51R, R80H, R191Q, V73E, D175G, I174M, K198R, R312W) demonstrated decreased serine/threonine kinase activity compared to WT cells.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_007e16ed-7392-4050-88b1-2b2158ca2a28-2022-06-15T060000.000Z,537,PubMed:33944995 +Skin fibroblast alteration,Functional Alteration Patient cells,"Dominguez I, et al., 2021, PMID: 33944995","Skin fibroblast cell lines produced from three patients (R47G, K198R, and D156E). The K198R variant showed a significantly reduced percentage of cells with fibers and significantly different morphology of the fibers and was mislocalized to the nucleus. Additional variants show decreased protein kinase CK2α activity and CK2α localization/morphology alterations.",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_007e16ed-7392-4050-88b1-2b2158ca2a28-2022-06-15T060000.000Z,537,PubMed:33944995 +shRNA knockdown,Functional Alteration Non-patient cells,"Yang CP, et al., 2018, PMID: 29483533","Mouse neural stem cells (NSCs) (derived from embryonic day 14.5) were transfected with small hairpin RNAs (shRNAs) targeting CSNK2B. Experiments used two shRNAs and a scramble shRNA control. Knockdown cells showed an increased rate of proliferation while protein markers of differentiation (fig 3) and proteins regulating differentiation were significantly reduced compared to controls (fig 4 and 5). +Knockdown of CSNK2B in primary hippocampal neurons altered neuron morphology: the dendritic length, number of dendrites, and branch points were significantly reduced in neurons after shRNA treatment compared with controls, (Fig. 5). +Patch clamp electrophysiology recording demonstrated that knockdown of CSNK2B in primary hippocampal neurons alters synaptic transmission, the frequency of miniature excitatory postsynaptic currents (mEPSC) was increased in the knockdown cells and the amplitude and frequency of the miniature inhibitory postsynaptic currents (mIPSC) was increased (Fig. 6).",Score,0.5 (0.5),The experiments point to CSNK2B having important roles in neurodevelopment through regulating the proliferation and differentiation of NSCs. CSNK2B may also be involved in regulating dendritic morphology and modulating synaptic transmission which could be consistent with the ID phenotype.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_64552de0-3f81-4110-90f7-97de14b0387b-2022-04-08T050921.681Z,538,PubMed:29483533 +CSPP1 in ciliary compartment / module,Protein Interaction,"Patzke S, et al., 2010, PMID: 20519441",RPGRIP1L (NPHP8) has been shown to be associated with Joubert Syndrome upon loss-of-function. CSPP requires common C-terminal domain to interact with Nephrocystin 8 (NPHP8/RPGRIP1L) and to form a ternary complex with NPHP8 and NPHP4.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e24d1591-91b7-4c2f-bd79-d4dc8be0974d-2021-06-23T160000.000Z,539,PubMed:20519441 +"Ehsan et al., knock-in mouse model",Model Systems Non-human model organism,"Ehsan M, et al., 2018, PMID: 30048712","KI/KI mice developed HCM phenotype with diastolic and systolic LV dysfunction and increased heart weight measurements (Fig. 1); RNA-seq showed pro-fibrotic signaling, induction of fetal gene programme, and activation of markers of hypertrophic signaling - also validated by ex vivo analyses (Fig. 2); MLP was reduced by 80% in KI/KI mice and 50% in KI/+ mice (Fig. 3)",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_012b9b15-798a-46e2-8164-61a829ceeda1-2023-08-09T160000.000Z,541,PubMed:30048712 +"Li et al., CSRP3 knock-out hESC cell line",Model Systems Cell culture model,"Li X, et al., 2019, PMID: 31406109","MLP protein deficiency (Fig. 1D); phenotypic features of HCM - enlarged cell size, multinucleation, disorganized sarcomeric ultrastructure (Fig. 2); progressed to exhibit feature of heart failure by 30 days post-differentiation with mitochondrial damage, increased ROS generation, and impaired Ca2+ handling (Fig. 3), 5; restoration of Ca2+ homeostasis shown to prevent HCM and heart failure features - suggesting elevated intracellular Ca2+ is part of mechanism of pathogenicity in MLP protein deficiency (Fig. 7)",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_012b9b15-798a-46e2-8164-61a829ceeda1-2023-08-09T160000.000Z,541,PubMed:31406109 +Chandra_Ctnnbl1-/- mouse,Model Systems Non-human model organism,"Chandra A, et al., 2013, PMID: 23343763","Homozygous Ctnnbl1-/- mice were not viable as determined by interbreeding different lines of mice, indicating that germline deficiency of Ctnnbl1 is embryonic lethal. B-cell specific knock-out of Ctnnbl1 revealed that although Ctnnbl1 is essential for embryonic development, it is dispensable for the generation and maturation of B cells. However, Ctnnbl1-deficient B cells showed reduced immunoglobulin class switching. +Comparison of switching to IgG1 in splenic B cells revealed that the Ctnnbl1-deficient B cells gave roughly one-third less switching. This reduced switching did not correlate with any change in the abundance of AID. Similar results regarding diminished class switching were obtained using B cells stimulated with anti-CD40 and IL4 as well with regard to switching to IgG3",Score,1 (2),A reduced score is awarded as the mouse model recapitulates the B-cell phenotype observed in the human patient of reduced class switch recombination.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_4e151724-c8a5-4f3e-a7ac-bd0b1d180fae-2022-05-17T160000.000Z,551,PubMed:23343763 +Expression-level evidence: Human embryos,Expression A,"Alharatani R, et al., 2020, PMID: 32196547","At human Carnegie stage 13, there was high embryonic mRNA CTNND1 expression in the cephalic region at the pharyngeal areas, and limb buds. Expression was specifically strong surrounding the nasal region and maxillary and mandibular areas. At this time, there was also high expression in the growing heart, frontonasal area, the trigeminal ganglion, and the tenth cranial nerve. Additionally, there was high expression in the brain within the rhombomeres, forebrain, and midbrain. +At human Carnegie day 21, there was high embryonic expression in the muscular area of the tongue: the superior longitudinal, the transversal muscles of tongue, and the extrinsic genioglossus muscle. At this time, there was also high CTNND1 mRNA expression in the epithelium of the developing tooth bud. Additionally, there was high CTNND1 expression in the dorsal epithelium of the palatal shelf and the tongue’s epithelium.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5000144a-71c1-4ae7-95a9-17ad67a388c5-2024-03-21T160000.000Z,552,PubMed:32196547 +Xenopus Model,Model Systems Non-human model organism,"Alharatani R, et al., 2020, PMID: 32196547",The fact that the mutants had small craniofacial cartilages and reduced survival falls in line with the craniofacial phenotype seen in humans. The abnormal heart looping seen in the mice falls in line with the ventricular and atrial septal defects seen in a few affected human probands.,Score,1 (2),Downgrading as the phenotype is not super specific to the craniofacial features seen in humans.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5000144a-71c1-4ae7-95a9-17ad67a388c5-2024-03-21T160000.000Z,552,PubMed:32196547 +Mouse model,Model Systems Non-human model organism,"Alharatani R, et al., 2020, PMID: 32196547",The cleft palate and brain structural anomalies seen in the mice reflect anomalies seen in affected humans.,Score,1 (2),"The heterozygous mutants had no cleft lip/palate, or facial/arm/leg anomalies, so the score is downgraded.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5000144a-71c1-4ae7-95a9-17ad67a388c5-2024-03-21T160000.000Z,552,PubMed:32196547 +Zebrafish p.Q236X knock in,Model Systems Non-human model organism,"Elmonem MA, et al., 2017, PMID: 28198397","zebrafish larvae show early cystine accumulation, with highest concentration in adult zebrafish kidney. Model is characterized by impaired glomerular permselectivity and defective tubular reabsorption, and podocytes present partial foot process effacement and narrowed slit diaphragmatic space",Score,3 (2),Recapitulation of all human renal phenotype processes,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_51c40c8e-b9e5-4f2e-a587-f75b029397af-2022-03-02T170000.000Z,553,PubMed:28198397 +CUL3WT/D403–459 mice recapitulate PHAII imbalances due to ov,Model Systems Non-human model organism,"Schumacher FR, et al., 2015, PMID: 26286618",CUL3WT/D403–459 mice recapitulate the PHAII imbalances due to over-activation of the renal WNK4-SPAK pathway.,Score,4 (2),"CUL3WT/D403–459 mice recapitulate the PHAII imbalances due to over-activation of the renal WNK4-SPAK pathway. The WNK4 E3 ubiquitin ligases containing the cullin-3 protein tag proteins called WNK1 and WNK4 with ubiquitin. These proteins are involved in controlling blood pressure in the body. By regulating the amount of WNK1 and WNK4 available, cullin-3 plays a role in blood pressure control. The mice show interaction with the WNK4-SPAK pathway as well as it is over-activated in the presence of the CUL3WT/D403–459 mice.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_f697fb5e-72de-4116-9cad-706e2d651268-2021-12-01T013000.000Z,558,PubMed:26286618 +Representative immunohistochemical staining of KLHL3 and CUL,Expression A,"Schumacher FR, et al., 2015, PMID: 26286618","Healthy Adult Kidney single cell expression (Wu and Uchimura et al, Cell Stem Cell 2018) shows normal expression of CUL3 in disease tissue.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_f697fb5e-72de-4116-9cad-706e2d651268-2021-12-01T013000.000Z,558,PubMed:26286618 +CUL3D403–459 is unable to ubiquitylate WNK1 or WNK4 kinases,Protein Interaction,"Schumacher FR, et al., 2015, PMID: 26286618","WNK1 has already been curated as definitive for PHA2. In normal settings, E3 ubiquitin ligases containing the cullin-3 protein tag proteins called WNK1 and WNK4 with ubiquitin. These proteins are involved in controlling blood pressure in the body. By regulating the amount of WNK1 and WNK4 available, cullin-3 plays a role in blood pressure control. In this experiment, CUL3D403–459 is unable to ubiquitylate WNK1 or WNK4 kinases in an in vitro system and the deficiency was found to not be able to be rescued by the presence of CUL3-WT.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_f697fb5e-72de-4116-9cad-706e2d651268-2021-12-01T013000.000Z,558,PubMed:26286618 +CUL3-KLHL15 complex interacts and regulates CtIP,Protein Interaction,"Ferretti LP, et al., 2016, PMID: 27561354","Using CtIP as a bait protein, only two proteins, CUL3 and KLHL15, were identified with multiple peptides in two independent mass spectrometry analyses. To confirm that CtIP and CUL3-KLHL15 form a complex, the authors performed an immunoprecipitation experiment and found that endogenous KLHL15 and CUL3 efficiently co-precipitated with GFP-tagged CtIP. Along with other experiments, the authors showed that CUL3-KLHL15 specifically interacts with CtIP and controls its protein turnover.",Score,0.5 (0.5),"Pathogenic variants in the KLHL15 gene have been associated with X-linked Mental retardation 103 (OMIM #300982). Two additional OMIM disease genes, LZTR1 and RHOBTB2, also support the disease association through protein interaction. The study of Abe T et al. (PMID: 31337872) and Wilkins A et al. (PMID: 15107402) detailed above support direct protein interactions of CUL3 with LZTR1 and RHOBTB2, respectively. A total of 0.5 points were awarded for the supporting evidence from the three publications.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_fb529ace-86b5-4209-9974-9c07a1c32956-2021-01-16T030942.670Z,559,PubMed:27561354 +enzymatic activity of cyp1b1 variants in human kidney cells,Model Systems Cell culture model,"Campos-Mollo E, et al., 2009, PMID: 19234632",Patients carrying two null alleles showed severe phenotypes featured by very early PCG onset usually at birth or in the first month of life (0.6+/-0.9 months). Incomplete penetrance was detected in patients carrying hypomorphic alleles.,Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_107502fc-115b-4ee0-ba83-7081a17d1ebc-2023-01-19T170000.000Z,567,PubMed:19234632 +Involvement of CYP1B1 in MYOC upregulation,Protein Interaction,"Mookherjee S, et al., 2012, PMID: 23028769","Mutations in CYP1B1 have also been reported in primary open angle glaucoma (POAG) cases and suggested to act as a modifier of the disease along with Myocilin (MYOC). Over-expression of MYOC leads to POAG pathogenesis. The study shows a functional interaction between CYP1B1 and myocilin where 17β estradiol acts as a mediator. 17β estradiol can induce MYOC expression through the putative estrogen responsive elements (EREs) located in its promoter and CYP1B1 manipulates MYOC expression by metabolizing 17β estradiol to 4-hydroxy estradiol, thus preventing it from binding to MYOC promoter. Hence any mutation in CYP1B1 that reduces its 17β estradiol metabolizing activity might lead to MYOC upregulation, which in turn might play a role in glaucoma pathogenesis.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_107502fc-115b-4ee0-ba83-7081a17d1ebc-2023-01-19T170000.000Z,567,PubMed:23028769 +Cyp2u1-/- mouse model,Model Systems Non-human model organism,"Pujol C, et al., 2021, PMID: 34546337","Macular degeneration / vision impairment is a common phenotype in people with CYP2U1 variants. +Additionally, intellectual disability has been reported in approximately 50% of cases. +Mouse model did not recapitulate any of the locomotor phenotypes that are the predominant phenotype in humans. This lack of locomotor phenotype has also been observed in other HSP mouse models (Fink, 2013).",Score,1 (2),"GCEP elected to reduce to 1 as the model is a knock out and does not recapitulate what is happening with respect to human genetic variants (i.e., truncated proteins or missense). This may be why the phenotype is not recapitulated in the model.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e2d550d2-5653-45dc-a8a3-2dccf4bb49f6-2023-01-16T020000.000Z,569,PubMed:34546337 +BCD patient-specific iPSC-RPE cells,Functional Alteration Patient cells,"Hata M, et al., 2018, PMID: 29581279","degenerative changes, such as vacuole formation, larger cell size, and pronounced pigmentation changes, were observed by phase-contrast microscopy in all lines of BCD iPSC-RPE cells. +CYP4V2 WT protein level increased only in BCD iPSC-RPE cells infected with CYP4V2 WT, and the CYP4V2 mut1 protein level increased only in those infected with CYP4V2 mut1.",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_da577a4b-5c65-43fa-9a03-b275eaacb6eb-2021-04-01T160000.000Z,570,PubMed:29581279 +Mouse ESC,Model Systems Cell culture model,"Inácio JM, et al., 2021, PMID: 33928078",Differences in cardiac differentiation could have a role in heterotaxy-related congenital heart disease,Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_af4ba5de-8e77-4d22-bd42-691451f37472-2024-06-10T160000.000Z,571,PubMed:33928078 +RSPO2 mutant,Biochemical Function B,"Lee H, et al., 2024, PMID: 38307837",Left-right patterning abnormalities consistent with human heterotaxy,Score,0.25 (0.5),Abnormal heart looping in Rspo2 mutant but Dand5 only studied in relation to Left-Right organizer and not heart,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_af4ba5de-8e77-4d22-bd42-691451f37472-2024-06-10T160000.000Z,571,PubMed:38307837 +Mice over-expressing DAO p.Arg299Trp,Model Systems Non-human model organism,"Kondori NR, et al., 2017, PMID: 29194436",Motor neuron degeneration,Score,1 (2),"Does not fully recapitulate mechanism or phenotype. Marked overexpression of p.Arg199Trp compared to WT (therefore not mimicking heterozygous state in humans). Of note, this variant was previously identified in family with ALS. Survival in mice is not impacted, unlike human ALS. However, motor neuron degeneration is observed in mice. While a mutation can cause a lethal disease in humans, no overt ALS phenotype was evident in mice expressing DAO p.Arg199Trp. However, marked structural and abnormal motor features were evident which were associated with a significant loss of lumbar motor neurons.Therefore, points awarded, but decreased from default.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_35ac00ac-3279-4c7e-89b6-8a75e3cae414-2022-04-12T103808.867Z,572,PubMed:29194436 +review paper,Biochemical Function A,"Diodato D, et al., 2014, PMID: 24639874","Aminoacyl-tRNA synthetases (aaRSs) are key enzymes in the translation of the genetic information. In fact, they catalyze the specific attachment of each of the 20 amino acids (aa) to a cognate tRNA, through a two-step reaction, where they first activate the amino acid with ATP, forming an intermediate aminoacyl-adenylate, and then transfer the aminoacyl group to the 3'-end of its own tRNA. There are 19 mt-aaRSs, which are enoded by nuclear genes, imported into mitochondria, and their interaction with cognate tRNAs seems to be essential for their amount and stability. Biallelic variants in 16 of these genes (table 1) have been associated with human disease including: AARS2 (OMIM#612035, OMIM#614096, 615889), CARS2 (OMIM#612800, OMIM#616672), DARS2 (OMIM#610956, OMIM#611105), EARS2 (OMIM#612799, OMIM#614924), FARS2 (OMIM#611592, OMIM#614946, 617046), GARS (OMIM# 600287, OMIM#600794), HARS2 (OMIM#600783, OMIM#614926), KARS (OMIM#60142, OMIM#613641), LARS2 (OMIM#604544, OMIM#617021, 615 300), MARS2 (OMIM#609728, OMIM#616430, 611 390), NARS2 (OMIM#612803, OMIM#616239), RARS2 (OMIM#611524, OMIM#611523), SARS2 (OMIM#612804, OMIM#613845), TARS2 (OMIM#612805, OMIM#615918) VARS2 (OMIM#611390, OMIM#615917), YARS2 (OMIM#610957, OMIM#613561).",Score,2 (0.5),>10 products with gene disease association. Can score at 2 points as per LSS scoring rubric.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c3fc3cd8-48aa-4e02-8324-b3412fcfa64f-2022-05-04T160000.000Z,573,PubMed:24639874 +rescue of oxidative growth in yeast,Rescue Non-human model organism,"Stellingwerff MD, et al., 2021, PMID: 33977142","""The functional consequences of 10 missense variants on mitochondrial metabolism in yeast using the DARS2 orthologous gene MSD1, in which a wild-type residue has been substituted with the corresponding one found in patients. Six missense variants affecting conserved residues (Leu250, Phe484, Ala262, Arg179, Ser597, and Lys606 corresponding to yLeu232, yPhe487, yAla244, yArg157,ySer617, and yLys626, respectively), the yeast MSD1 codons were directly mutated, producing the pathologic allele. For the 4 variants affecting nonconserved residues located in an otherwise conserved stretch (Arg58, Phe157, Val481, and Leu588 corresponding to yLys42, yAla136, yIle484, and yMet608, respectively), the yeast amino acid was replaced by the human wild-type mtAspRS amino acid to serve as humanized control. Subsequently, the variants were introduced at these amino acids and results obtained with these yeast strains were compared with their humanized controls. The yeast mutant alleles and the humanized controls were +expressed in a yeast strain deleted of MSD1 (Δmsd1) that failed to grow in medium containing oxidative carbon sources. The ability to grow in the presence of respiratory substrates (ethanol) at 28°C was first analyzed (data not shown). The humanized MSD1 alleles (msd1Lys42Arg, msd1Ile484Val, and msd1Met608Leu) rescued the absence of MSD1. By contrast, the oxidative growth of both the humanized +msd1Ala136Phe allele and the corresponding mutant msd1Phe136Ile was compromised and therefore not further assessed. The oxidative growth ability of the strains expressing the msd1Leu232Val, msd1Phe487Leu, msd1Arg157Cys, msd1Ser617Gly, and msd1Leu608Val variants was severely affected, whereas the msd1Ala244Val variant led to a mild reduction of growth (fig 4). The growth of the strains expressing msd1Arg42Gly, msd1Lys626Met, and msd1Val484Met was similar to that of wild type. However, incubation at 37°C revealed a severe growth defect for the msd1Val484Met strain, indicating that a change in this position affects mitochondrial function in yeast in a temperature sensitive manner. +""",Score,1 (2),Reduced points as yeast is used as a model organism,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c3fc3cd8-48aa-4e02-8324-b3412fcfa64f-2022-05-04T160000.000Z,573,PubMed:33977142 +Yeast two hybrid analysis: ODA16 and IFT46,Protein Interaction,"Ahmed NT, et al., 2008, PMID: 18852297",ODAs are actively transported into cilia via the intraflagellar transport (IFT) system and the transport adaptor ODA16. IFT46 is a core component of the intraflagellar transport machinery and is required for the formation of all cilia. Knockdown of IFT46 causes shortening of the body axis as well as the formation of fewer and shorter cilia (PMID: 33628615). IFT46 and ODA16 are thought to interact to transport ODAs via the IFT.,Score,0.25 (0.5),Downscored because IFT46 has not been directly implicated in PCD,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_8610990f-63cf-466a-8cd7-fbf7ae58d0f2-2024-06-13T160000.000Z,574,PubMed:18852297 +Mouse Model,Model Systems Non-human model organism,"Homanics GE, et al., 2006, PMID: 16579849",All phenotypes listed are consistent with the human disease. The authors used a transgenic strategy to rescue the BCAA elevation and neonatal lethality by expressing human E2 in the liver which resulted in mice with the intermediate form of MSUD.,Score,2 (2),"Gene targeting in mouse ES cells to disrupt the E2 gene. The construct was designed to replace a 1.67kb genomic DNA fragment encompassing part of exon 4 and all of exon 5 with a selectable marker cassette. Targeted ES cells were used to produce chimeric mice who were bred to C57BL/6J mice. Heterozygous mice were used to produce homozygous animals. E2 protein was undetectable in liver and embryonic fibroblasts. Absent BCKDH activity in liver homogenates, reduced blood levels of alanine, glutamate, and glutamine.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_cfd1ebde-e447-4877-977e-f5b9fe434adc-2018-10-30T160000.000Z,576,PubMed:16579849 +Friedrich 2012 Zebrafish Model,Model Systems Non-human model organism,"Friedrich T, et al., 2012, PMID: 22046030",Elevated BCAA's is a hallmark of MSUD patients.,Score,1 (2),"A mutagenesis screen identified a strain, que, which exhibit a progressive locomotor defect. The authors used a positional cloning technique to identify a single base pair substitution in the splice donor site of exon 6. RT-PCR on RNA from homozygous mutants revealed an altered transcript. The entire 86 base pairs of intron 6 were included, which alters the sequence downstream of Lys268 and has 4 stop codons. Non-mammalian model",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_cfd1ebde-e447-4877-977e-f5b9fe434adc-2018-10-30T160000.000Z,576,PubMed:22046030 +Function,Biochemical Function B,"Blackburn PR, et al., 2017, PMID: 28919799","Disruption of any subunit of the BCKAD complex leads to an increase and BCAAs, causing toxicity of tissues.",Score,1 (0.5),"Well-known disease mechanism. Review: MSUD is caused by decreased function of the BCKAD enzyme complex, which is composed of E1, E2 (encoded by DBT) and E3 subunits. The BCKAD complex is involved in the second step of catabolism of branched-chain amino acids (BCAAs), which are essential for life.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_cfd1ebde-e447-4877-977e-f5b9fe434adc-2018-10-30T160000.000Z,576,PubMed:28919799 +DCAF17 KO mice,Model Systems Non-human model organism,"Ali A, et al., 2018, PMID: 29907856",Reproduces part of human male phenotype: mimicks gonadal disease,Score,0.5 (2),Reproduces only part of human phenotype.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6a1d7719-4261-494d-87aa-745518580673-2021-07-27T153526.827Z,577,PubMed:29907856 +Zebarfish morpholino,Rescue Non-human model organism,"Durst R, et al., 2015, PMID: 26258302",By whole organism imaging,Score,1 (2),"Downgraded for morpholino technology rather than germline mutants, as well as lack of direct correlation with mitral valve phenotype",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ff470254-615c-4f86-8893-0431889c1472-2024-04-02T160000.000Z,581,PubMed:26258302 +Expression in developing valve,Expression A,"Moore KS, et al., 2022, PMID: 35200715",Mouse valve expression at embryonic day 15.5,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ff470254-615c-4f86-8893-0431889c1472-2024-04-02T160000.000Z,581,PubMed:35200715 +Cardiac fibroblast model,Biochemical Function B,"Moore KS, et al., 2022, PMID: 35200715",Abnormal mitral valve formation could contribute to congenital heart disease,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ff470254-615c-4f86-8893-0431889c1472-2024-04-02T160000.000Z,581,PubMed:35200715 +Null mouse,Model Systems Non-human model organism,"Moore KS, et al., 2022, PMID: 35200715",Lack of DCHS1 disrupts leads to abnormal anterior leaflet,Score,1 (2),Null mouse model whereas human genes associated with non-congenital mitral valve disorders are generally autosomal dominant,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ff470254-615c-4f86-8893-0431889c1472-2024-04-02T160000.000Z,581,PubMed:35200715 +"Expression in human, mouse and chick development",Expression A,"Zhu W, et al., 2023, PMID: 37147909",Single cell expression,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ff470254-615c-4f86-8893-0431889c1472-2024-04-02T160000.000Z,581,PubMed:37147909 +V(D)J recombination,Functional Alteration Patient cells,"Nicolas N, et al., 1998, PMID: 9705945","Analyzed the V(D)J recombination activity in fibroblasts from T−B− RS SCID patients; the DNA-repair phase of the V(D)J recombination was analyzed by transient transfection of RAG1, RAG2, and an extrachromosomal substrate into fibroblasts. Two substrates were used, pHRecCJ, in which the LacZ gene is interrupted by a DNA stuffer flanked by two RSS, and pHRecSJ, in which the two RSS sequences were inverted. The ratio of blue colonies to white colonies is therefore indicative of the capacity of the cells to fully accomplish V(D)J recombination. The coding joint formation was found to be profoundly affected in all cases with recombination frequencies <0.08 × 10−3.",Score,1 (1),These results clearly establish that the DNA repair machinery necessary for the completion of the V(D)J recombination is profoundly impaired in T−B− SCID with increased cell radiosensitivity.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_603e0855-2b57-4463-a9b7-1c5d70089a4f-2021-02-18T154301.245Z,582,PubMed:9705945 +Generation of the dnc-1-depleted C. elegans model,Model Systems Non-human model organism,"Ikenaka K, et al., 2013, PMID: 23408943","The results showed that the knockdown of dnc-1 caused progressive motor deficits in C. elegans, and the pathological changes observed in the model shared several features with those seen in SALS patients, e.g., the axonal accumulation of membranous structures, such as mitochondria and autophagosomes, and motor neuron degeneration characterized by axonal degeneration including axonal spheroids. They also observed the disrupted transport of autophagosomes in the degenerated motor neurons of this model. The model exhibited adult-onset motor neuron degeneration even though the shRNA::gfp had already expressed in the larval stage.",Score,0.5 (2),Reduced score as C. elegans is not a typical ALS model and clinical features of disease largely cannot be captured. GCEP chose to reduce further to 0.5.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5cd19f2c-2499-417f-94c8-2bd4bedf34ef-2023-08-04T160000.000Z,583,PubMed:23408943 +Depletion of p150 in mice neurons,Model Systems Non-human model organism,"Yu J, et al., 2018, PMID: 29490687","The loss of SMN with a late onset, loss of motor control, muscle atrophy, and gliosis are all features commonly observed in patients with ALS.",Score,1 (2),No differences of cerebral spinal motor neurons. Lack of clinical similarity to ALS (eg. lifespan),https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5cd19f2c-2499-417f-94c8-2bd4bedf34ef-2023-08-04T160000.000Z,583,PubMed:29490687 +Rescue of DCTN1 (dynactin1a) KD in zebrafish,Rescue Non-human model organism,"Bercier V, et al., 2019, PMID: 31291987","At 6dpf the human protein was able to rescue the CaP morphological phenotype in mok m632−/− larvae, as mutant CaPs had larger, more complex axonal arbors than wild-type CaPs, based on total cell length and number of projections, while maintaining average projection length. +Touch evoked espace responses of 2dpf mok m632−/− and mok m632−/+ embryos injected with Dynactin1-GFP were of similar duration and distance while being significantly different from uninjected mok m632−/−, demonstrating rescuing of locomotor behaviours.",Score,0.5 (2),"As described in the ""Data Knock-down of DCTN1 (dynactin1a) in zebrafish"" evidence, the defects of the model system were considered milder than other ALS zebrafish models and there is also concern about the phenotypes being present in embryos rather than adult zebrafish. However, the phenotypes were rescued with human DCTN1, so a reduced score was given.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5cd19f2c-2499-417f-94c8-2bd4bedf34ef-2023-08-04T160000.000Z,583,PubMed:31291987 +Knock-down of DCTN1 (dynactin1a) in zebrafish,Model Systems Non-human model organism,"Bercier V, et al., 2019, PMID: 31291987","Observed locomotion deficits, while statistically significant, were less severe than what has been described in previous ALS models. In patients, impairment of NMJ function is reported to arise before the onset of motor neuron degeneration and clinical symptoms in early ALS, which the authors say is consistent with their observation of synapse instability and slight locomotion deficits in the 2dpf before the CaP MN morphological changes and loss of NMJ structure in 6dpf. +NMJs had variable amplitudes and higher rate of response failure to action potentials, which were similar to FUS loss of function ALS models.",Score,0 (2),"The authors suggest that their results do not show that DCTN1 variants would be causative of ALS, rather a potential risk factor. They instead propose their results show a novel role of DCTN1 in stabilizing the neuromuscular synapses and impairing function, but we do know these pathways have roles in ALS. Yet the defects they reported are milder than previous established zebrafish models of ALS. +There is also concern that the results are only shown in zebrafish embryos/larvae. Therefore it is unclear if these are showing issues with neurodevelopment, rather than representing neurodegeneration.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5cd19f2c-2499-417f-94c8-2bd4bedf34ef-2023-08-04T160000.000Z,583,PubMed:31291987 +Effects of DCTN1 G59S on TDP-43 aggregation,Functional Alteration Non-patient cells,"Deshimaru M, et al., 2021, PMID: 33924373","DCTN1G59S and DCTN1F52L (Perry syndrome) mutants induced TDP-43 cytoplasmic aggregation only at low levels, but caused significant levels of TDP-43 nuclear aggregation. Quantitative analysis revealed that DCTN1F52L, but not DCTN1G59S, induced significant mislocalization of TDP-43 into the cytoplasm. DCTN1G59S induced statistically significant levels of aggregation of itself and TDP-43 in the nucleus and cytoplasm.",Score,0.25 (0.5),"Although the variant induced aggregation of DNCT1 and TDP-43, functional implications remain unclear. It also did not induce cytoplasmic aggregation",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5cd19f2c-2499-417f-94c8-2bd4bedf34ef-2023-08-04T160000.000Z,583,PubMed:33924373 +DCTN1 interacts with TDP-43,Protein Interaction,"Deshimaru M, et al., 2021, PMID: 33924373","Coimmunoprecipitation of Dctn1 and Tdp-43 in murine brains was performed. An anti-DCTN1 antibody was used to immunoprecipitate Dctn1 from the brain cell lysates, and an anti-TDP-43 antibody was used to detect Tdp-43 in the immunoprecipitates through Western blotting, and interaction was observed in vivo. +Coimmunoprecipitation of tagged DCTN1 and TDP-43 was also performed in monkey fibroblast COS-7 cells, and again reciprocal coimmunoprecipitation was observed. +Serially truncating DCTN1-myc and transfecting into COS-7 cells with full length TDP43 determined that DCTN1 interacted with TDP-43 via not only the CAP-Gly-basic domain but also via the dynactin domain, CC2 domain-containing region, and extreme C-terminal region, indicating the multivalency of DCTN1-TDP-43 interactions. A similar experiment revealed that the C-terminal region of TDP-43 preferentially contributes to the DCTN1 interaction.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5cd19f2c-2499-417f-94c8-2bd4bedf34ef-2023-08-04T160000.000Z,583,PubMed:33924373 +Review of evidence for DDC function,Biochemical Function B,"Montioli R, et al., 2021, PMID: 33808712","DDC encodes aromatic amino acid decarboxylase (AADC), also known as dopa decarboxylase, an enzyme that catalyzes the decarboxylation of L-Dopa to dopamine, and L-5- hydroxytryptophan to serotonin, and which requires pyridoxal phosphate (PLP) as a cofactor and functions as a homodimer. +The function of the gene is consistent with the biochemical and clinical features observed in individuals with AADC deficiency. Biochemical findings in CSF include low levels of 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) (due to low levels of their precursors i.e. serotonin and dopamine respectively), and elevated concentrations of L-Dopa (a substrate of DCC), L-5-hydroxytryptophan (L-5HTP, also a substrate of DCC), and 3-O-methylDopa (product of dopamine). As expected, low levels of dopamine and serotonin in human patients result in neurological features including dystonia, movement disorder, and oculogyric crises and autonomic dysfunction.",Score,2 (0.5),"This paper provides a a detailed review of the many studies which have elucidated the function of DDC (AADC), and the role of this enzyme in the biochemical and clinical features of individuals with DDC (AADC) deficiency. A primary research article was also curated (PMID 12718431).",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1dea33e3-7cf6-47f9-aa52-2525b439031a-2022-02-25T170000.000Z,586,PubMed:33808712 +Gene therapy in patients with AADC deficiency,Rescue Human,"Tai CH, et al., 2022, PMID: 34763085","This paper reports the combined results of a long-term follow-up from the three human AADC gene (rAAV2-hAADC, eladocagene exuparvovec) gene therapy trials; 26 patients who had received intraputaminal infusion of rAAV2-hAADC had been evaluated at 1 year, and eleven of them had been followed >5 years. Rapid improvements in motor and cognitive function occurred within 12 months after gene therapy and were sustained during follow-up for >5 years. An increase in dopamine production was demonstrated by positron emission tomography and neurotransmitter analysis. Patient symptoms (mood, sweating, temperature, and oculogyric crises), patient growth, and patient caretaker quality of life improved. A younger age was associated with greater improvement.",Score,3 (2),"A relatively large (n=26) number of patients treated by gene therapy, showing both clinical improvement and increase in dopamine (the product of the deficient enzyme, AADC).",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1dea33e3-7cf6-47f9-aa52-2525b439031a-2022-02-25T170000.000Z,586,PubMed:34763085 +Ddhd1 KO mouse model,Model Systems Non-human model organism,"Morikawa T, et al., 2021, PMID: 33600578","Spastic paraplegia patients have common phenotype of gait disturbance. The aged Ddhd1 KO mice showed significant decrease in foot-base angle, indicating abnormal locomotion.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0ba9bbb1-e36f-41db-9e56-23496613e46d-2022-12-01T200000.000Z,587,PubMed:33600578 +Decr Knockout Mice,Model Systems Non-human model organism,"Miinalainen IJ, et al., 2009, PMID: 19578400","No human disease has been genetically linked to variation in DECR1. The authors note that ""a common feature of individuals affected with inborn errors of mitochondrial fatty acid oxidation is that they are asymptomatic under normal conditions. The same phenomenon is observed in several animal models of fatty acid oxidation disorders. Clinical symptoms arise only after metabolic stress, such as prolonged physical exercise or fasting, which is often associated with infectious illness."" +The phenotypes observed in the homozygous Decr1 knockout mice supports the possibility that a clinical phenotype in humans may only occur in individuals experiencing acute metabolic stress. +A severe form of DECR deficiency has previously been reported in a patient with identified homozygous nonsense variants in the NADK2 gene (Houten et al.) Houten et al. suggested that the severe phenotype observed in the proband likely resulted from impairment of multiple mitochondrial NADP-dependent processes.",Score,0 (2),Unable to score. There are no genetically confirmed human phenotypes to compare the mouse model to.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1d25dfe8-8d0b-4b45-b04c-b315ebdceaaa-2021-01-25T194921.121Z,592,PubMed:19578400 +Li Protein Interaction,Protein Interaction,"Li D, et al., 2013, PMID: 23325789","Many binding partners of DIAPH1 were identified, including ACTB and ACTG1, several tubulins, and OSBPL2, a moderate hearing loss gene",Score,0.5 (0.5),"No connection made to hearing loss, but supports role in regulation of microfilament/microtubule function, which are important in hair cells. Downgraded to 0.25, however scoring for this model is combined with Carreira 2003 study to equal 0.5 points.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_43c017fd-ce70-4fbe-ad30-90f216adaa7d-2018-01-05T170000.000Z,598,PubMed:23325789 +Ueyama Non-patient cells,Functional Alteration Non-patient cells,"Ueyama T, et al., 2016, PMID: 27707755",MDCK cells transfected with WT and R1213* mutant DIAPH1 with mCherry tag. R1213* induced microvilli elongation and congestion. Same results in HeLa cells.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_43c017fd-ce70-4fbe-ad30-90f216adaa7d-2018-01-05T170000.000Z,598,PubMed:27707755 +Ueyama Animal Model,Model Systems Non-human model organism,"Ueyama T, et al., 2016, PMID: 27707755","Dia1-null mice were generated- no hearing loss. Heterozygous R1213* mice were then generated, and mouse showed elevated ABR thresholds by 10 weeks, and HL progressively deteriorated. SEM of mutant mouse cochlea showed loss of OHCs beginning at 10 weeks. Loss of OHCs and IHCs at all turns was significant by 25 weeks. Homozygous R1213* mice had more pronounced hearing impairment at all frequencies along with exacerbated hair cell loss",Score,2 (2),LOF is likely not a mechanism of disease,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_43c017fd-ce70-4fbe-ad30-90f216adaa7d-2018-01-05T170000.000Z,598,PubMed:27707755 +Animal Model 2,Model Systems Non-human model organism,"Schoen CJ, et al., 2013, PMID: 23441200","Two mouse lines were generated by inserting a human cytomegalovirus promoter enhancer along with the Diap3 coding sequence in order to overexpress Diap3, modeling the results of the human studies in Schoen 2010. Two mouse lines were successful, and each had a progressive hearing loss with onset at either 4-8 or 16 weeks of age. By 24 weeks HL had progressed to severe at 12 and 24 kHz. Hearing was determined to be caused by inner, and not outer hair cell dysfunction, consistent with auditory neuropathy. This was based on preserved otoacoustic emissions even after progression to severe HL, indicative of preserved OHCs, and a decrease in IHC ribbons over time in Diap3-overexpressing mice. Comparison of morphological features of whole mount stereocilia showed sparseness and variable length in transgenic mice compared to WT.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_fc54aaf6-8e1b-4c98-bcbe-e1f337f6eadc-2020-02-06T170000.000Z,599,PubMed:23441200 +Expression,Expression A,"Schoen CJ, et al., 2013, PMID: 23441200","Diap3 expression was detected in mouse cochlea in addition to cortex, liver, and heart tissue. Expression in the cochlea of transgenic mice described below was found to be 700-1100x higher than in WT controls",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_fc54aaf6-8e1b-4c98-bcbe-e1f337f6eadc-2020-02-06T170000.000Z,599,PubMed:23441200 +miRNA microarray analysis,Functional Alteration Patient cells,"Pugh TJ, et al., 2014, PMID: 24909177",Microarray analysis of multiple tumours showed reduced 5p-derived miRNAs indicating skewed miRNA processing. Direct sequencing of miRNA in tumour and culture derived cells derived from a patient (case 14 in this study) showed decreased 5p miRNAs.,Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_aeabfc3b-63a9-40f2-9c71-41b079fee4e2-2023-07-05T170000.000Z,600,PubMed:24909177 +DICER KO MSC rescue,Rescue Cell culture model,"JnBaptiste CK, et al., 2017, PMID: 28446596","miRNA expression was rescued and the endogenous targets of the miRNA, mRNA, expression pattern correlated with previous reported changes. doxorubicin-induced sensitivity (culminating in cell death) was also returned to wildtype levels. Some specific miRNA target mRNAs remained activated, authors explain as a 'stable state transformation' induced by DICER1 deletion.",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_aeabfc3b-63a9-40f2-9c71-41b079fee4e2-2023-07-05T170000.000Z,600,PubMed:28446596 +Dis3l2 LOF recapitulates Perlman syndrome in mice,Model Systems Non-human model organism,"Hunter RW, et al., 2018, PMID: 29950491","Consistent with the hypotonia commonly reported in Perlman syndrome, Dis3l2Δ11/Δ11 animals exhibited bradykinesia and abnormal curvature of the lumbar spine (Fig. 2B, arrowheads), a characteristic of neuromotor defects. Also consistent with Perlman syndrome, highly penetrant GU abnormalities, including hydroureter, hydronephrosis, and prematurely filled bladders, were present in knockout mice (Fig. 2C; Supplemental Table S2) Dis3l2Δ10/Δ10 mice, which mimic deletion of human DIS3L2 exon 9, also displayed the same phenotypes (Fig. 3).",Score,2 (2),"Although absence of overgrowth or kidney neoplasms, default points are still given because three mouse lines were investigated, including Dis3l2Δ10/Δ10 mice which mimic deletion of human DIS3L2 exon 9. It is not surprising that Wilms tumors did not develop in the Dis3l2 mutant mice because it has been shown that, in mouse models, Wilms tumor arises only if Igf2 up-regulation is on the background of additional mutations, such as in Wt1 (Hu et al. 2011; Huang et al. 2016). The absence of overgrowth phenotype in these mutants could be because of species- and tissue-specific promoter usage, which needs to be investigated separately.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e68b93df-e0e7-4d46-8934-8b86064c0b37-2019-11-21T193052.781Z,601,PubMed:29950491 +Pyruvate dehydrogenase complex,Biochemical Function A,"Rahman J, et al., 2017, PMID: 27977873","DLAT shares biochemical function with PDHA1, PDHB, DLD and PDHX, all of which are part of the pyruvate dehydrogenase complex and associated with similar phenotype.",Score,1 (0.5),Points increased based on scoring guide.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_78e45dbe-ea30-434d-9522-aa1731b9a764-2021-01-14T212056.234Z,605,PubMed:27977873 +Mouse model-MGI:6262286,Model Systems Non-human model organism,"Bult CJ, et al., 2019, PMID: 30407599",The DLAT mouse model presents with preweaning lethality and complete penetrance. Embryonic lethality suggests that DLAT is essential for embryonic development.,Score,0.5 (2),This model does not recaptulate the phenotype observed in patients and points were awarded for embryonic lethality.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_78e45dbe-ea30-434d-9522-aa1731b9a764-2021-01-14T212056.234Z,605,PubMed:30407599 +Mouse model knockout,Model Systems Non-human model organism,"Jiang-Xie LF, et al., 2014, PMID: 25071926",Social behaviors can be used to approximate human behaviors in autism spectrum disorders,Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_efeafdd5-9105-470f-b332-8c7a3dd65078-2021-10-14T160000.000Z,610,PubMed:25071926 +Recessive mouse Dnaaf1 mutation as PCD model,Model Systems Non-human model organism,"Ha S, et al., 2016, PMID: 27261005","Mice homozygous for a recessive Dnaaf1 splicing mutation exhibit phenotypes consistent with those seen in PCD patients carrying DNAAF1 mutations. Phenotypes in common include severe respiratory infection and laterality defects. Both these phenotypes are consistent with cases of ciliary defect or dysfunction. In humans, TEM analysis shows the absence of both inner and outer dynein arms in DNAAF1 PCD patients. Unfortunately this analysis was not done for these mice. High-resolution immunofluorescence microscopy in control and DNAAF1 mutant respiratory cells from PCD patients, using specific antibodies directed against various dynein-arm components showed a loss of the ODA heavy chains DNAH5 and DNAH9 and the ODA intermediate chain DNAI2 from the ciliary axonemes, indicating that loss of DNAAF1 affects the assembly of proximally (type 1) and distally (type 2) located ODA complexes in respiratory cells. DNALI1, an IDA component, was also absent from all mutant ciliary axonemes and instead accumulated in the cytoplasm. These data are consistent with DNAAF1 assisting in the cytoplasmic assembly/transport of axonemal dyneins. In mutant mice, immunofluorescent studies showed normal localization of DNAH9, a result that the authors of this study did not really explain. While not noted by the authors, in Figure 6 Dnaaf1 mice appear to have lower levels of DNAH9 than wild type and there appears to be accumulation of DNAH9 in the cytoplasm.",Score,1.5 (2),Down-scored 0.5 because of missing or ambiguous data on axonemal ultrastructure and localization of dyneins.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_41e4b8cd-35bd-4e99-ba2d-606f191a13cf-2023-03-09T170000.000Z,613,PubMed:27261005 +DNAAF1 interacts with RUVBL1 and RUVBL2,Protein Interaction,"Hartill VL, et al., 2018, PMID: 29228333","PCD can arise from mutations in genes encoding any of an array of cytoplasmic proteins collectively known as dynein axonemal assembly factors, DNAAFs, that help pre-assemble axonemal dynein motors in the cytoplasm before deployment to cilia (PMID: 32943623). An interaction of DNAAF1 with a RUVBL1-RUVBL2 complex is consistent with a model where DNAAF1 is part of a larger cytoplasmic multi-protein complex that assembles inner and outer dynein arm components. The AAA+ ATPases RUVBL1 and RUVBL are thought to form a scaffold for complex protein-protein interactions. The structure and ATPase activity of RUVBL1-RUVBL2 can be affected and regulated by the interaction with different proteins (PMID: 33129013). While RUVBL1 and RUVBL2 have not been directly associated with human PCD, they have been associated with dysfunction of motile cilia in zebrafish and mice (PMIDs: 23858445, 29959317).",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_41e4b8cd-35bd-4e99-ba2d-606f191a13cf-2023-03-09T170000.000Z,613,PubMed:29228333 +"Horani, et al. 2013",Functional Alteration Non-patient cells,"Horani A, et al., 2013, PMID: 23527195","Consistent with the axonemal defect observed in affected subjects, ultrastructural analyses of cilia from silenced airway epithelial cells had truncated or absent dynein arms",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7063ef1e-8ce2-4f35-a765-f08efc2e541a-2023-06-08T160000.000Z,614,PubMed:23527195 +Cho et al. 2018,Protein Interaction,"Cho KJ, et al., 2018, PMID: 29601588",The stability of LRRC6 was increased upon co-expression of ZMYND10.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7063ef1e-8ce2-4f35-a765-f08efc2e541a-2023-06-08T160000.000Z,614,PubMed:29601588 +Omran et al. 2008 Chlamydomonas,Model Systems Non-human model organism,"Omran H, et al., 2008, PMID: 19052621",One of the recurring phenotypes of PCD in human patients is ODA and IDA defects. This experiment with Chlamydomonas demonstrates loss of motility (paralyzed flagella) as well as recurrence of the partial ODA and IDA loss.,Score,1 (2),Downscored due to the model being unable to display the respiratory phenotypes like humans,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_39e5de96-3f16-4dde-a7bc-b3e27364b7f8-2024-02-08T170000.000Z,615,PubMed:19052621 +Omran et al. 2008 Medaka,Model Systems Non-human model organism,"Omran H, et al., 2008, PMID: 19052621","The phenotypes presented by the medaka showed a lot of similarities to the ones displayed by the human probands. For example, the medaka phenotype of situs inversus totalis matches with the human phenotype of situs inversus totalis. The medeka phenotype of male infertility matches with the human phenotypes of female and male infertility. While the medeka had immotile ciliopathy and absent ODA/IDA, the humans had immotile cilia and cilia with ODA/IDA defects.",Score,1.5 (2),Downscored because the fish lacks the ability to display respiratory phenotypes,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_39e5de96-3f16-4dde-a7bc-b3e27364b7f8-2024-02-08T170000.000Z,615,PubMed:19052621 +Omran et al. 2008,Rescue Non-human model organism,"Omran H, et al., 2008, PMID: 19052621","Gene identity was confirmed by rescuing the mutant phenotype with wild-type genomic clones (Supplementary Table S5), and by the absence of the gene product in mutant cells (Supplementary Fig. S4f).",Score,1.5 (2),Because the model cannot display multiciliary phenotypes.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_39e5de96-3f16-4dde-a7bc-b3e27364b7f8-2024-02-08T170000.000Z,615,PubMed:19052621 +Aprea et al. 2021,Biochemical Function B,"Aprea I, et al., 2021, PMID: 33635866","The deletion of DNAAF2 affected the formation of cilia, movement and length which is consistent with PCD phenotypes.",Score,0 (0.5),This was downscored to 0 because there wasn’t an appropriate figure available to cite as evidence.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_39e5de96-3f16-4dde-a7bc-b3e27364b7f8-2024-02-08T170000.000Z,615,PubMed:33635866 +Structural defects in respiratory cilia from DNAAF3 patients,Functional Alteration Patient cells,"Mitchison HM, et al., 2012, PMID: 22387996","Transmission electron microscopy of representative cilia cross sections from respiratory epithelial cells of sibling PCD patients (UCL89) show a loss of both outer and inner dynein arms. Additionally, immunofluorescence to further characterize cilia structure in these cells showed an absence of DNAH5, DNAH9 and DNAI2 (outer dynein arm components) and an absence of the inner dynein arm component DNALI1. The absence of these dyneins suggests a disruption of outer and inner dynein arm assembly in the airway of patients carrying DNAAF3 mutations. Reduced amounts of DNAH5 in the apical cytoplasm in one of the DNAAF3 patient cells, suggests that some outer row dynein proteins are present in a form that cannot assemble into cilia. These data are consistent with DNAAF3 assisting in the cytoplasmic assembly of axonemal dyneins.",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_40329b6f-2d65-49dd-863b-f79dcd1b5a23-2022-05-09T155600.823Z,616,PubMed:22387996 +Morpholino knockdown of dnaaf3 in zebrafish embryos,Model Systems Non-human model organism,"Mitchison HM, et al., 2012, PMID: 22387996","Morpholino-mediated knockdown of dnaaf3 in zebrafish disrupted dynein assembly and caused loss of ciliary motility in several tissues. The morphology and number of cilia in the olfactory placode of morphant fish was normal, but the reduction and absence of both ODAs and IDAs in these cilia is consistent with the role of zebrafish dnaaf3 and human DNAAF3 in the assembly of axonemal dyneins. The loss of motility in olfactory placode cilia recapitulates the immotile nasal cilia seen in humans with DNAAF3 mutations. Ciliary motility provides essential developmental signals during embryogenesis in humans and zebrafish. Morphant fish with axis curvature defects and laterality defects parallel the laterality defects seen in human DNAAF3 patients. Hydrocephalus, perturbed otolith development, and the development of pronephric (kidney) cysts are zebrafish phenotypes consistent with the loss of ciliary motility, a loss of function consistent with human PCD. +In situ hybridization of wild type embryos with dnaaf3 specific probes show expression in the ciliated cells of the spinal cord floor plate, the olfactory placodes, pronephros, and lateral line organs. These are all motile ciliated structures in zebrafish (PMID: 34445067).",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_40329b6f-2d65-49dd-863b-f79dcd1b5a23-2022-05-09T155600.823Z,616,PubMed:22387996 +Chlamydomonas PF22 rescue experiment,Rescue Non-human model organism,"Mitchison HM, et al., 2012, PMID: 22387996","Transformation of pf22 mutant Chlamydomonas with wild type copies of pf22 rescues the pf22 phenotype of short flagella, lack of motility and dynein assembly defects. Assembly of all three missing flagellar dyneins (DHC5, DHC9, and IC2) is rescued by transformation with untagged or Myc-tagged wild type copies of the pf22 gene.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_40329b6f-2d65-49dd-863b-f79dcd1b5a23-2022-05-09T155600.823Z,616,PubMed:22387996 +Co-localization of Dnaaf3 with dynein assembly proteins,Protein Interaction,"Huizar RL, et al., 2018, PMID: 30561330","PCD can arise from mutations in genes encoding any of an array of cytoplasmic proteins collectively known as dynein axonemal assembly factors, DNAAFs, that help preassemble axonemal dynein motors in the cytoplasm before deployment to cilia (PMID: 32943623). Huizar et al., 2018 show that in Xenopus embryos DNAAFs concentrate together with axonemal dyneins and chaperones into organelles that form specifically in multiciliated cells, which they term DynAPs, for dynein axonemal particles. Laser scanning confocal microscopy showed that GFP-Dnaaf3 protein co-localized with Cherry-Dnaaf2 (Ktu) at DynAPs. (Dnaaf4, Dnaaf5, Dnaaf6, Spag1, Dnaaf11, Zmynd10 also co-localized with Cherry-Dnaaf2 (Ktu) as did the dynein subunits Dnai1, Dnai2, and DNAli1). A 3D object-based co-localization algorithm was used to quantify co-localization data of GFP-fusion proteins to cherry-Ktu. The co-localization of DnaaFf3 with various DNAAFs in DynaPs is consistent with the role of DNAAF3 being part of a cytoplasmic multiprotein complex that assembles inner and outer dynein arm components.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_40329b6f-2d65-49dd-863b-f79dcd1b5a23-2022-05-09T155600.823Z,616,PubMed:30561330 +Drosophila Dnaaf3 required for dynein motor pre-assembly,Model Systems Non-human model organism,"Zur Lage P, et al., 2021, PMID: 34553759","RNAi depletion and CRISPR-generated null alleles of Drosophila Dnaaf3 specifically exhibit phenotypes consistent with ciliary/flagellar immotility with loss of both ODA and IDA, depletion of of dynein heavy chains, and the absence of DNAH5 in mutant motile cilia. Male infertility, immotile sperm, and the loss of auditory/vibration mechanotransduction in Ch neurons in null Dnaaf3 mutants in Drospohila are phenotypes consistent with the human DNAAF3 mutations that result in cilial immotility in respiratory cells resulting in respiratory symptoms and infertility caused by cilial and flagellar defects in reproductive cells (Fallopian tubes, efferent ducts, sperm). Human DNAAF3 mutations have also been shown to result in the absence of inner and outer dynein arms and have been associated with the loss of dynein proteins (DNAH5 and DNALI1) in respiratory cilia (PMID: 22387996).",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_40329b6f-2d65-49dd-863b-f79dcd1b5a23-2022-05-09T155600.823Z,616,PubMed:34553759 +Drosophila model,Model Systems Non-human model organism,"Diggle CP, et al., 2014, PMID: 25232951",Flies have uncoordinated movement and are missing ODA+IDA. Also infertility.,Score,1 (2),Drosophila cannot recapitulate respiratory phenotype in PCD.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9b47c717-e0a5-43ce-865b-0b14289216d7-2024-06-19T110000.000Z,618,PubMed:25232951 +Expression and localisation in control human cells,Expression A,"Diggle CP, et al., 2014, PMID: 25232951","DNAAF5 is highly expressed in the cytoplasm of control human ciliated cells but is absent in cilia. +Cytoplasmic DNAAF5 is expressed during early ciliogenesis. DNAAF5 highly expressed in developing MMC where ODA+IDA components are predominantly cytoplasmic. Lower levels of DNAAF5 in fully mature MMC where ODA+IDA components are exclusively axonemal",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9b47c717-e0a5-43ce-865b-0b14289216d7-2024-06-19T110000.000Z,618,PubMed:25232951 +Mouse model,Model Systems Non-human model organism,"Horani A, et al., 2023, PMID: 37104040",Hydrocephaly is a PCD marker in PCD mice. Situs inversus and low CBF like patients.,Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9b47c717-e0a5-43ce-865b-0b14289216d7-2024-06-19T110000.000Z,618,PubMed:37104040 +Analysis of the sperm motility of DNAH1 deficient mice,Model Systems Non-human model organism,"Khan R, et al., 2021, PMID: 34867808","Progressive motility is severely compromised in Dnah1△iso1/△iso1 mice, while no progressive motile sperm was observed in Dnah1-/- mice. This is similar to the sperm motility in patients with DNAH1 mutations",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_4a5dff5a-ff66-4e80-9eca-cb5f924edb73-2022-05-26T160000.000Z,620,PubMed:34867808 +Dnah5 siRNA knockout in mouse tracheal epithelial cells,Model Systems Cell culture model,"Zahid M, et al., 2020, PMID: 32823934","High-speed video microscopy of cilia beating in human DNAH5 mutants shows a range of effects on cilia motility depending on the particular variants. Phenotypes can range from completely immotile respiratory cilia to altered motility with stiff movements and low amplitudes (Raidt et al PMID:25186273). +There was no significant change in ciliogenesis or cilia length with Dnah5 knockdown. However, approximately half of the ciliated cells were immotile. Where motile cilia were present, the ciliary beat frequency was normal, though some motile cilia exhibited dyskinetic ciliary motion (Supplementary Video S6 and S7).",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_4390dba1-012d-4e08-a841-ffc08ebdc737-2022-01-07T190607.723Z,624,PubMed:32823934 +Dnaic1 knockdown in mouse ciliated tracheal epithelium,Model Systems Cell culture model,"Zahid M, et al., 2020, PMID: 32823934","Although knockdown of the murine Dnaic1 gene did not affect the generation or length of the cilia, half of ciliated cells were rendered immotile (Table 1), while some of the remaining motile cilia showed dyskinetic motion (Supplementary Videos S6 and S7). This matches the human patient phenotype of immotile cilia, and is indirectly related to molecular phenotypes such as absence of outer dynein arms and organ-level phenotypes such as recurrent bronchitis and sinusitis.",Score,0.5 (1),This experiment was down-scored out of concern that its value in describing the cellular level of the disease mechanism might partially overlap with the previously scored mouse model.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_396be572-5b2c-4859-90dd-434a91c1ce96-2022-06-30T160000.000Z,628,PubMed:32823934 +Mouse model with DNAI2 Knockdown,Model Systems Non-human model organism,"Yang Z, et al., 2019, PMID: 30387321","infertility, pathology of the lung both are consistent with the human PCD patient",Score,1.5 (2),"The phenotypes are consistent with PCD but not highly specific for PCD (could be from acute or chronic respiratory disease). Thus, down-scoring of the model was performed.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_225300ab-ad49-4043-875b-a27a54d37b72-2022-08-11T160000.000Z,629,PubMed:30387321 +DNAJC7 is an interacting partner of FUS,Protein Interaction,"Wan C, et al., 2015, PMID: 26344197",High-performance liquid chromatography tandem mass spectrometry (LC–MS/MS) of digested protein fractions of each human and mouse cell lines coupled with machine learning identified that DNAJC7 is an interacting partner of FUS.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e2a12a19-b37a-4654-87fa-3a921c202c87-2022-10-27T160000.000Z,634,PubMed:26344197 +Serpas_2019_Plasma DNA Fragmentation by DNASE1 +DNASE1L3,Biochemical Function A,", , PMID: 30593563","DNASE1L3 is also an endonuclease capable of cleaving both single- and double-stranded DNA that has been strongly associated with SLE in a loss-of-function autosomal recessive pattern. This experiment shows the effect of deletions in DNASE1L3 only, DNASE1 only, DNASE1 + DNASE1L3, and WT mice on the degree of plasma DNA fragmentation, by showing the frequency of short plasma DNA fragments in each group of mice. The method used was paired-end sequencing followed by genome sequence alignment of both end sequences of each DNA molecule for fragment size determination. Mice with double deletions of DNASE1 + DNASE1L3 show the highest frequency of short plasma DNA fragments, suggesting a synergistic function of the two gene products.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b71d9246-5a7e-4e81-8fc6-925181d124cd-2024-06-14T190000.000Z,635,PubMed:30593563 +Lacy DNASE1/DNASE1L3 mouse,Model Systems Non-human model organism,"Lacey KA, et al., 2023, PMID: 36928522",DNASE1 and DNASE1L3 KO mouse kidneys manifested severe pathology. Single KO and double KO both differed significantly from WT.,Score,0 (2),"DNASE1 and its homolog DNASE1L3 jointly facilitate resistance to systemic infection with Staphylococcus aureus by digesting bacterial biofilms. Deletion of murine DNASE1 neither caused autoreactivity in isolation nor exacerbated lupus-like disease in DNASE1L3-deficient mice. However, combined deficiency of DNASE1 and DNASE1L3 rendered mice susceptible to bloodstream infection with Staphylococcus aureus. DNASE1/DNASE1L3 double-deficient mice mounted a normal innate response to S. aureus and did not accumulate neutrophil extracellular traps (NETs). However, their kidneys manifested severe pathology, increased bacterial burden, and biofilm-like bacterial lesions that contained bacterial DNA and excluded neutrophils. Furthermore, systemic administration of recombinant DNASE1 protein during S. aureus infection rescued the mortality of DNase-deficient mice and ameliorated the disease in wild-type mice. Thus, DNASE1 and DNASE1L3 jointly facilitate the control of bacterial infection by digesting extracellular microbial DNA in biofilms, suggesting the original evolutionary function of secreted DNases as antimicrobial agents. This paper contradicts earlier mouse models (PMID: 30758851) which showed that KO of DNASE1 resulted in lupus-like phenotypes in mice.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b71d9246-5a7e-4e81-8fc6-925181d124cd-2024-06-14T190000.000Z,635,PubMed:36928522 +Dnase1l3 deletion causes aberrations in length of plasma DNA,Functional Alteration Non-patient cells,", , PMID: 30593563","DNASE1L3 is released into the circulation to fragment DNA. DNASE1L3-KO mice have aberrant size of plasma DNA in circulation (increase in the very short plasma DNA as well as increase in the longer DNA molecules). There was also an increase in the motifs that started with CC compared to wild-type DNA, suggesting aberrant fragmentation of DNA found in plasma.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_77450e46-30fa-4be0-aa0e-4e31f04a117e-2024-05-08T190000.000Z,636,PubMed:30593563 +Plasma DNA Profile Associated with DNASE1L3 Gene Mutations:,Rescue Non-human model organism,"Chan RWY, et al., 2020, PMID: 33022220",,Score,1 (2),"It is not the clinical disease phenotype that is rescued. Instead, the study shows rescue of plasma DNA size and motif, which is not the same as clinical disease phenotype.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_77450e46-30fa-4be0-aa0e-4e31f04a117e-2024-05-08T190000.000Z,636,PubMed:33022220 +Plasma DNA Profile Associated with DNASE1L3 Gene Mutations:,Functional Alteration Patient cells,"Chan RWY, et al., 2020, PMID: 33022220","There is aberration in size and reduction in of a ""CC"" end motif in plasma DNA in patients with homozygous loss of function mutations of DNASE1L3.",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_77450e46-30fa-4be0-aa0e-4e31f04a117e-2024-05-08T190000.000Z,636,PubMed:33022220 +DNASE1L3 Arg206Cys protein secretion and enzymatic activity,Functional Alteration Non-patient cells,"Coke LN, et al., 2021, PMID: 33455918","Wild-type DNASE1L3 protein is secreted into supernatants of HEK293 cells transiently expressing the DNASE1L3 gene from 1-day post-transfection, but rDNASE1L3 Arg206Cys protein is not. The variant protein appears to retain DNase activity, and a low level of secretion can sometimes be observed.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_77450e46-30fa-4be0-aa0e-4e31f04a117e-2024-05-08T190000.000Z,636,PubMed:33455918 +Wakabayashi_Complete and Conditonal KO Mouse models,Model Systems Non-human model organism,"Wakabayashi J, et al., 2009, PMID: 19752021","DNM1L heterozygous mice were viable, fertile and normal in size. Homozygous mice were not seen in the litter indicating that homozygous null DNM1L is embryonic lethal. These null embryos lookes smaller than age-matched littermates that were WT-DNM1L or DNM1L-/+, indicating developmental delay. +Mouse embryonic fibroblasts from DNM1L-/- mice showed highly connected, elongated mitochondrial tubules that could be rescued by reexpression of DNM1L. IF using antibodies to Pex14 and EM of peroxisomal catalase staining showed relatively round peroxisomes in WT but elongated ones in DNM1L-/-. Using the conditional KO mouse, the authors showed that the cerebellum of mutant mice had completely smooth surfaces, and itssize was decreased to ∼60% of control cerebella, while in control mice, cerebellum was round, but the lobule formations were relatively shallow fissures. Gerber et al (PMID: 28969390) show in these heterozygous knock-out mice that Dnm1l variation caused mitochondrial elongation in retinal ganglion cells without axonal degeneration and no optic nerve defects in 3mo mice. +Ishihara et al, (PMID: 19578372) also generated Dnm1l- knock-out mice, which resulted in embryonic lethality. Reduced development of heart and liver, thinned neural tube cell layer were observed in dead embryos, along with enlarged/extended mitochondria and swollen peroxisomes. Neural-specific Dnm1L deletion also led to death shortly after birth.",Score,2.5 (2),The score is slightly increased for evidence on both complete and conditional knock out models.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_320f4ab3-19c3-458e-9e81-0f380cbfebbd-2022-04-15T160000.000Z,639,PubMed:19752021 +DNM2 Mutants Alter Aspects of Function,Functional Alteration Non-patient cells,"Koutsopoulos OS, et al., 2011, PMID: 22096584","Both of the CMT-associated mutants did not have any significant impact on the localization of DNM2, as they formed a filamentous pattern and localized per normal to the mitochondria. However, both mutants showed a significant decrease in transferrin uptake when clathrin-mediated endocytosis was measured. The CMT mutants were seen in association with clustered punctae, demonstrating that they altered the typical formation of DNM2 structures.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7bc54e5d-eed5-4d40-9e0d-143bfeb88cac-2020-10-27T131827.010Z,641,PubMed:22096584 +DNM2-KO Mice Show Neuropathy Phenotypes,Model Systems Non-human model organism,"Gerber D, et al., 2019, PMID: 30648534","Immunoblotting confirmed that DNM2 expression was substantially reduced in the P0-DNM2_KO mouse sciatic nerves compared to the controls. Evaluation of clarathin-mediated endocytosis also confirmed a markedly reduced transferrin uptake in the mutant schwann cells, showing the function was affected. Behavioral abnormalities were noted in the mutant mice, with tremor and limb clasping developing. Biopsy confirmed that signs of a neuropathy, including reduced numbers of myelinated axons and myelinated fibers, were present in the mutant mice. Investigation determined that DNM2 is necessary for correct radial sorting of axons and subsequent myelination. Conditonal knock-out mice, P0ERT2-DNM2_KO, were generated to determine what the impact on myelin maintenance is for DNM2. These mice demonstrated a progressive gait impairment and severely reduced mNCVs and CMAPs that then improved rapidly afterwards. This indicates that demyelination and subsequent remyelination is the cause of the observed phenotype. Therefore, DNM2 is essential for myelin maintenance as well as initial development and formation. Investigation into DNM2's role in schwann cells for survival demonstrated that both developing and adult SCs depend critically on DNM2 for their survival and that, upon DNM2 loss, cells other than SCs invade developing peripheral nerves. Mutant cells also showed a decrease in mitotic events, abnormal cell cycle progression, and imapired cytokinesis. Notably, DNM2 was not necessary for oligodendrocyte differentiation and CNS myelination, which are typically unaffected in human CNM probands.",Score,1.5 (2),"This model, although not perfectly matching the inheritance pattern or pathogenic mechanism for the human disorder, clearly demonstrates a role for DNM2 in the development and maintenance of myelin as well as schwann cells. These systems are the most severely impacted in the human probands, with clear demyelinating signs and decreased nerve conduction velocities. This evidence demonstrates that, in all stages of an organism's life, DNM2 expression is necessary for proper schwann cell function. Furthermore, it is likely that differences between mice and humans affects the amount of WT DNM2 that can be present for phenotypes to occur. Therefore, for recapitulating the phenotypes in a system not identical to the human probands, this evidence scores a reduced 1.5 points.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7bc54e5d-eed5-4d40-9e0d-143bfeb88cac-2020-10-27T131827.010Z,641,PubMed:30648534 +Mouse K562E Knock-In Model,Model Systems Non-human model organism,"Pereira JA, et al., 2020, PMID: 32129442","Both control and DNM2 wt/K562E mice were healthy and had no alterations in their behavior, with the heterozygous mice showing a slight reduction of body weight with substantial variability. Hot plate, rotarod and forepaw grip strength tests revealed no significantly impaired performance of DNM2 wt/K562E mutants compared to controls in 2-month-old and 1-year-old mice. Minor gait abnormalities and less movement than controls show that the K562E mutation mildly affects locomotion in the mice. However, when performing electrophysiology measurements, there were no differences in the csNCV or mNCV. There was a decrease in the CMAP amplitude which was confirmed via repetitive stimulation analyses. Therefore there is no major damage to the neural component of these mice, however there are defecits in the muecular systems. Histological analysis of peripheral nerves revealed only minor morphological abnormalities in the myelin of DNM2 wt/K562E mice with no major signs of demyelination or remyelination, indicating no typical features of a neuropathy even up to 1 year of age. No reduction in myelinated axons or reduction in axonal diameters were observed either. Given the import of DNM2 in axonal sorting and clathrin-mediated endocytosis, both were observed in P0Cre Dnm2 fl/K562E mice that contain the Dnm2 K562E allele but lack wild-type DNM2 in schwann cells. It appears that neither early PNS development nor CME is affected by the lack of WT DNM2 and can be carried out by the K562E mutant. However, when the nerves and axons were compared to the controls, a strong reduction of myelinated axons and demyelination signs were observed. Paired with this, there was drastically reduced mNCV together with decreased CMAP amplitude compared to controls. These together show multiple hallmarks of a severe demyelinating neuropathy. Further investigation into the wt/K562E heterozygous mice showed signs of a primary myopathy, including muscle fiber degeneration and reduced diameter. This extended from even beyond the soleus muscle and is likely not affected by primary denervation. Furthermore, the mice do not develop signs of neutropenia. WT/null mice were also generated and had no significant changes in muscle or nerve formation, indicating that haploinsufficency is not the underlying mechansim for the myopathic features.",Score,1 (2),"This knock-in model of a well-characterized CMT variant in humans, K562E, is unusual in that the heterozygous model itself does not recapitulate the primary phenotypes of a neuropathy, instead showing signs of a mild myopathy. This is likely due to the physiological differences of mice and humans necessitating a homozygous occurence to accurately reflect the phenotypes (which is supported by the Null/K562E mouse line recapitulating a severe demyelinating neuropathy). Therefore, due to only the line solely expressing the K562E mutant showing phenotypes, these models are downgraded to 1.0 point.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7bc54e5d-eed5-4d40-9e0d-143bfeb88cac-2020-10-27T131827.010Z,641,PubMed:32129442 +DNM2 Myopathy Phenotype Rescue in Mice,Rescue Non-human model organism,"Trochet D, et al., 2018, PMID: 29246969","When treated with the AAV-sh9, mice displayed a significant change in their properties closer to that of the wild-type than their mutant control counterparts. Mutant TA muscles displayed a 28% decrease in mass compared to their wild-type counterparts but AAV-sh9 injected mice recovered to almost wild-type values while AAV-sh10 mice showed partial improvement. Muscle fiber diameter showed similar results, with the AAV-sh9 mice showing a full rescue of the phenotype compared to the control. The decrease in absolute/specific force was also alleviated, with sh9 expression returning these values to their wild-type control levels. The central accumulation of oxidative cell components, a classic histopathological abnormality, were almost absent in sh9 mice. The results were more moderate for a 1-month treatment compared to a 3-month treatment, but significant improvement was still seen with the sh9 mice.",Score,2 (2),"This siRNA treatment which blocks the action of the pathogenic gain-of-function variant clearly rescues the phenotypes that result from the mutant including the muscle weakness, atrophy, contractile strength, and the histopathological abnormalities displayed in both humans and this mouse model. Although only AAV-sh9 retained utility in vivo, this still demonstrates the link between expression of the variant and the phenotypes. With that in mind, this rescue earns a default 2.0 points.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e4156721-f6b9-482c-b610-97753f3f722d-2019-12-20T170000.000Z,642,PubMed:29246969 +Modified Endocytosis in Fibroblasts,Functional Alteration Patient cells,"Trochet D, et al., 2018, PMID: 29246969","One of the functions of DNM2 is a mediator of clathrin-dependent endocytosis. This process has been shown to be related to the pathogenicity of CNM mutations due to the reduced uptake of transferrin and low-density lipoprotein (LDL) complex and has been idenfified in multiple CNM patients (PMID:19623537). Both this and the aforementioned publication demonstrated the reduced uptake, with all three patient fibroblasts showing over 50% reduced transferrin uptake and an over 20% reduced LDL uptake. Additionally, expression of an siRNA to block the action of the R465W mutation restored normal endocytosis to the fibroblasts.",Score,1 (1),"Due to the clear impacted function of clathrin-dependent endocytosis which is involved in the mechanism of various myopathies, plus the rescue of the phenotype when the variant expression is selectively blocked, this evidence earns default points.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e4156721-f6b9-482c-b610-97753f3f722d-2019-12-20T170000.000Z,642,PubMed:29246969 +In vivo mouse model,Model Systems Non-human model organism,"Heyn P, et al., 2019, PMID: 30478443",A mouse model was generated via CRISPR. The mouse model had similar findings of small body size and brain size consistent with microcephaly dwarfism of human subjects.,Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6c4959e0-72fe-49e2-8e7e-639539dc9095-2023-06-08T060000.000Z,643,PubMed:30478443 +crispr correction,Rescue Patient cells,"Toubiana S, et al., 2019, PMID: 31738163","iPSCs with rescued DNMT3B mutations reacquire normal methylation at some regions, while other regions are only partially methylated.",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3482d453-c6c8-483d-8333-dbe4d5bd9b66-2023-04-16T170000.000Z,645,PubMed:31738163 +T cell repertoire studies,Biochemical Function B,"Fang M, et al., 2022, PMID: 34825286","T cell dysfunction is often associated with risk of infection from opportunistic pathogens, which can be seen in some patients with ICF1",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3482d453-c6c8-483d-8333-dbe4d5bd9b66-2023-04-16T170000.000Z,645,PubMed:34825286 +DOCK7 is important for interkinetic nuclear migration,Functional Alteration Non-patient cells,"Yang YT, et al., 2012, PMID: 22842144","Cells overexpressing DOCK7 showed impaired migration towards the ventricle, while cells lacking DOCK7 migrated faster towards the ventricle.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0b6ed421-950b-4862-bade-dc545555ac29-2021-07-28T192512.688Z,648,PubMed:22842144 +CD8 T cell impaired function in DOCK8 mouse KO model,Model Systems Non-human model organism,"Randall KL, et al., 2011, PMID: 22006977","They show a similar reduction in naive T cells in mice and humans deficient in DOCK8. As well, the DOCK8 KO mice CD8 T cells do not respond well to secondary viral rechallenge, suggesting abnormalities in T cell memory and ability to control viral infections. Recurrent and/or diffuse viral infections are commonly seen in DOCK8 deficient patients, suggesting they also have poor memory CD8 T cell responses.",Score,1 (2),"This paper shows defects in the naive and memory CD8 T cell population along with poor proliferative response to stimuli in DOCK8 deficient patients. In the mouse model, they show similar loss of naive CD8 T cells as in humans, but do not replicate the same proliferative defect. However, they do show that DOCK8 deficient CD8 T cell as are functionally unable to expand/accumulate after a secondary challenge in a heterosubtypic influenza model. This rechallenge model and phenotype is likely a better comparison to make to human patient data, but it is not further investigated. There is no analysis of IgE or eosinophilia that is typically seen in DOCK8 deficiency, so only part of the phenotype is replicated (-1).",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_07811d37-10c8-44dd-88b2-a2b574e59ac4-2021-04-09T142917.716Z,649,PubMed:22006977 +Microscopy of patient cells,Functional Alteration Patient cells,"Zhang Q, et al., 2014, PMID: 25422492",Inability of DOCK8 null cells to maintain a normal shape and cellular organization while migrating in collagen gel matrices and human foreskin tissue. They show that migration of the patient cells leads to cytothripsis and cell death. This data is suggestive that DOCK8 deficiency leads to T cell death in vivo and inability to generate T resident memory cells that make patients more prone to viral skin infections.,Score,0.5 (1),"This work by Zhang postulates that the DOCK8 deficiency in skin homing lymphocytes leads to alterations in cytoskeletal regulation and the inability to support sustained resident memory T cells (TRM) in the skin, and may be why patients are more prone to viral skin infections. This inability for DOCK8 null T cells to migrate through collagen containing structures is correlated with increased herpes simplex virus skin infection and the inability to sustain TRM in DOCK8 KO mice. This work shows that DOCK8 null patient T cells have an elongated morphologic phenotype associated with worse survival in migration assays, and that this phenotype is also seen in mouse models. However, they do not show that this leads to reduced TRM in the patients, or that DOCK8 can reduce this morphology. Due to this, I have reduced the score to 0.5.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_07811d37-10c8-44dd-88b2-a2b574e59ac4-2021-04-09T142917.716Z,649,PubMed:25422492 +Highest expression levels of DOLK mRNA in fetal and adult br,Expression A,"Lefeber DJ, et al., 2011, PMID: 22242004",,Score,1 (0.5),Highest expression levels of DOLK mRNA were found in fetal and adult brain.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_2b780e34-fb4d-47d7-8436-6bdb6025bc72-2024-04-04T160000.000Z,650,PubMed:22242004 +Involvement of dolichol kinase (DOLK) in N-glycosylation,Biochemical Function B,"Lefeber DJ, et al., 2011, PMID: 22242004","Dolichol kinase deficiency results in abnormal N-glycosylation and reduced O-mannosylation of alpha-dystroglycan, leading to a clinical phenotype of dilated cardiomyopathy.",Score,1 (0.5),Shows interaction of other genes and how to the function of those genes continue to display and lead to clinical phenotypes of those seen in patients.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_2b780e34-fb4d-47d7-8436-6bdb6025bc72-2024-04-04T160000.000Z,650,PubMed:22242004 +Li Mouse Model,Model Systems Non-human model organism,"Li H, et al., 2020, PMID: 32714760","While decreased fertility has not been noted in humans with DPAGT1 mutations (likely due to most patients not reaching reproductive age), the decreased N-glycosylation of the zona pellucida (a coating on vertebrate oocytes) is consistent with decreased N-glycosylation in humans.",Score,1 (2),"Decreased due to primary focus on oocyte development and fertility, which are not phenotypes associated with human disease.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ac9d420c-dfeb-460a-924f-ae80a3203188-2024-06-17T170000.000Z,651,PubMed:32714760 +Hyde Mouse Model,Model Systems Non-human model organism,"Hyde LF, et al., 2022, PMID: 36233305","Retinal degeneration has not been observed in humans with DPAGT1 mutations. In addition, the homozygous missense model showed normal N-glycosylation of retinal proteins compared to wt mice. Finally, homozygous missense mice do not exhibit muscular abnormalities as are found in humans with DPAGT1 mutations.",Score,0 (2),No recapitulation of human phenotype.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ac9d420c-dfeb-460a-924f-ae80a3203188-2024-06-17T170000.000Z,651,PubMed:36233305 +DPM1 knockdown in a zebrafish model,Model Systems Non-human model organism,"Ardiccioni C, et al., 2016, PMID: 26729507","Knocked down DPM1 in zebrafish using morpholino antisense oligonucleotides (MOs). The morpholino animal displayed most features of congenital disorder of glycosylation type 1e (CDG1e) associated with DPM1 mutations, with a smaller head (microcephaly) and smaller eyes, kinked tail, and occasional vascular defects in the tail vein (arrowhead).",Score,1 (2),"Based on expert call, this was down scored because zebrafish is not the ideal model to capitulate the phenotypes for this disease",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_2a4d2b7f-1de8-4f6c-8136-b62b62e1c226-2023-10-04T160000.000Z,654,PubMed:26729507 +Rescue of DPM1 knockdown in a zebrafish model,Rescue Non-human model organism,"Ardiccioni C, et al., 2016, PMID: 26729507",Injection of human DPM1 mRNA was able to significantly rescue the dpm1 morphant phenotypes showing that the function is conserved between humans and zebrafish and that the phenotypes observed are due to the loss of dpm1 (Supplementary Fig. 15f),Score,1 (2),the exact extent of the rescue is not detailed in the paper,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_2a4d2b7f-1de8-4f6c-8136-b62b62e1c226-2023-10-04T160000.000Z,654,PubMed:26729507 +Gehmlich 2011 Protein Interaction,Protein Interaction,"Gehmlich K, et al., 2011, PMID: 21062920",Used GST-pulldown in rat heart lysates to show that DSC2 interacts with PKP2 and JUP. Also shown in COS-1 cells.,Score,1 (0.5),Increased because it interacts with 2 ARVC gene products.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_74238dee-a847-4f27-9d30-3050c7bf9bf2-2018-09-14T160000.000Z,658,PubMed:21062920 +Brodehl 2017 OE mouse model,Model Systems Non-human model organism,"Brodehl A, et al., 2017, PMID: 28339476",Mice developed severe mycocardial necrosis and fibrosis. Fibrotic plaques localized to the epicardium and endocardium has been observed in humans with ARVC where fibro-fatty infiltration starts primarily at the epicardium.,Score,1.5 (2),Mouse model did not fully recapitulate the disease.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_74238dee-a847-4f27-9d30-3050c7bf9bf2-2018-09-14T160000.000Z,658,PubMed:28339476 +N266S Overexpression Mouse Model 1,Model Systems Non-human model organism,"Pilichou K, et al., 2009, PMID: 19635863","These mice recapitulate many of the features of the disease (sudden death, spontaneous ventricular arrhythmias, ECG findings, cardiac dysfunction, ventricular dilatation and aneurysms, myocardial atrophy, and fibrosis.",Score,1.5 (2),"The lower expressing transgenic mouse line also recapitulated some of the phenotypes, but at a slower rate, so there seems to be a dose-dependent, dominant negative effect. The lower expressing mouse is discussed in a subsequent paper PMID: 22764152. That mouse model was given 0.5 points to combine for a total of 2 points.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_f679611d-6e25-45f9-aac3-4a8ad37b1592-2018-09-14T160000.000Z,660,PubMed:19635863 +Murine model,Model Systems Non-human model organism,"Gomes J, et al., 2012, PMID: 22240500","ARVC patients carrying heterozygous DSP mutations experienced unexplained syncope, ventricular tachycardia or ventricular fibrillation. Isochronal mapping identified a clearly prolonged reight ventricular depolarization (outflow tract) in these patients. Immunohistochemistry from biopsies from DSP-ARVC patients revealed mislocalization of Cx43. +DSP± mice had normal ECG but delayed conduction and inducible ventricular tachycardia associated with mislocalization and reduced intercalated disc expression of Cx43. Histological studies of DSP heterozygous KO mice showed focal myocyte loss and fibro-fatty replacement",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b23da580-269c-4e5d-8f13-91dbe7ea6a57-2019-07-12T160000.000Z,661,PubMed:22240500 +Lee Functional Alteration,Functional Alteration Non-patient cells,"Lee SK, et al., 2012, PMID: 23509818","The c.50C>T (p.P17L) variant does not interfere with normal pre-mRNA splicing, but mutant DSP was shown by fluorescent immunocytochemistry to be localized throughout the cytoplasm. Wildtype DSP localizes exclusively in the Golgi apparatus.",Score,0.5 (0.5),Good evidence of variant pathogenicity. Scoring default points because it suggests mechanism of disease for multiple reported variants.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_39f5492a-97a3-49a6-929d-f24f23b51217-2018-04-17T160000.000Z,662,PubMed:23509818 +Double-ligation axonal transport studies in KO mice,Biochemical Function B,"Liu JJ, et al., 2003, PMID: 14581450","Axonal transport is an important function in several neuropathy subtypes, including DCTN1-related neuropathy",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d90c7de8-a72a-4c54-bab8-fe9d4aef0409-2021-12-14T170000.000Z,663,PubMed:14581450 +Heterozygous conditonal deletion allele for Dynch1h1,Model Systems Non-human model organism,"Di Pizio A, et al., 2023, PMID: 36218033",abnormal hind limb posture when suspended by the tail is indicative of motor phenotypes in mice,Score,1 (2),Downgraded because the disease mechanism in patients is GoF probably and this is a LoF model (discussed at the CMT GCEP meeting),https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c1e12eb9-aea0-4597-8893-48df533f6ad9-2023-07-12T160000.000Z,668,PubMed:36218033 +Behavioral analysis,Model Systems Non-human model organism,"Arqué G, et al., 2008, PMID: 18648535","Dyrk1A +/- mice showed impaired spatial learning, which is similar to intellectual disability phenotype in human patients.",Score,0 (2),"This paper used the same mouse model as Fotaki et al., 2002, and added behavioral assays to assess learning ability in Dyrk1A +/- mice. Altogether, phenotypes in this mouse line get a total of 2 points, which were already scored from Fotaki et al.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b336707e-f3a5-4554-9b37-0d29621b3562-2020-07-15T195802.528Z,670,PubMed:18648535 +assessment of dendritic spine growth,Model Systems Cell culture model,"Dang T, et al., 2018, PMID: 28167836",Mutations in genes that associate with ID and ASD have been reported to show defects in dendritic spine growth and radial migration. The findings for DYRK1A in this paper fit the disease mechanism.,Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b336707e-f3a5-4554-9b37-0d29621b3562-2020-07-15T195802.528Z,670,PubMed:28167836 +Boczonadi EARS2 biochemical function,Biochemical Function A,"Boczonadi V, et al., 2018, PMID: 29980628",27977873: Rahman et al. 2017,Score,2 (0.5),Mitochondrial GCEP criteria met,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_774e378c-2636-41ad-be48-a2c00328ab9c-2020-03-19T190729.531Z,671,PubMed:29980628 +Role of EBP on oligodendrocyte formation,Biochemical Function B,"Hubler Z, et al., 2018, PMID: 30046109","In mouse stem cell-derived oligodendrocyte progenitor cells, inhibition of EBP by small molecules enhanced formation of myelin basic protein-positive oligodendrocytes. EBP knock-down by CRISPR–Cas9 targeting enhanced formation of oligodendrocytes under differentiation-permissive conditions. Tamoxifen-induced accumulation of 8,9-unsaturated sterols enhanced remyelination in mouse brain.",Score,0 (0.5),no evidence of oligodendrocye/myelin dysfunction in patients with MEND syndrome,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_21e97c32-52ae-4331-8788-64d652f20af3-2022-09-07T180000.000Z,673,PubMed:30046109 +Analysis of palmitate-dependent OCR in fibroblast cell lines,Functional Alteration Patient cells,"Haack TB, et al., 2015, PMID: 26000322","Analysis of palmitate-dependent OCR in fibroblast cell lines (F5, F9, F10 - not counting F7 given this was used for case level evidence of variant functional impact) revealed impaired respiration in patients’ cells in comparison to controls. The experiment was performed several times with very similar results. The data are shown from one experiment performed with more than 10 +replicates for each cell line grown and treated in parallel.",Score,2 (1),Done in cells from patients with LSS,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1d443f3c-fe02-4104-9e92-ca1c73b85a81-2021-04-09T142601.823Z,674,PubMed:26000322 +Genes associated with LSS and amino acid metabolism,Biochemical Function A,"Rahman J, et al., 2017, PMID: 27977873","Per LeighMap, there is one other gene associated with amino acid metabolism and LSS (HIBCH)",Score,0.5 (0.5),0.5 points given shared function with one other LSS gene (HIBCH),https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1d443f3c-fe02-4104-9e92-ca1c73b85a81-2021-04-09T142601.823Z,674,PubMed:27977873 +EED Expressed in Neuroblasts,Expression A,"Sun B, et al., 2018, PMID: 29415247","Western blots showed core PRC2 protein, Eed expression in several brain areas at P4 as well as in SVZ-derived neurospheres. In 6-week-old brains, Eed immunofluorescence was detected in the SVZ, the striatum and cerebral cortex. All DAPI+ nuclei examined in the SVZ expressed Eed, indicating it is expressed in all cells of the lineage. Similar to Eed, PRC2 epigenetic mark H3K27me3+ nuclei were found throughout the brain. GFAP+ astrocytes in the corpus callosum and SVZ, as well as S100β+ niche astrocytes and ependymal cells and Dcx+ neuroblasts were all H3K27me3+.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_44531e19-7957-424f-81e9-fc455095f14a-2022-12-06T190000.000Z,678,PubMed:29415247 +EEF1A2 mice show behavioral deficit,Model Systems Non-human model organism,"Dickinson ME, et al., 2016, PMID: 27626380","Heterozygous mice were shown to have defects in acoustic startle and PPI amplitude (http://www.mousephenotype.org/phenoview/?gid=10566-19-3&qeid=IMPC_ACS_006_001&ctrl=3144161). Testing in open field also showed significant difference in response from wildtype and eef1a2 heterozygous deletion mice (http://www.mousephenotype.org/phenoview/?gid=10566-19-3&qeid=IMPC_OFD_016_001&ctrl=3144161) including reduced center time. Mice were also noted as having the following phenotypes: mortality, cardiovascular , body and growth size, skeletal (bone density)",Score,1 (2),"This mouse model is part of the International Mouse Phenotyping Consortium (IMPC) and shows some phenotypic manifestations that are similar to those observed in individuals with EEF1A2 variants, including learning difficulties, reduced bone density, however these mice are not noted to exhibit seizures. The mice have not gone through extensive studies, nor have they been published in an article outlining there phenotypes, therefore, the score has been reduced.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_17551147-b62c-47a9-a12a-f425c23d90ff-2019-03-19T160000.000Z,679,PubMed:27626380 +"EEF1A2 expressed in rabbit brain, heart and skeletal muscle",Expression A,"de Kovel CG, et al., 2016, PMID: 27652284","Northern blot analysis of rabbit tissue was performed to indicate expression of EEF1A2. Figure 2 shows that EEF1A2 (1.8kb-1.9 kb specific band) is highly expressed in skeletal muscle, followed by brain and heart (aorta). This expression pattern is similar to that observed by RNA-seq from human tissue and is consistent with the organ systems involved in individuals harboring heterozygous EEF1A2 variation, including intellectual disability, seizures, hypotonia, as well as individuals harboring biallelic EEF1A2 variants that present with cardiomyopathy.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_17551147-b62c-47a9-a12a-f425c23d90ff-2019-03-19T160000.000Z,679,PubMed:27652284 +Functional studies of E345 variants,Functional Alteration Non-patient cells,"Hulleman JD, et al., 2011, PMID: 22031286","Hulleman et al. (2011) noted that arg345 is adjacent to cys344, which is required to form the second disulfide bond of EGF domain-6 in EFEMP1. By examining secretion of mutant EFEMP1 proteins in transfected HEK293T cells, they found that the R345W mutation or substitution of R345 with a different aromatic residue interfered with disulfide bond formation and secretion of EFEMP1. EFEMP1 with the R345W mutation accumulated intracellularly.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_2859008e-eeb1-4af4-8a6e-1bf5372bb3ab-2021-08-05T160000.000Z,680,PubMed:22031286 +Lei-Zebrafish-Model,Model Systems Non-human model organism,"Lei L, et al., 2017, PMID: 27899647",abnormal brain development,Score,0.5 (2),Downgraded by 1 point because it is a non-mammalian model organism; downgraded an additional 0.5 points because of the lack of phenotype in heterozygous knock-outs,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_66012775-240c-4640-ac66-12647021eee5-2022-07-20T160000.000Z,683,PubMed:27899647 +EFTUD2 knock-out zebrafish rescue,Rescue Non-human model organism,"Lei L, et al., 2017, PMID: 27899647",EFTUD2 knock-out zebrafish exhibit abnormal apoptosis in neural progenitors; expression of wildtype EFTUD2 in EFTUD2 knock-out zebrafish rescued apoptosis phenotype by >80%,Score,1 (2),Partial rescue,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_66012775-240c-4640-ac66-12647021eee5-2022-07-20T160000.000Z,683,PubMed:27899647 +Mice tumorigenesis,Model Systems Non-human model organism,"Regales L, et al., 2007, PMID: 17726540",Both mice lines harboring either p.T790M or p.T790M+p.L858R expressing alleles developed lung lesions ranging from nodules on lung MRI to histologically documented adenocarcinomas upon continuous treatment with expression inducing doxycycline. The latency period of tm development in mice carrying p.T790M or p.T790M+p.L858R is corresponding to the observations in humans such that the presence of the p.L858R variant in the tm tissue (in cis) in addition to the germline p.T790M variant is more common in patients with young age of onset and/or more advanced/aggressive tumors.,Score,3 (2),"They also showed the regression of tm lesions after discontinuation of doxycycline treatment (rescue in non-model organism), which is also consistent with relatively indolent nature of these lesions, particularly in humans with only p.T790M variants. The authors also showed that there is not a random second mutation occurence in the tm tissue of p.T790M mice.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_49342c73-96d7-45ba-9c90-d2d5e5710636-2020-07-30T202207.418Z,684,PubMed:17726540 +Dissociated cortical cell cultures,Model Systems Cell culture model,"Martens MB, et al., 2016, PMID: 27767173","This study knocked down the expression of EHMT1 to approximately 55% in cultured neuron cells. They observed the irregulatory activity of the neurons which were extracted during development in the rats can be correlated to the developmental delay, hypotonia and intellectual disability seen in patients with Kleefstra syndrome.",Score,1 (1),Gave default for cell culture model,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_db91a861-6a88-4848-b6d5-4772bdef52ff-2018-06-07T040000.000Z,687,PubMed:27767173 +EHMT1 null variant results in reduced H3K9 dimethylation,Functional Alteration Patient cells,"Blackburn PR, et al., 2017, PMID: 28361100","H3K9me2, a mark of transcriptonal repression catalyzed by EHMT1/2 heterodimeriaztion was ~50% reduced which is characteristic of KS mutations",Score,1 (1),H3K9me2 is a regulator of neuronal networks which has been shown in several studies to be linked to EHMT1 which has been shown to alter neuronal activity when its expression is varied which would explain the ID phenotype. Gave default patient cell functional alteration points because variant has more than enough evidence to stand alone without func.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_db91a861-6a88-4848-b6d5-4772bdef52ff-2018-06-07T040000.000Z,687,PubMed:28361100 +Functional alteration of neurons cultured from patient,Functional Alteration Patient cells,"Nagy J, et al., 2017, PMID: 28742076",This study was able to successfully differentiate the hiPSC derived cells to form an active neuronal network in a cell culture model from isolated stem cells from a patient with Kleefstra syndrome and a p.Trp1138Ter EHMT1 varaint. They found that EHMT1 expression was significantly reduced in these cells relative to controls via mRNA seq. They found impaired neurite development in the derived neurons from the KS-ASD patient by showing that the number of neuritesgrown out of the cell body and the number of the ends of all the neurites of a cell were fewer and the neurites were shorter in the patient's cells. These alterations in the neurons of this patient may be indicative of the DD/ID and hypotonia features of the patient with KS-ASD,Score,1 (1),"Gave default score to model showing variant caused neuron development that was altered in patient stem cells KS-ASD. While this may be better suited to be scored in the cell culture model section, the evidence for animal models already maxed out that section, and the expression of the EHMT1 in the neurons alone could be considered evidence which would max out the functional score, but since this does show an alteration in patient cells consistent with disease resulting from this variant, this strong piece of evidence can be scored here as well to max out experimental evidence.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_db91a861-6a88-4848-b6d5-4772bdef52ff-2018-06-07T040000.000Z,687,PubMed:28742076 +EHMT1 +/- KO mice,Model Systems Non-human model organism,"Iacono G, et al., 2018, PMID: 29554304","This heterozygous knockout mouse model was used not only to demonstrate the intellectual disability seen in Kleefstra syndrome, but it also attempted to identify the molecular mechanism of the haploinsufficiency that leads to the phenotype. They found that EHMT1 is a histone methyltransferase responsible for deposition of dimethylated H3K9 which acts as a regulator of protocadherin expression which is critical to neuronal diversity.",Score,2 (2),"Mouse model demonstrates ID using rotarod test, social recognition test, circadian activity tests, shock threshold tests, hot plate tests, pavlovian fear conditioning, mazes etc. and were found to present with severe cognitive deficits",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_db91a861-6a88-4848-b6d5-4772bdef52ff-2018-06-07T040000.000Z,687,PubMed:29554304 +Apoptosis assay,Functional Alteration Non-patient cells,"Gregory LC, et al., 2019, PMID: 30878599","The cells transduced with LV vector encoding EIF2S3- targeting shRNA failed to survive for as long as control cell populations. Furthermore, the EIF2S3 KD cell line had significantly higher basal and cytokine-stimulated caspase activities compared to control cells, suggesting increased apoptosis.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_bb96fe11-dd31-47b2-820d-9071035ec7b0-2021-11-11T170000.000Z,693,PubMed:30878599 +Migunova_drosophila,Model Systems Non-human model organism,"Migunova E, et al., 2021, PMID: 34338278","Authors found that the phenotype of these flies is consistent with the pathological features in human patients and recapitulated the main phenotypes including increased thickness of the heart wall, dilated heart lumen and decreased cardiac contractility.",Score,1 (2),Strongly recapitulated phenotype.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ff57f761-51cd-41aa-a287-7387e0f5f028-2022-07-21T040000.000Z,695,PubMed:34338278 +NADPH oxidase activity,Functional Alteration Patient cells,"Liu Q, et al., 2019, PMID: 31176364","This study showed all 9 SCN patients with 8 different variants of ELANE gene had eosinophilia and neutrophenia, the ROS profiles of eosinophils from these patients are similar to that from healthy control, but eosniophilia cannot compensate for the neutropenia regarding ROS-mediated function in these patients due to different ROS profiles of eosinophiles and neutropenia. I use variant [XM_011527775.1(ELANE):c.670_671del (p.Ala224LeufsTer?)] from P01 for this Curation.",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_259c43d2-b114-43bd-9e4e-a7beeb644323-2020-05-14T000924.456Z,696,PubMed:31176364 +NADPH oxidase activity,Functional Alteration Patient cells,"Liu Q, et al., 2019, PMID: 31176364","This study showed all 9 SCN patients with 8 different variants of ELANE gene had eosinophilia and neutrophenia, the ROS profiles of eosinophils from these patients are similar to that from healthy control, but eosniophilia cannot compensate for the neutropenia regarding ROS-mediated function in these patients due to different ROS profiles of eosinophiles and neutropenia. I use variant [XM_011527775.1(ELANE):c.593del (p.Cys198PhefsTer14)] from P09 for this Curation.",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_259c43d2-b114-43bd-9e4e-a7beeb644323-2020-05-14T000924.456Z,696,PubMed:31176364 +The PAX6 DRR (located in ELP4) drives ocular expression.,Biochemical Function B,"Kleinjan DA, et al., 2006, PMID: 17014839","Deletion of the DRR elements triggers loss of reporter gene expression, revealing the mechanism by which the loss of PAX6 can be accomplished by variants outside the coding sequencing.",Score,0.75 (0.5),The data convincingly argue for the role of the ELP4 cis elements in driving disease-relevant gene expression. Additional scoring has been considered due to the inclusion of a control deleting the DRR portion specifically.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_095db206-85a6-491a-929c-bb4db8d1240a-2023-11-16T170000.000Z,699,PubMed:17014839 +Cis motifs in the ELP4 locus control the expression of PAX6.,Protein Interaction,"Williamson KA, et al., 2020, PMID: 31700164","Intron 7, intron 8, and particularly intron 9 of ELP4 contain cis motifs that promote the expression of PAX6, which is definitively associated with ocular dysgenesis, including cases of aniridia. PAX6 associates with these cis motifs, as shown by immunoprecipitation of PAX6 from the chromatin fraction (PMID: 31700164).",Score,0.5 (0.5),This scoring is considered appropriate given the definitive relationship between the PAX6 gene and aniridia / the broader disease entity of ocular dysgenesis.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_095db206-85a6-491a-929c-bb4db8d1240a-2023-11-16T170000.000Z,699,PubMed:31700164 +Brielmaier knockout mouse model,Model Systems Non-human model organism,"Brielmaier J, et al., 2012, PMID: 22829897","Brielmaier et al. 2012 demonstrated that En2 null mice exhibit deficits in reciprocal social interactions as juveniles and adults, and absence of sociability in adults, replicated in two independent cohorts. Fear conditioning and water maze learning were impaired in En2 knockout mice as well.",Score,0 (2),"In the absence of human genetic evidence, the experimental evidence will be downgraded to 0 points to be consistent with the other curations from the ID/Autism GCEP.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_91eb2fc6-864c-4a4a-9b2d-0b2bdd695999-2021-02-16T170000.000Z,702,PubMed:22829897 +Takabayashi_mouse model,Model Systems Non-human model organism,"Takabayashi S, et al., 2014, PMID: 24770645","Like the human phenotype, the mice showed periarticular calcification",Score,1 (2),Model downgraded because it does not fully recapitulate the human phenotype,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_50cf1e96-1629-41c5-a5db-1c37e8b24aaa-2022-06-17T040000.000Z,704,PubMed:24770645 +Apschner_zebrafish,Model Systems Non-human model organism,"Apschner A, et al., 2014, PMID: 24906371","Human phenotype includes ectopic mineralization, early onset perichondrial ossification with calcification in the inter-cranial space, myocardium, and in the skin, and ectopic calcifications in the eye and craniofacial bones",Score,1 (2),Syndromic disorders GCEP downgrades zebrafish model to 1 point because of potential off-target effects of morpholinos,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_50cf1e96-1629-41c5-a5db-1c37e8b24aaa-2022-06-17T040000.000Z,704,PubMed:24906371 +Li_mouse model,Model Systems Non-human model organism,"Li Q, et al., 2014, PMID: 25479107","Like humans, the mice showed mineralization affecting the arterial vasculature",Score,1 (2),Model was downgraded because it did not fully recapitulate the human phenotype,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_50cf1e96-1629-41c5-a5db-1c37e8b24aaa-2022-06-17T040000.000Z,704,PubMed:25479107 +Expression 2,Expression A,"Soysal SD, et al., 2013, PMID: 23519058",shRNA knockdown of EPCAM in breast cancer cell lines has variable effects on cell proliferation.,Score,0 (0.5),Data is not scored due to no clear association with breast cancer phenotype.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_efe1b152-d818-49bd-9f6f-cebe944b3404-2023-12-21T180000.000Z,710,PubMed:23519058 +Xenopus embryo model,Protein Interaction,"Rohani N, et al., 2014, PMID: 25247423","Xenopus embryo model +Characterization of ephrin-Eph specificity in ectoderm explants +40nM EphrinB1, B2, B3, Fc fragments +Endogenous EphB4, EphB2, EphA4(GFP tagged) immunoprecipitated and blotted for phospho-tyrosine +Shows phospo dependent EPHB2 interaction",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d1a3438a-72a7-41f7-b140-2041ea7a39c1-2022-11-03T160000.000Z,713,PubMed:25247423 +Conditional knockout; Ephb4fl/fl Prox1-CreERT2 R26-mTmG mice,Model Systems Non-human model organism,"Martin-Almedina S, et al., 2016, PMID: 27400125","4-hydroxytamoxifen injected for 5 consecutive days from E10.5-E15.5 +Ephb4fl/fl Prox1-CreERT2 R26-mTmG embryos showed subcutaneous edema +Whole-mount IF of skin shows tortuous and dilated dermal lympathic vessels in knockouts +Injecting tamoxifen at E12.5, after initiation of dermal lymphatic vessel formation results in normal vasculature",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d1a3438a-72a7-41f7-b140-2041ea7a39c1-2022-11-03T160000.000Z,713,PubMed:27400125 +EPS8 KO Mouse,Model Systems Non-human model organism,"Zampini V, et al., 2011, PMID: 21526224",Both experience hearing loss. Hearing phenotype described in detail in KO mice.,Score,0.5 (2),Same mouse as Manor 2011. 0.5 points given for describing hearing phenotype of KO mice in detail,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7a6bd2bf-8ede-45cb-a1c1-65ee5221b440-2020-02-06T171614.553Z,715,PubMed:21526224 +Membrane Potential,Functional Alteration Non-patient cells,"Zampini V, et al., 2011, PMID: 21526224","Don't totally understand ion current/conductance/polarization experiments, but changes were significant (Fig 5)",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7a6bd2bf-8ede-45cb-a1c1-65ee5221b440-2020-02-06T171614.553Z,715,PubMed:21526224 +Immunofluorescence labeling,Expression A,"Zampini V, et al., 2011, PMID: 21526224",Eps8 localized to stereociliary tips,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7a6bd2bf-8ede-45cb-a1c1-65ee5221b440-2020-02-06T171614.553Z,715,PubMed:21526224 +Immunofluorescence labeling,Expression A,"Behlouli A, et al., 2014, PMID: 24741995","Immunofluorescent localization showed EPS8 concentrated at stereociliary tips, consistent with all other reports. Due to USH2 phenotype in patients with WHRN mutations, co-immunlabelling of Eps8 and whirlin in the macaque retina was used- found not to colocalize as they due in the mouse cochlea, indicating EPS8 is probably not cause usher syndrome",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7a6bd2bf-8ede-45cb-a1c1-65ee5221b440-2020-02-06T171614.553Z,715,PubMed:24741995 +Immunofluorescence/SEM,Protein Interaction,"Ebrahim S, et al., 2016, PMID: 27117407","In EPS8 KO mice, whirlin-S immunofluorescence was not detected at the tips of the tallest row of IHC or OHC stereocilia, but was present in shorter rows in OHCs only, indicating EPS8 functions to localize WHRN-S to stereocilia tips.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7a6bd2bf-8ede-45cb-a1c1-65ee5221b440-2020-02-06T171614.553Z,715,PubMed:27117407 +Dysregulation of ErbB4 immunoreactivity in the motor neurons,Expression B,"Takahashi Y, et al., 2019, PMID: 31124187","Loss of ErbB4 immunoreactivity in motor neurons from CNS tissue in some people. Where immunoreactivity was seen ErbB4 was mis-localized - for example being localized in the nucleus, some times as threads or dots. Glial and spheroid immunoreactivity also recorded. Sub-cellular TDP-43 staining and ErbB4 immunoreactivity was negatively correlated.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_fdd26ab6-0c1f-4322-9f70-cad651bb789f-2021-09-30T143144.993Z,717,PubMed:31124187 +ERCC6 essential to neuronal differentiation & neuritogenesis,Biochemical Function B,"Ciaffardini F, et al., 2014, PMID: 24874740",These findings are relevant to disease as they underscore the molecular basis of some of the neurological symptoms reported in patients with Cockayne syndrome.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e9dbf99e-d648-465c-8aa5-0840e76c0aeb-2022-08-18T100000.000Z,722,PubMed:24874740 +Espin gene therapy,Rescue Cell culture model,"Taura A, et al., 2016, PMID: 26886463",Reverses effects of aminoglycoside exposure to mouse hair cells. Unknown if rescues hearing phenotype in vivo,Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7c63a581-ad69-4f18-b68b-d1b2cef5e699-2018-02-27T170000.000Z,727,PubMed:26886463 +ETFA Zebrafish,Model Systems Non-human model organism,"Kim SH, et al., 2013, PMID: 23785301","The zebrafish model showed large increases of acylcarnitines and glutaric acid associated with multiple abnormalities of organs including brain, liver, kidneys and heart. A large increase in triacylglycerides and decrease of phosphatidylserine species was also shown and has been observed in human tissue from a patient with MADD (Galloway, 1987). The defects in the model recapitulate many of the abnormalities seen in human patients with MADD.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3d6848e7-6e9e-4545-9f97-69480face058-2018-05-22T160000.000Z,730,PubMed:23785301 +Song 2009 Zebrafish model,Model Systems Non-human model organism,"Song Y, et al., 2009, PMID: 20020044","Both xav and fibroblasts from a phenotypically severe MADD patient have similar metabolic defects and mitochondrial dysfunction, including altered energy metabolism, dysregulated ROS production and altered expression of genes critical for mitochondrial function. Tandem mass spectroscopy of plasma acylcarnitine detected a markedly higher level of a spectrum of intermediate acyl-fatty acid species in xav mutants, including C4, C5, C6, C8, C14, C16 and C18, together with a drastic reduction of C2 acylcarnitine (Figure 2A), suggesting dysregulation of mitochondrial β-oxidation and alterations in multiple intermediary mitochondrial metabolic pathways in xav, similar to that observed in MADD patients. Additionally altered respiratory capacity and compensation was observed in MADD patient cells as in xav mutants.",Score,1 (2),"Similar metabolic defects to patients were observed in this model, however there was not recapitulation of clinical phenotypes.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_062e336e-cfda-45f7-b509-cd44a5079034-2018-05-22T160000.000Z,731,PubMed:20020044 +ETHE1 K/O mouse rescue,Rescue Non-human model organism,"Di Meo I, et al., 2017, PMID: 28753212",AAV of wild type ETHE1 partially rescued ETHE1 mouse knock out phenotype. There was a partial resoration of cytochrome oxidase activity in muscle and brain.,Score,0.5 (2),Partial rescue of biochemical phenotype of ETHE1 knock out mouse.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d29d908d-ea85-4eb4-a6a5-400c95511c9a-2019-04-08T161759.443Z,732,PubMed:28753212 +Megakaryocyte Differentiation,Functional Alteration Non-patient cells,"Noetzli L, et al., 2015, PMID: 25807284","Cells transduced with lentivirus expressing Pro214Leu or Arg418Gly ETV6 showed delayed/decreased maturation when compared to control cells and those transduced with lentivirus expressing wild-type ETV6, as indicated by increased numbers of small, immature megakaryocytes and decreased generation of proplatelets.",Score,0.5 (0.5),Human CD34+ hematopoietic stem/progenitor cells (HSPCs) were transduced with lentiviral vectors expressing wild-type or patient-derived mutant ETV6 cDNA and cultured with thrombopoietin to support megakaryoctye development.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_92a8c1cb-91c1-45cd-adbe-4180b1f6da7d-2020-01-22T170000.000Z,734,PubMed:25807284 +Tail Suspension Test Mice KO,Model Systems Non-human model organism,"Yoon Y, et al., 2018, PMID: 29731676",KO mice display increased limb clasping and slightly higher torso flexion with decreased limb coordination which indicates a dystonia-like phenotype.,Score,0 (2),"KO homozygous EWSR1 mice do not capitulate the ALS phenotype, which is traditionally that heterozygous missense mutations contribute to the phenotype, and they might not necessarily be loss of function as the expression of the gene product is the same in WT and mutants.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_4e210cfa-3eb4-4f9b-ad0c-67cfae624029-2022-10-11T160000.000Z,735,PubMed:29731676 +Coulter - Zebrafish Model,Model Systems Non-human model organism,"Coulter ME, et al., 2020, PMID: 32103185","Zebrafish with homozygous loss of exoc7 showed head edema, microcephaly, and small eyes, as well as increased neuronal apoptosis in the developing telencephalon. These findings suggested that the microcephaly and brain atrophy in human with NEDSEBA results from loss of proliferating progenitor cells and postmitotic neurons, consistent with a neurodegenerative process.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_cfa8fad2-3961-4f16-861f-45ce6c859ad8-2023-06-20T160000.000Z,737,PubMed:32103185 +Osteochondromas form in the cranial base of Ext1 mutant mice,Model Systems Non-human model organism,"Sinha S, et al., 2017, PMID: 28445472","A retrospective analysis of cervical spine MRI and CT scans from 50 consecutive HME patients that included cranial skeletal images. Half of the patients displayed moderate defects or osteochondroma-like outgrowths in the cranial base and specifically in the clivus. In good correlation, osteochondromas developed in the cranial base of mutant Ext1f/f;Col2-CreER or Ext1f/f;Aggrecan-CreER mouse models of HME along the synchondrosis growth plates.",Score,1 (2),"The cranial base of many HME patients does in fact exhibit defects and osteochondroma-like outgrowths and that similar lesions form in the cranial base of mouse models of HME. Reduce points to 1 point, because this is a report of osteochondroma only in cranial base.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0ced1387-c0a8-4f03-bd70-1595cb7683fd-2018-06-04T170000.000Z,738,PubMed:28445472 +Li Animal Model,Model Systems Non-human model organism,"Li Y, et al., 2010, PMID: 19951260","Xenopus embryos injected with mutant Eya1 mRNAs had a number of morphological defects, including delayed overall development, reduced otic vesicle size, disordered surrounding tissue to otic vesicle. Mutant protein reduced normal expression of other developmentally regulated genes NT3, NeuroD, Ngn1, Tbx1, and BDNF",Score,1 (2),evidence for dominant-negative effect of EYA1 variaints. Downgraded points because frog cannot completely recapitulate BOR phenotype,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_dca41ef6-ee63-4b1f-93d3-8b114dafcc58-2017-11-21T170000.000Z,740,PubMed:19951260 +Li Rescue,Rescue Non-human model organism,"Li Y, et al., 2010, PMID: 19951260","Oligo-mediated knockdown of EYA1 was rescued by injection of Eya1 mRNA. Reduction of EYA1 caused impaired otocyst development, and was rescued with wildtype EYA1",Score,0.5 (2),scored 0.5 points to max out experimental evidence,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_dca41ef6-ee63-4b1f-93d3-8b114dafcc58-2017-11-21T170000.000Z,740,PubMed:19951260 +subcellular localization of EYS to cilia,Biochemical Function B,"Alfano G, et al., 2016, PMID: 27846257","Many ciliopathies present with features of retinitis pigmentosa, including night blindness",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7f70860e-464d-4d26-aee0-07ef03e4da1b-2022-11-03T160000.000Z,743,PubMed:27846257 +Alfano Macaque retina expression,Expression A,"Alfano G, et al., 2016, PMID: 27846257","presence of EYS in rods and cones by performing co-stainings with markers specific to each type of photoreceptors. As expected, we detected EYS +as unilaterally concentrated whip-like signal present in rods that were highlighted by labelling +of Rhodopsin. +Also expressed in cones",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7f70860e-464d-4d26-aee0-07ef03e4da1b-2022-11-03T160000.000Z,743,PubMed:27846257 +"zebrafish retinal morphology, ERG and protein localization",Model Systems Non-human model organism,"Lu Z, et al., 2017, PMID: 28378834",Human retinal degeneration is caused by photoreceptor cell death; increased zebrafish retinal apoptosis is analogous. The zebrafish also have reduced number of photoreceptors. Loss of photoreceptors outer segments could be explained by loss of proper protein localization. ERG is abnormal in humans and zebrafish.,Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7f70860e-464d-4d26-aee0-07ef03e4da1b-2022-11-03T160000.000Z,743,PubMed:28378834 +Danio Rerio locomotor visual response,Model Systems Non-human model organism,"Messchaert M, et al., 2018, PMID: 30052645","The zebrafish model has reduced visual function and abnormal retinal structure, like human patients",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7f70860e-464d-4d26-aee0-07ef03e4da1b-2022-11-03T160000.000Z,743,PubMed:30052645 +EYS expression (normal vs. mutant) in photoreceptor-fibrobla,Expression B,"Westin IM, et al., 2021, PMID: 33833316","Expression levels of exon 24–25 were significantly lower in Pt#1 (Wilcoxon test, p < 0.001) and Pt#2 (P = 0.0011) compared to the average of three normal volunteers. Those of Pt#1 was also lower than age-matched control, N#3",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7f70860e-464d-4d26-aee0-07ef03e4da1b-2022-11-03T160000.000Z,743,PubMed:33833316 +Fibroblast-derived photoreceptor model,Model Systems Cell culture model,"Rai D, et al., 2022, PMID: 35410372",The authors suggest that differential gene expression in EYS mutation patients may account for retinal degeneration; they also suggest an ER dysfunction model in affected patients.,Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7f70860e-464d-4d26-aee0-07ef03e4da1b-2022-11-03T160000.000Z,743,PubMed:35410372 +Expression levels of phototransduction genes in EYS cells,Functional Alteration Patient cells,"Rai D, et al., 2022, PMID: 35410372","cells derived from patients had reduced expression of photoreceptor genes; many genes were assayed, NRL was notably reduced",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7f70860e-464d-4d26-aee0-07ef03e4da1b-2022-11-03T160000.000Z,743,PubMed:35410372 +EZH2 mutants in vitro methyltransferase activity,Functional Alteration Non-patient cells,"Cohen AS, et al., 2016, PMID: 26694085",Weaver syndrome associated EZH2 variants showed reduced methyltransferase activity in vitro.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5dcf5941-6076-4486-94be-7ba3944abaee-2022-08-03T160000.000Z,744,PubMed:26694085 +Methylation assay using patient blood,Functional Alteration Patient cells,"Choufani S, et al., 2020, PMID: 32243864",Blood samples from weaver syndrome patient with EZH2 variant showed distinct DNA Methylation Signature that are different from control samples,Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5dcf5941-6076-4486-94be-7ba3944abaee-2022-08-03T160000.000Z,744,PubMed:32243864 +Tai_Mouse,Rescue Non-human model organism,"Tai SJ, et al., 2008, PMID: 18036190","F10-knockout mice were embryonically and perinatally lethal. Mice expressing the Fruili mssense variant showed survival rates similar to wild-type. FX:Ag was normal on Western blot, while FX:C was about 5.5% of wild-type. The Fruili mice also showed iron deposition in myocardium and colocalized fibrosis.",Score,2 (2),The evidence shows that the FX construct with the missense variant rescues embryonic lethality and the minimal FX activity is sufficient for survival. Default points are scored since humans with the Friuli variant also show mild disease and reduced FX activity.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_4adcc848-b354-4975-801f-4b55bbca64ad-2019-11-27T170000.000Z,745,PubMed:18036190 +IMPC_Mouse,Model Systems Non-human model organism,"Dickinson ME, et al., 2016, PMID: 27626380",Homozygous knockout of the F10 alleles resulted in embryonic lethality in mice.,Score,1 (2),"The evidence confirms that complete loss of FX activity is incompatible with life. The score is reduced; although the severity is much greater than that seen in humans, the evidence does not show recapitulation.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_4adcc848-b354-4975-801f-4b55bbca64ad-2019-11-27T170000.000Z,745,PubMed:27626380 +Guan_Rescue,Rescue Non-human model organism,"Guan Y, et al., 2016, PMID: 26964564","Average aPTT for WT was 22.1 ± 1.75 s, while F9-Y381D was 51.88 ± 2.71 s, which dropped to 32.7 ± 2.02 s. aPTT of treated mice was significantly shortened compared to mock-treated group, but was not significantly different from Wild-type group. With the tail-clip challenge, survival rate was increased from 38% in untreated group to 86% in F9-Y381D treated mice. Sequence analyses suggested the G>T correction in 0.56% of endogenous F9 alleles was sufficient to restore clotting activity. +Note: The nucleotide change specified in the paper is 31094T>G; however, the ClinGen Allele Registry and Mutalyser (https://tinyurl.com/y828dhsf) suggest the nucleotide change of 36061T>G for the p.Tyr371Asp amino acid consequence.",Score,2 (2),The CRISPR/Cas9 genome editing system has been successfully used to rescue Hemophilia B phenotype. The evidence is awarded default points.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3d56d08d-48d0-4523-b433-dbd44c5b9e45-2019-05-22T190226.728Z,756,PubMed:26964564 +Zebrafish faap24 LOF,Model Systems Non-human model organism,"Ramanagoudr-Bhojappa R, et al., 2018, PMID: 30540754","Homozygous knockout fish were observed among the surviving adults for all genes, indicating no lethality at earlier developmental stages for the generated alleles. However, lower proportion of homozygous knockouts found. Hypersensitivity to crosslinking DEB was not observed.",Score,0 (2),"No distinct phenotype noted in Zebrafish upon knockout of FAAP24, however, most phenotypes related to human disease were not assessed. No additional non-human models were found published.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_640890b8-ed2f-46bd-bf07-74e59da80cc2-2024-06-07T160000.000Z,758,PubMed:30540754 +FAM111B & dysfunctional role in diseases,Biochemical Function B,"Arowolo A, et al., 2022, PMID: 35860584","Mutational dysfunction of FAM111B protein causes POIKTMP by downregulating FAM111B gene and protein expression that are resulting in inadequate DNA repair, genome instability, chronic inflammation, and aberrant apoptosis of the epithelial cells. These effects may result in chronic inflammation causing the alopecia, joint contractures, and other features of POIKTMP",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d13f8dba-f9ae-42f3-a97a-dcc34b063e5b-2023-12-19T170000.000Z,759,PubMed:35860584 +"Fancb mutant mice, Kinetics of BM recovery, HSC function.",Model Systems Non-human model organism,"Du W, et al., 2015, PMID: 26658157","The cells of the hematopoietic system of Fancb−/y mice are hypersensitive to DNA cross-linking agent mitomycin C (MMC), just the same that in human FANCB deficient cells. +The hematopoiesis in adult Fancb deficient (Fancb−/y) mice have decreased hematopoietic stem +cell (HSC) quiescence accompanied by reduced progenitor activity in vitro and reduced repopulating capacity, similar to humans with FANCB deficiency.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_eb559b04-602e-42cc-aad3-ce634c145c26-2022-12-30T180000.000Z,761,PubMed:26658157 +Structure-based yeast two-hybrid analysis,Functional Alteration Non-patient cells,"Nookala RK, et al., 2007, PMID: 17308347","When tested in the yeast two-hybrid assay, no interaction was observed between the R371W FANCE protein and FANCD2 (Figure 5). This data provides a structural rationale for the pathological effect of the R371 mutation in FANCE.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6da55a6e-2cf8-499c-b842-b5a435dbff3f-2020-05-14T001745.604Z,764,PubMed:17308347 +Bone marrow hematopoiesis assays,Model Systems Non-human model organism,"Dubois EL, et al., 2019, PMID: 31219578",Lower peripheral blood platelet counts in in both single mutant mice and double mutant mice compared to the wild-type mice. None marrow hematopoietic progenitors from all mutant mice were hypersensitive to mitomycin C.,Score,2 (2),"Fanci knockout mice displayed typical FA features such as delayed development in utero, microphtalmia, cellular sensitivity to mitomycin C, occasional limb abnormalities and hematological deficiencies. Interestingly, the deletion of Fanci leads to a strong meiotic phenotype and severe hypogonadism. Embryonic lethality of Fanci-/- in mice is also observed.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a103db2f-a8b3-403b-993a-ac4215c118df-2021-06-15T233841.081Z,767,PubMed:31219578 +Leigh map,Biochemical Function A,"Rahman J, et al., 2017, PMID: 27977873","According to Leigh map, there are 13 nuclear genes involved in mitochondrial translation associated with Leigh syndrome, including the mitochondrial tRNAs, EARS2, IARS2, and NARS2.",Score,2 (0.5),scored according to GCEP rubric,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_2cf7594a-d934-4b6c-8052-94066d608c5a-2019-11-25T144756.827Z,771,PubMed:27977873 +Vantroys 2017 patient cell,Functional Alteration Patient cells,"Vantroys E, et al., 2017, PMID: 29126765","To verify whether the observed reduced availability of aa-mt-tRNAPhe resulted in impairment of the mitochondrial translation rate, mtDNA-encoded polypeptides were labeled using 35S-L-methionine upon inhibition of cytoplasmic protein synthesis. A considerable decrease of translation of mitochondrially-encoded polypeptides was detected in primary fibroblasts from probands 1 and 2 (Fig. 5). The defect in mitochondrial protein synthesis rate was, for some of the subunits, stronger in proband +2, consistent with a more pronounced defect in aminoacylation of mttRNAPhe. The defect in synthesis rate was not general for all subunits of the same complex, e.g. for complex I a decreased synthesis of ND6 can be seen, while ND3 synthesis is comparable to controls. To investigate if the decreased translation rate of mitochondrial encoded subunits impaired the assembly of mitochondrial complexes,complex I assembly was evaluated in fibroblasts from proband 2 using an antibody against the subunit NDUFS2, which is present from the earliest subcomplexes. In normal control fibroblasts, this subcomplex was visible in 60% of cases at 7.15 ± 3.50%, maximum 13% of the fully assembled complex. In proband 2, there was an increased amount 18–28% of the subcomplex at 230 kDa (Fig. 6). The 230 kDa subcomplex is the point at which the first mitochondrial DNA encoded subunit ND1 is added to the growing complex and an increase in the 230 kDa subcomplex is observed in other defects of mitochondrial DNA translation.",Score,1.5 (1),"Evidence of disrupted mitochondrial translation in cells from 2 patients, evidence of disrupted complex assembly in cells from 1; scored according to GCEP rubric",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_2cf7594a-d934-4b6c-8052-94066d608c5a-2019-11-25T144756.827Z,771,PubMed:29126765 +FASTKD2 RNAi and CRISPR mediated knockdown in HEK293 cells,Functional Alteration Non-patient cells,"Popow J, et al., 2015, PMID: 26370583","Fig 4. iCRISPR mediated knock out (null) and siRNA mediated knockdown (85%) FASTKD2 in stably transduced HEK293 cells. Complete knockout of FASTKD2 expression of in HEK293 cells resulted in a reduction in mitochondrial protein translation (D), reduction in overall oxygen consumption rate (E) and reduction in complex I, Complex III, IV and V (I) as measured in isolated mitochondria.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_82883e8c-7ee6-447e-bdc6-8898c4848e7a-2022-07-21T160000.000Z,772,PubMed:26370583 +FBLN5 promotes the proliferation of Scwann cells,Functional Alteration Non-patient cells,"Won SY, et al., 2020, PMID: 33107705","S16 cells were treated with recombinant FBLN5 protein in a dose‐dependent manner followed by cell counting kit‐8 (CCK‐8) analysis (Figure ​(Figure2A). The results revealed that 10 ng/mL of recombinant FBLN5 was sufficient to facilitate the proliferation of S16 cells (Figure 2A‐C). Next, WJ‐MSCs were transfected with two kinds of verified siRNAs for FBLN5 then co‐cultured with S16 cells. The S16 cells cultivated with FBLN5‐depleted MSCs showed fewer cells than S16 cells cultured with control MSCs (Figure 2B,C). In order to clarify the role of FBLN5 in SC proliferation, 5‐bromo‐2′‐deoxyuridine (BrdU) assay was performed in S16 cells with or without recombinant FBLN5. The assay data showed that the proliferation of FBLN5‐treated S16 cells was more accelerated (Figure 2D,E).",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a863341a-9dcf-4a4f-a82d-7edb5e63fe92-2023-11-28T170000.000Z,775,PubMed:33107705 +WJ‐MSCs derived paracrine factors affecting Schwann cells,Expression A,"Won SY, et al., 2020, PMID: 33107705",Antibody microarrays identified elevated FBLN5 secretion under co‐culture with S16 cells (Figure ​1E). Enzyme‐linked immunosorbent assay (ELISA) for FBLN5 confirmed that WJ‐MSCs cultured with S16 cells secreted more FBLN5 than the cells cultured alone (Figure 1F).,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a863341a-9dcf-4a4f-a82d-7edb5e63fe92-2023-11-28T170000.000Z,775,PubMed:33107705 +Zebrafish Model,Model Systems Non-human model organism,"Won SY, et al., 2020, PMID: 33107705","Lack of fbln5 led to a decrease in cell proliferation, whereas the exogenous fbln5 increased cell proliferation. Knockdown of fbln5 results in myelination defects in the zebrafish PNS without gross morphological defects depending on the concentration of MOs. Symptoms in humans are a result of demyelination.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a863341a-9dcf-4a4f-a82d-7edb5e63fe92-2023-11-28T170000.000Z,775,PubMed:33107705 +Zebrafish Rescue,Rescue Non-human model organism,"Won SY, et al., 2020, PMID: 33107705","Overexpressed exogenous fbln5 in the CMT zebrafish model rescues the myelination defects to normal levels (Figure 6A,B). Further TEM analysis revealed that the uncompact myelin sheaths of the Mauthner neuronal axons and reticulospinal tracts in the CMT zebrafish are significantly recovered by exogenous fbln5 (Figure 6C,D).",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a863341a-9dcf-4a4f-a82d-7edb5e63fe92-2023-11-28T170000.000Z,775,PubMed:33107705 +Reduced FBN1 microfibril incorporation in MFS mutants,Functional Alteration Non-patient cells,"Jensen SA, et al., 2015, PMID: 25979247","When either GFP-tagged FBN1- C1564Y, -C1719Y, or -C1720Y Marfan syndrome related mutation were expressed in HEK293 cells, incorporation of FBN1 was reduced in the cell medium. The transfected cells still expressed the constructs, indicating that FBN1 was either not effectively secreted and/or incorporated into the microbrils of the extracellular matrix. In addition, co-culturing of the transfected HEK293 cell with human dermal fibroblasts (microfibril incorporation assay) further supported the lack of microfibril incorporation of the MFS related FBN1 mutants C1564Y, C1719Y, and C1720Y, as no GFP fluorescence was observed in the microfibril network in these co-cultures. To deduce whether secretion of incorporation was an issue, MSU-1.1 cells (human fibroblast line) that are able to assemble extracellular microfibril and contain all cellular factors required to fibrillin-1 folding, processing, secretion, and assembly were used. Expression of the FBN-1 MFS mutants (C1564Y, C1719Y, and C1720Y) resulted in reduced expression of the recombinant Npro-cbEGF18-26 FBN-1 mutant constructs, indicating impaired secretion of the mutant FBN-1 by these cells.",Score,1 (0.5),"Because they used two different cell lines to show that the problem was with secretion and incorporation, and not with levels of expression of the constructs.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d3fc0bea-4d6e-449e-885c-b204e6a0b2bf-2019-03-04T170000.000Z,777,PubMed:25979247 +Leigh map,Biochemical Function A,"Rahman J, et al., 2017, PMID: 27977873",Leigh map,Score,1 (0.5),shares a function with 2-5 gene products,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_fed67104-182c-48f2-85c0-ecb05cd6dd72-2020-11-23T193117.246Z,778,PubMed:27977873 +Emperador rescue patient cells,Rescue Patient cells,"Emperador S, et al., 2020, PMID: 31969900","Genetic complementation studies. Stably transduced patient cells showed a robust expression of wildtype FBXL4 (wt-FBXL4) at transcript and protein levels (Figures 2A, B). The quantification of FBXL4 transcripts by qRT-PCR revealed decreased steady-state levels of FBXL4 mRNA in S1 and S2 by approximately 80% when compared with an age matched control cell line, C1. These levels were increased significantly in the over-expressing cell lines (Figure 2A). The WB immunodetection assay failed to detect the FBXL4 protein in the total protein lysate of non-transduced cells (Figure 2B). Delivery of the wt-FBXL4 gene increased significantly the amount of mtDNA in both patient cell lines (Figure 2C). As a result, the mtDNA copy number deficiency in S1 cells was corrected (compared to C), whereas in S2 cells the mtDNA levels increased up to 200% of the levels of controls. In both S1 and S2 cells over-expressing wt-FBXL4, the steady state levels of respiratory complex subunits were fully rescued (Figure 1D), the CIV specific activity was increased to control values (Figure 2D), and the CS activity and lastly the mitochondrial ATP levels were also increased significantly (Figures 2E, F). Genetically complemented S1 cells recovered partially the tubular appearance of the mitochondrial network observed in C1 but interestingly, genetically complemented S2 cells maintained a fragmented mitochondrial network (Fig. 3).",Score,1 (1),Complete or partial rescue of mitochondrial dysfunction. Some variability between patient cell lines. S1 meets inclusion criteria; S2 does not.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_fed67104-182c-48f2-85c0-ecb05cd6dd72-2020-11-23T193117.246Z,778,PubMed:31969900 +Emperador patient cells,Functional Alteration Patient cells,"Emperador S, et al., 2020, PMID: 31969900","Analysis of mtDNA copy number revealed severe mtDNA depletion in muscle biopsies of the patients (85% in S1 and 93% in S2). In cultured skin fibroblasts, milder mtDNA depletion was detected in S1 (38%) whereas normal levels of mtDNA were observed in S2 (Figure 1B). The levels of five mitochondrial transcripts (transcripts of MT-ND1 and MT-ND6 subunits from CI; MT-CYB subunit from CIII, MT-CO1 subunit from CIV and MT-ATP6 subunit from CV) were consistently reduced in S1 and S2 compared with control fibroblasts (Figure 1C). Notably, S2, with normal mtDNA copy number, showed the highest reduction of the five transcripts measured. The steady-state levels of subunits from respiratory chain complexes were also found decreased in fibroblasts from S1, and, to a greater extent, in fibroblasts from S2 (Figure 1D). The levels of the nDNA-encoded ATP5A subunit from CV, however, remained unchanged in S1, or were mildly decreased in S2, excluding a global problem in the mitochondrial protein content. The expression of two subunits (SDHA and SDHB) of the nuclear encoded complex II, the citrate synthase (CS) of the TCA cycle, and the translocase of the outer mitochondrial membrane (TOMM20) were partially decreased in S2 (Figure 1D). Fully assembled CIV levels were clearly lower in patient fibroblasts relative to controls (Figure 1E). Enzymatic measurements provided evidenced of a severe CIV dysfunction (Figure 1F). Noteworthy, the CS activity in fibroblasts from S1 and S2 was also significantly diminished (Figure 1F). Assessment of mitochondrial content by staining with the cationic lipophilic dye MitoTracker Green showed a small but significant increase in mitochondrial content (15–20%) in S1 and complemented S1 cell lines compared to control (C1), and a remarkable increase (250% of C1) was detected in S2 fibroblasts and in the S2 cell line overexpressing wt-FBXL4. S1 and S2 cell lines showed fragmentation of the mitochondrial network. (Fig. 3)",Score,1 (1),Evidence of mitochondrial dysfunction in patient cells.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_fed67104-182c-48f2-85c0-ecb05cd6dd72-2020-11-23T193117.246Z,778,PubMed:31969900 +TCR-dependent T-cell activation,Functional Alteration Non-patient cells,"Łyszkiewicz M, et al., 2020, PMID: 32098969","FCHO1-deficient Jurkat clones were reconstituted with either wt or mutated FCHO1 using retroviral vectors and TCR distribution was analyzed upon stimulation using confocal microscopy. After 60 min of TCR triggering by an α-CD3 monoclonal Ab, large intracellular CD3-positive puncta were formed in wt cells, whereas in FCHO1 ko clones CD3 molecules remained in diffuse form. Knockout clones reconstituted with wt FCHO1 formed large CD3-positive puncta, essentially indistinguishable from those in wt cells. In contrast, none of the FCHO1 mutants were able to rescue the phenotype. +The authors next measured the intracellular accumulation of CD3:TCR complexes upon anti-CD3-mediated TCR triggering over time using flow cytometry. Consistent with the confocal microscopy studies, they noted that FCHO1 ko cells accumulated approximately two-fold less CD3:TCR complexes when compared to wt cells. Finally, they assessed whether FCHO1 directly modulated TCR responsiveness by investigating Jurkat cells, sufficient or deficient for FCHO1, stimulated with an α-CD3 antibody and assessed for release of intracellular Ca2+. When compared to controls, FCHO1-deficient cells released less Ca2+ upon CD3:TCR triggering. Furthermore, only reconstitution with wt but not mutated forms of FCHO1 restored normal levels of Ca2+, directly demonstrating that physiological TCR signalling depends on FCHO1.",Score,0.5 (0.5),"Provides evidence that FCHO1 plays a role in TCR-dependent T-cell activation. It affects TCR clustering upon receptor triggering and modulates its internalization. Finally, FCHO1 deficiency results in impaired mobilization of Ca2+, directly linking the FCHO1 to TCR-associated signaling.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ae21f2b2-e283-404b-9517-74fad00a352a-2023-07-20T170000.000Z,780,PubMed:32098969 +Mouse Model of c.315-48C variant for EPP,Model Systems Non-human model organism,"Barman-Aksözen J, et al., 2017, PMID: 28093505",Skin photosensitivity is the main clinical symptom of patients suffering from EPP. The emi mice exhibit acute symptoms on exposed skin (while controls did not). They additionally showed behavioral changes indicating pain.,Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d1b6529d-0a99-4ffd-9bbf-6bc15d76cb10-2023-01-27T200000.000Z,782,PubMed:28093505 +Vo_Zebrafish model,Model Systems Non-human model organism,"Vo AH, et al., 2013, PMID: 24098662","About 2% of larvae with fgb knocked down showed signs of hemorrhage; primarily intracranial hemorrhage, but also intramuscular and peri-orbital hemorrhage and hematomas.",Score,1 (2),"Although the model organism recapitulates the human phenotype, the evidence is scored reduced points since the gene alteration accomplished partial knock down. Score may be upgraded to default upon expert review.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_638c1588-9674-4bc3-a39c-2fc8f8b0ef09-2020-01-22T170000.000Z,785,PubMed:24098662 +Frabin/Fgd4 regulates endocytosis in Schwann cells,Functional Alteration Non-patient cells,"Horn M, et al., 2012, PMID: 23171661","reduced Fgd4 levels shown to cause lower levels of active Cdc42 in rat schwannoma cell line RT4 (Fig. 9A,B), transferrin uptake assay shoed reduced transferrin uptake ability (Fig. 9C,D), this data is suggestive of impaired Schwann cell endocytosis",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e0aae8cd-9d57-4d8c-83ae-ed968cf186bc-2020-04-14T131822.010Z,787,PubMed:23171661 +FGD4 LoF mouse model for CMT4H,Model Systems Non-human model organism,"Horn M, et al., 2012, PMID: 23171661","Western blot of Fgd4 -/- (null) mice sciatic nerve lysates show lack of Fgd4 protein expression (Fig. 1B), null mice were viable and had not major abnormal behavior by SHIRPA analysis up to 60wks of age, mice had normal body size and weight (Supplementary Table S1), grip strength test at 60wks showed null mice have mildly impaired performance compared to WT mice, null mice at 60wks had increased distal latencies and increased F-wave latencies, reduced nerve conduction velocity, and dispersed compound muscle action potentials with reduced amplitude compared to WT (Fig. 1C,D). All analyzed nerves of null mice showed aberrant myelin structures, with myelin outfoldings and infoldings, absent/thin myelin, myelin debris and polyaxonal myelination (Fig. 2, Supplementary Fig. 1), null mice had more aberrant myelin structures compared to WT at all time points from post-natal day 14-80wks, with alterations being progressively more severe with age (Fig. 4A,B), myelinated axons without aberrations had normal myelin thickness (Fig. 4C), In 60wk null mice there was an increased growth ratio suggesting thinner myelin (Fig. 4D), the number of fibers with signs of demyelination and partial remyelination reached statistical significance at 80wks in null mice, with a steep rise from 60-80wks (Fig. 4E), there was no evidence of major primary or secondary axonal loss in null or WT mice (Fig. 4F). +Null mice had normal levels of AKT, ErbB2, regulatory phosphatases, and PTEN interactor Dlg1 (Fig. 7A,B), the active form of Cdc42 was significantly reduced in sciatic nerves of adult null mice compared to WT, with total levels of Cdc42 remaining unchanged, but ratios of active-Cdc42/total-Cdc42 and active-Cdc42/glyceraldehyde-3-phosphate dehydrogenase being reduced (Fig. 7C,D), this data supports role of Fgd4 acting as a GEF for Cdc42 in peripheral nerves in vivo",Score,3 (2),Multiple evidence from CMT4H mouse models used to ascertain role of FGD4 in nerve development and homeostasis in context of CMT4H disease mechanism.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e0aae8cd-9d57-4d8c-83ae-ed968cf186bc-2020-04-14T131822.010Z,787,PubMed:23171661 +G112S exerts GOF effect on Nav1.6 and Nav1.2 channels,Functional Alteration Non-patient cells,"Seiffert S, et al., 2022, PMID: 36029553",Gain-of function effect of the variant G50S/G112S on Nav1.6 on the voltage-dependence of fast inactivation (similar to R52H/R114H on Nav1.6),Score,0 (0.5),"Scored as variant level evidence, not functional evidence for gene",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_54324da6-e7c7-4ad2-a669-d8ccd1a6b71a-2023-11-01T160000.000Z,788,PubMed:36029553 +S8P exerts GOF effect on Nav1.6 and Nav1.2 channels,Functional Alteration Non-patient cells,"Seiffert S, et al., 2022, PMID: 36029553","S8P caused GOF changes in NaV1.6 and NaV1.2 channels, mainly by affecting the time constant of fast inactivation components of both channels. These changes lead to a stronger deceleration of fast inactivation of NaV1.6 and reduced the regulating effect of WTA on the recovery from fast inactivation especially on the slow component (t2).",Score,0 (0.5),Scored as variant level evidence; not functional evidence for gene,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_54324da6-e7c7-4ad2-a669-d8ccd1a6b71a-2023-11-01T160000.000Z,788,PubMed:36029553 +Lahlou Biochemical Function,Biochemical Function A,"Lahlou H, et al., 2018, PMID: 29902227",combined FGF10/FGF3 exposure to hiPSCs induces conversion to otic/placodal progenitor cells,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5ca11e8c-6703-4be5-a8c2-82e6dcc865e4-2019-05-21T160000.000Z,789,PubMed:29902227 +Expression in human embryonic stem cells,Expression A,"Zhou S, et al., 2020, PMID: 32664970","Studied expression in human embryonic stem cells undergoing differentiation to cardiomyocytes and expression in the human embryonic heart. +FGF8 was expressed in the outflow tract (OFT) of human embryos, further supporting the role of FGF8 and FGF10 in development of the OFT",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_fcfc7314-105a-428b-b4a0-0a0da4702192-2024-05-07T160000.000Z,790,PubMed:32664970 +Calvert Mouse Model,Model Systems Non-human model organism,"Calvert JA, et al., 2011, PMID: 21479780","Variant is: p.Trp691Arg. Not in ClinVar or HGMD. Some skull involvement which is consistent with disease, but did not fully recapitulate disease specific phenotypes. Given the unspecific phenotypes and that this variant is not seen in association with HS, and that there are other diseases associated with FGFR1 (other variants), model not scored.",Score,0 (2),"Only skull size was studied, not brain size and deformities. Did not recapitulate disease specific phenotypes. Other diseases associated with different FGFR1 variants; not disease specific. For these reasons, model given 0 points.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ec5034c6-70cb-4ba3-bbb9-f65f6cad393d-2021-03-16T235509.401Z,793,PubMed:21479780 +Perrine Mouse Model,Model Systems Non-human model organism,"Motch Perrine SM, et al., 2019, PMID: 31064775","Variant mice were shown to have mandibles with distinct morphology relative to their unaffected littermates. Variant mice also show increased bone density compared to control mice. This recapitulates the facial abnormalities in human PS patients, and shows the GOF mechanism of disease.",Score,0 (2),This study used to upgrade score of original model (Eswarakumar et al. 2004; PMID: 15316116) instead of being scored individually.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_eccfe56b-15d7-4ba9-abf2-163dfd3dab3c-2022-03-21T210958.425Z,797,PubMed:31064775 +Hypochondroplasia Mouse Model,Model Systems Non-human model organism,"Loisay L, et al., 2023, PMID: 37345656","The presence of the Fgfr3 p.Asn534Lys mutation impairs the function of both long bone cartilage and cranial synchondroses, resulting in defective bone growth and foramen magnum formation. Similarly, the spine was severely affected, with abnormalities of the IVD visible from birth and throughout adulthood. Unexpectedly, analysis of osteogenesis in adult Fgfr3Asn534Lys/+ mice demonstrated opposing effects of the p.Asn534Lys mutation in the trabecular and cortical compartments of long bones. As observed previously in juvenile ACH and TD mice, the HCH gain-of-function mutation resulted in decreased trabecular bone mineral density (BMD) in tibiae, femurs, and vertebral bodies. However, in contrast, increased tibial and femoral cortical BMD in adult Fgfr3Asn534Lys/+ mice was observed, demonstrating that long bones were brittle with reduced toughness. Consistent with this, transcriptional profiling of the femoral cortical bone demonstrated a downregulation of markers of the osteoblast lineage and high-resolution micro–computed tomographic (μCT) analyses of cortical bone highlighted anomalies of the osteocyte lacunae in the Fgfr3Asn534Lys/+ mouse model of HCH. Altogether, these findings indicate that the N534K mutation leads to aberrant regulation of mature osteoblasts and osteocytes in trabecular and cortical bone. The mouse also presents with macrocephaly and prognathism.",Score,3 (2),This mouse was scored higher than the default for phenotypic specificity along with knock-in of the variant seen in the majority of FGFR3-hypochondroplasia cases.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_518a0eb2-f7ea-40e8-acad-afc34f5b188e-2023-09-28T160000.000Z,800,PubMed:37345656 +Sun Zebrafish Model,Model Systems Non-human model organism,", , PMID: 32641982",This model partially recapitulates phenotypes seen in human patients: microcephaly and hearing loss.,Score,0.5 (2),Downgraded for partial recapitulation of human phenotypes.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_90130560-3e24-46a9-beaa-c67792773d3d-2022-06-07T160000.000Z,801,PubMed:32641982 +A391E HEK 239 T Cells Follow Up,Functional Alteration Non-patient cells,"Chen F, et al., 2013, PMID: 23437153","In HEK239T Cells, FGFR3/A391E cells were shown to have increased fgf1 ligand-dependent activity. There was a noted increase in Y647 and Y648 activity in the activation loop of the FGFR3 kinase domain.",Score,0 (0.5),"Not scored as this is a follow-up, complementary functional alteration experiment by the same lab group.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_98727c21-26dd-4e65-b75e-8ec82d95ba97-2021-11-18T170000.000Z,802,PubMed:23437153 +Krejci Phosphorylation assay,Functional Alteration Non-patient cells,"Krejci P, et al., 2008, PMID: 19088846","K650M and K650E increase STAT1 activation/phosphorylation, ERK/MAP strongly induced by these variants (and others), which leads to inhibited proliferation in RCS chondrocytes.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a7daa910-8226-46cc-8a65-034c0833d9cc-2022-05-09T160000.000Z,803,PubMed:19088846 +Hearing loss in a mouse model of Muenke syndrome,Model Systems Non-human model organism,"Mansour SL, et al., 2009, PMID: 18818193","gfr3 P244R/+ and P244R/P244R mice showed dominant, fully penetrant low-frequency hearing loss that was similar but more severe than in Muenke syndrome patients. Mouse hearing loss correlated with an alteration in the fate of supporting cells (Deiters-to-pillar cells) along the entire length of the cochlear duct, especially at the apical or low-frequency end. There was excess outer hair cell development in the apical region. Hearing loss was dosage sensitive as homozygotes were more severely affected than heterozygotes (OMIM)",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e94c1870-5413-4f75-8925-8bea54199d47-2022-03-29T172023.530Z,805,PubMed:18818193 +Kan-O KO mouse model,Model Systems Non-human model organism,"Kan-O M, et al., 2012, PMID: 23213483",Abnormal cardiac development demonstrated with embryonic lethality. Rescue with transgenic KO mice expressing FHOD3. Transgenic mice with mutated FHOD3 had abnormal myofibril maturation,Score,0.5 (2),Not an HCM model (reduced further to 0.5 by working group at presentation),https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c31027fe-8143-4022-8bbb-867eb1692c51-2023-09-29T160000.000Z,807,PubMed:23213483 +Pale tremor mice,Model Systems Non-human model organism,"Ferguson CJ, et al., 2009, PMID: 19793721","p62/ubiquitin inclusion bodies are a hallmark of ALS. Detection of p62/ubiquitin inclusions in Fig4-deficient mice support the role of this gene in ALS. +Markers of autophagy are elevated in brain from Fig4−/− brain. To determine whether the elevated p62 in Fig4−/− brain is associated with ubiquitinated protein, brain slices were immunostained for p62 and ubiquitin. Co-localization of p62 and ubiquitin was evident in sections of the cortex and other regions of the brain.",Score,0.5 (2),"Pale tremor mice have an AR inherited disorder, with phenotypes reminiscent of Charcot-Marie-Tooth disease. Overall, the mouse does not model ALS but there is still some support for how FIG4 could relate to ALS via the p62/ubiquitin inclusion bodies.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d038fb84-1f98-4047-b6c5-039a53756775-2022-08-09T160000.000Z,808,PubMed:19793721 +Drosophila models of FITM2,Model Systems Non-human model organism,"Zazo Seco C, et al., 2017, PMID: 28067622","The causative association of the syndrome with a loss-of-function mutation in FITM2 is supported by modeling of the disease in Drosophila melanogaster, which has been proven to be a suitable model for studying conserved aspects of lipid metabolism and LD biology. RNAi knockdown of the single Drosophila Fitm ortholog recapitulated hearing impairment, locomotor defects and abnormalities of the sensory system.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0a18aeda-fbe1-49b3-9542-6402ea61b4c0-2022-10-17T160000.000Z,809,PubMed:28067622 +Van der Ven protein interaction,Protein Interaction,"van der Ven PF, et al., 2000, PMID: 11038172",Y2H method showed 2 Ig-like domains from myotilin interacted directly with Ig-like domain 20 of FLNC – indicating that the amino-terminal of FLNC may be indirectly anchored to 𝛼-actinin in the Z-disc via myotilin,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d61672a0-06f2-4df4-845b-57566075fdb1-2023-10-26T010000.000Z,812,PubMed:11038172 +Zebrafish flncb-MO,Model Systems Non-human model organism,"Begay RL, et al., 2016, PMID: 28008423","Knockdown of flncb in zebrafish induces poor systolic function that is required for normal cardiac morphology and contractile behavior. There is a difference in the severity of the phenotypes, which is not unexpected because the human subjects are heterozygous and experiencing late-onset phenotype, whereas our zebrafish +model depicts the consequences for embryonic, full, or strong LoF of FLNC.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_edb5197f-05dc-42a4-a497-fff472985c6b-2020-11-06T170000.000Z,813,PubMed:28008423 +Mouse I304N,Model Systems Non-human model organism,"Zang JB, et al., 2009, PMID: 20011099","The most widely used model for Fragile +X Syndrome is a complete null due to the +insertion of the neo cassette in exon 5 of the Fmr1 gene. By causing +loss of FMRP expression, the mutation largely +recapitulates the human Fragile X Syndrome at the protein level. As a +model system, the I304N mouse genocopies the human I304N +patient better than the null mouse genocopies the CGG repeat +expansion. The I304N mutation causes defective KH2-mediated RNA +binding in neurons, and decreased FMRP levels, particularly in +younger animals. The loss of KH2 function accounts for the +dissociation of the protein from brain polyribosomes. We propose +that this leads to a loss of proper translational control of FMRP +mRNA targets, which in turn leads to the cognitive and behavioral +deficits observed in the Fragile X Syndrome.",Score,1 (2),Downgraded as ID phenotype is difficult to assert in a mouse model.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e491d278-7123-434c-8de3-46e16afb4037-2019-06-03T160000.000Z,818,PubMed:20011099 +Knockdown/over-expression in mice,Expression A,"Yang C, et al., 2020, PMID: 32561820","FN1 knockdown was completed with siRNA and cells were triggered using osteogenic induction medium (Si-FN-1) and overexpression of FN1 (OE-FN1-1 & OE-FN1-2) was analyzed. The osteoblastic markers Runx 2, OCN, and OSX were expressed at lower levels in the knockdown mutants, and higher levels when FN1 was overexpressed, than in the respective controls.",Score,0.5 (0.5),Please note that only the knockdown/over-expression data from mice was scored. The general expression data from mice as they aged and from osteoporosis patients was not scored due to not being specific to SMDCF.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_33f71829-1d1a-4d34-b2ff-1df63ec5d0b5-2024-03-06T170000.000Z,819,PubMed:32561820 +Humphrey's Lab Expression,Expression A,"Wang Y, et al., 2021, PMID: 34424825",The data is not actually from this paper. It is Humphrey's lab expression data showing that there is high levels of expression of this gene in the glomerulus relative to other areas of the kidney.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3ffbb09f-bf2d-4d76-9176-4961ce8862e9-2023-10-04T160000.000Z,820,PubMed:34424825 +FOXC1 chromatin IP from trabecular meshwork cells,Biochemical Function B,"Ito YA, et al., 2014, PMID: 24556684","The ChIP / HSPA6 data help to link FOXC1 to the ability of trabecular meshwork cells to respond severe oxidative stress. This connection between FOXC1 and trabecular meshwork cell survival represents a potential connection between patients harboring FOXC1 loss-of-function variants and the development of glaucoma. Overall, the transcription factor function of FOXC1 (PMID: 11782474) helps explain the findings that some variants compromise nuclear localization, DNA binding, and/or transactivation.",Score,0.5 (0.5),FOXC1 functions as a transcription factor in trabecular meshwork cells to activate gene expression programs that protect against oxidative stress.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b2271229-84ea-4aff-81b4-3428c173ed7b-2021-12-15T031246.818Z,822,PubMed:24556684 +Van Der Meulen_Expression,Expression A,"Van Der Meulen KL, et al., 2020, PMID: 32528955",Whole-mount in situ hybridization for periocular mesenchyme marker gene mRNA expression patterns were observed during early to late stage eye development. foxd3 and sox10 genes were found to display partial periocular patterns of expression.,Score,0.25 (0.5),Minimal points are awarded for the evidence of periocular expression of FOXD3.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d4b3b44d-26d8-4519-9d0d-2259022e79c6-2022-12-15T170000.000Z,824,PubMed:32528955 +MECP2 Upregulation,Protein Interaction,"Orlic-Milacic M, et al., 2014, PMID: 24699272",Mecp2 knockout mouse fibroblasts were transfected with both isoforms of MECP2 gene. Both isoforms upregulated expression of FOXG1.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3f14c6c5-b051-4c94-b9c6-3b80771eed22-2018-07-02T140827.839Z,826,PubMed:24699272 +RNA in vitro,Rescue Cell culture model,"Fimiani C, et al., 2016, PMID: 27995975","small activating RNAs were used to upregulate expression of Foxg1 in murine neocortical precursors. Biological effect was measured by immunofluorescence of postmitotic Tubβ3+ neurons, presumed to be differentiating. Increase in Foxg1 caused decrease in differentiating cells, so gene inhibits exit of neurogenic precursors from the cell cycle. RNAs halved the neuronal output of the culture",Score,0.5 (1),"Biological effect was measured by immunofluorescence of postmitotic Tubβ3+ neurons, presumed to be differentiating",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3f14c6c5-b051-4c94-b9c6-3b80771eed22-2018-07-02T140827.839Z,826,PubMed:27995975 +Rescue of Xenopus Foxj1 knockdown,Rescue Non-human model organism,"Stubbs JL, et al., 2008, PMID: 19011629","The number of cells with cilia was doubled and the average ciliary length was quadrupled by co-injection of the wild-type transcript (Supplementary Figures 3E-3G), completely reversing the phenotypic effects of either Foxj1-targeting morpholino.",Score,0.5 (2),"Rescue was scored to acknowledge the specificity of the model, but done conservatively due to the use of the wild-type gene rather than a variant.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_53a48f3c-42fc-4c60-becb-149019b1e4bf-2022-07-14T160000.000Z,828,PubMed:19011629 +Xenopus model with morpholino-based disruption of Foxj1,Model Systems Non-human model organism,"Stubbs JL, et al., 2008, PMID: 19011629","The animals match the human patients at the cellular level in that they exhibit ciliary structural abnormalities (shortening) and loss of cilia (FIgures 2A, 2B, Supplementary Figure 4). They also show mislocalization of basal bodies and deficient anchoring to the apical actin network (Figure 2E). One caveat is the inability to model respiratory phenotypes, while another is that the knockdown model represents a more severe homozygous loss-of-function, whereas the human patients have a monoallelic defect in FOXJ1.",Score,0.5 (2),"The loss-of-function model has been scored for its match to the human patients at the cellular level, particular in recapitulating the basal body mislocalization defect that has not been scored in another model. Scoring was conservative due to the knockdown mechanism and inability to model certain features the human patients.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_53a48f3c-42fc-4c60-becb-149019b1e4bf-2022-07-14T160000.000Z,828,PubMed:19011629 +Foxp1 over-expression rescue,Rescue Non-human model organism,"Li X, et al., 2015, PMID: 26010426","The distribution of neurons transfected with pCMV10-mFoxp1 +plus shRNA-b was almost identical to that of the control group. Introduction of a plasmid overexpressing Foxp1 alone did not induce apparent neuronal migration anomalies since a +similar population of GFP-positive cells reached the superficial layers three days after transfection. These results indicate that endogenous Foxp1 depletion hindered the radial migration of cortical neurons.",Score,1 (2),Downgraded as mouse neuronal disorder not a direct correlation with human developmental delay/ID.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_db1c240c-7ffb-4a95-92ad-da9e8af2adc6-2019-05-09T162756.956Z,831,PubMed:26010426 +Foxp1 heterozygous knockout (Foxp1+/−),Model Systems Non-human model organism,"Araujo DJ, et al., 2015, PMID: 26494785","We demonstrated +reduced ultrasonic vocalizations (USVs) in Foxp1+/− mice with a significant +decrease in both the number of times a Foxp1+/− +mouse pup called (“bouts”) and the total number +of calls compared with littermate controls at P4 +and P7.",Score,1 (2),Downgraded as reduced mouse USVs are not a direct equivalent to human expressive language delay.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_db1c240c-7ffb-4a95-92ad-da9e8af2adc6-2019-05-09T162756.956Z,831,PubMed:26494785 +Foxp1 conditional knockout mice,Model Systems Non-human model organism,"Usui N, et al., 2017, PMID: 29138280","Foxp1 mouse model +displayed increased excitability of striatal medium +spiny neurons (MSNs) and demonstrated impairments in neonatal ultrasonic vocalizations +(USVs).",Score,1 (2),Downgraded as impairments in neonatal mouse USVs are not a direct equivalent to human expressive language delay.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_db1c240c-7ffb-4a95-92ad-da9e8af2adc6-2019-05-09T162756.956Z,831,PubMed:29138280 +Luciferase assay,Functional Alteration Non-patient cells,"Johnson TB, et al., 2018, PMID: 30385778","Luciferase activity resulting from transcriptional repression of the SV40 promoter show RX and RQ variants result in severely diminished transcriptional repression of the SV40 +promoter as compared to WT levels.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_db1c240c-7ffb-4a95-92ad-da9e8af2adc6-2019-05-09T162756.956Z,831,PubMed:30385778 +Songbird KO,Model Systems Non-human model organism,"Haesler S, et al., 2007, PMID: 18052609","Knockdown of FoxP2 resulted in an incomplete and inaccurate imitation of tutor song. Inaccurate vocal imitation was already evident early during song ontogeny and persisted into adulthood. The acoustic structure and the duration of adult song syllables were abnormally variable, similar to word production in children with developmental verbal dyspraxia (DVD).",Score,1 (2),"Downgraded as impairment of songbird vocal imitation is not a direct equivalent to human expressive language delay. +NOTE: ZEBRAFISH was selected as ZEBRA FINCH is currently not an option in the GCI",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b13348d1-1248-4507-aa29-60559e6b410e-2019-05-21T160000.000Z,833,PubMed:18052609 +CRISPR-based gene editing,Rescue Patient cells,"Goodwin M, et al., 2020, PMID: 32494707",Restored functional FOXP3 expression to IPEX patient Tregs and Teff cells after CRISPR-based FOXP3 editing,Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_f5864049-7fe7-42dd-ba85-2a1f1fdf9d50-2023-10-10T190000.000Z,834,PubMed:32494707 +Fibroblast Studies_Apatean,Functional Alteration Patient cells,"Apatean D, et al., 2019, PMID: 31065540","Cells demonstrated decreased complex I activity and assembly. The enzymatic activity of complex I (expressed as complex I / complex II ratio) was 18% of mean normal activity, confirming complex I deficiency. Blue-Native Polyacrylamide Gel Electrophoresis (BN-PAGE) analysis showed a significant decrease in CI/CII assembly level in patient's fibroblast (8% of mean normal control value)",Score,0.5 (1),This is a second patient cell culture model with FOXRED1 mutations demonstrating evidence of mitochondrial dysfunction (Awarded 0.5 pts),https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c74ba0cb-ccef-4a19-9fef-ef9996f72290-2019-10-16T143453.574Z,835,PubMed:31065540 +Immortal lymphoblast cells from patient with c.571+1G>A,Model Systems Cell culture model,"Nagayoshi Y, et al., 2021, PMID: 33771871","The 2′-O-methylation modifications at positions 32 and 34 of tRNAPhe were undetectable in the patient-derived cell line, which led to a decrease in OHyW modification at G37 of tRNAPhe (Fig. 1D). 2′-O-methylation at positions 32 and 34 of tRNATrp and position 34 of tRNASec was undetectable in the patient cells (fig. S2, C and D).",Score,0 (1),"shares 1 pt with Guy MP, et al., 2015, PMID: 26310293, who showed tRNA alterations in patient cells",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1bc0312a-eb44-4d79-8816-d9ef685e2c8c-2023-02-01T170000.000Z,840,PubMed:33771871 +Expression of human FTSJ1 cDNA in patient cells,Rescue Patient cells,"Nagayoshi Y, et al., 2021, PMID: 33771871",Immortal lymphoblast cells from patient with c.571+1G>A variant in FTSJ1 (Takano et al 2008). The variant resulted in abnormal tRNA modifications (see below) that were restored by expression of human FTSJ1 cDNA in patient cells.,Score,0 (1),"Rescued the tRNA defects in patient cells, but the significance of these alterations to the intellectual disability seen in affected individuals has not been demonstrated. To be conservative, we decided not to score this evidence",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1bc0312a-eb44-4d79-8816-d9ef685e2c8c-2023-02-01T170000.000Z,840,PubMed:33771871 +Ftsj1 KO mouse,Model Systems Non-human model organism,"Nagayoshi Y, et al., 2021, PMID: 33771871","Loss of 2'-O-methylation in Ftsj1 KO mouse selectively reduced the steady-state level of tRNAPhe in the brain, resulting in a slow decoding at Phe codons. Ribosome profiling showed that translation efficiency is significantly reduced in a subset of genes that need to be efficiently translated to support synaptic organization and functions. Ftsj1 KO mice display immature synaptic morphology and aberrant synaptic plasticity, which are associated with anxiety-like and memory deficits. +Impaired synaptic morphology in cortex and hippocampus +Impaired long-term potentiation and long-term depression in the hippocampus +behavioral abnormality: open-field and elevated plus maze tests suggest anxiety-like behavior; Barnes maze test suggest slower spatial learning; fear conditioning showed significantly less freezing behavior in response to the context-dependent stimuli and the cue-dependent stimuli.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1bc0312a-eb44-4d79-8816-d9ef685e2c8c-2023-02-01T170000.000Z,840,PubMed:33771871 +FUCA1 knockout mouse,Model Systems Non-human model organism,"Wolf H, et al., 2016, PMID: 27491075","FUCA1 knockout mice show non-detectable alpha-fucosidase enzyme activity, systemic fucose accumulation, cytoplasmic vacuolization, and neurologic impairment (psychomotor and memory deficits), recapitulating key features of the human fucosidosis phenotype",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e88e0ef6-e788-40e2-bbd4-7fb3efb6b0ea-2022-08-02T160000.000Z,841,PubMed:27491075 +R521C transgenic rat,Model Systems Non-human model organism,"Huang C, et al., 2011, PMID: 21408206","Overexpression of a mutant (R521C substitution), but not normal, human FUS induced progressive paralysis resembling ALS. Mutant FUS transgenic rats developed progressive paralysis secondary to degeneration of motor axons, denervation atrophy of skeletal muscles, and displayed a substantial loss of neurons in the cortex and hippocampus. Neuronal loss was accompanied by ubiquitin aggregation and glial reaction.",Score,3 (2),Transgenic rats expressing the the R521C variant (identified in multiple unrelated ALS patients) had strong recapitulation of the human ALS phenotype.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b2e8f55b-371e-438f-8923-73ca9b7ec034-2021-10-12T183601.087Z,842,PubMed:21408206 +Mislocalization in cytoplasm,Functional Alteration Non-patient cells,"Vance C, et al., 2013, PMID: 23474818","C-terminal ALS FUS mutants form cytoplasmic inclusions due to the disruption of the nuclear localization signal. In transiently transfected CV-1 cells, the GFP-FUSWT protein was predominantly nuclear, while the ALS mutants (GFP-FUSR521C, GFP-FUSR521H and GFP-FUSR514G) showed increased cytoplasmic localization in a high percentage of cells. The truncated FUS protein GFP-FUSK510X showed almost exclusive cytoplasmic localization, confirming that the C-terminal region contains the dominant NLS for FUS. This effect can be abolished by the addition of a wild-type NLS to mutant proteins; following the addition of the wild-type NLS to the wild-type protein FUS remained in the nucleus while its addition to each of the ALS mutant proteins (mutant + NLS) restored their nuclear localization. Furthermore, cytoplasmic mislocalized FUS associates with stress granule markers, a common feature of ALS associated proteins.",Score,0.5 (0.5),"The fundamental effects of mutant FUS proteins can be attributed to its aberrant gain-of-function properties that alter the homeostasis of the interactions of wild type FUS and its the interacting partners, including proteins, pre-mRNAs and lncRNAs, in the DNA damage response/repair and RNA splicing machinery..",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b2e8f55b-371e-438f-8923-73ca9b7ec034-2021-10-12T183601.087Z,842,PubMed:23474818 +Stress granules,Functional Alteration Patient cells,"Vance C, et al., 2013, PMID: 23474818","The authors found that FUS mutant fibroblasts have significantly greater levels of cytoplasmic FUS than control fibroblasts under basal culture conditions and stress granules (as measured by PABP granule formation) were almost absent from mutant and control fibroblasts under these conditions. Following treatment with 1 mm arsenite, the mean number of stress granules per cell was significantly increased in both mutant and control fibroblasts compared with untreated cells but a striking difference in the distribution of FUS was observed only in mutant fibroblasts treated with arsenite, as cytoplasmic FUS was recruited to stress granules. The mean number of FUS-positive cytoplasmic granules per cell was significantly increased following arsenite treatment only in mutant fibroblasts [ANOVA, with a Greenhouse-Geisser correction, P < 0.001, Dunnett's T3 post-hoc tests for FUSR521C (P < 0.01) and FUSR514G (P < 0.01)]. These experiments demonstrate that endogenous levels of cytoplasmic FUS are increased in mutant fibroblasts compared with controls, and that only the cytoplasmic pool of FUS is recruited into stress granules following oxidative stress.",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b2e8f55b-371e-438f-8923-73ca9b7ec034-2021-10-12T183601.087Z,842,PubMed:23474818 +Conditional transgenic mice,Model Systems Non-human model organism,"Sharma A, et al., 2016, PMID: 26842965","As in patients, mutant FUS was found mislocalized to the cytoplasm, modelling a pathological hallmark of ALS-FUS. Analysis of these mutants (R521C and P525L) reveals progressive, age- and mutation-dependent motor neuron (MN) degeneration that faithfully models several key aspects of the ALS phenotype, including selectivity for MN subtypes most vulnerable in the human disease. MN loss progressed steadily in both mutants to p360, but was more pronounced in the P525L mutant (∼30%), compared with the R521C mice (∼20%). MN loss in this model is associated with early synaptic failure and withdrawal of the motor axon from the neuromuscular junction.",Score,4 (2),"Demonstrated that expression of mutant hFUS (R521C or P525L) is sufficient to cause MN degeneration, and that alleles associated with aggressive, juvenile-onset forms of ALS (P525L) are more pathogenic in these disease models.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b2e8f55b-371e-438f-8923-73ca9b7ec034-2021-10-12T183601.087Z,842,PubMed:26842965 +GTEx Data,Expression A,"Pihakaski-Maunsbach K, et al., 2008, PMID: 18787637",GTEx data shows high expression of this gene (FXYD2) in the medulla and cortex of the kidney.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_aef2e6fc-52d8-4077-a5c9-0f70bbebea36-2023-06-29T160000.000Z,845,PubMed:18787637 +"FXYD2, IMCD3, Hypomagnesemia",Biochemical Function B,"Pihakaski-Maunsbach K, et al., 2008, PMID: 18787637","Due to the observations about the gamma subunit, it, not merely alpha/beta, then seems essential for the long-term adaptation to the hypertonic environments. Due to the studies of inhibition of the Cl- channel, it is evidence that the gamma subunit is expressed based on Cl- ions, rather than Na+ ions.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_aef2e6fc-52d8-4077-a5c9-0f70bbebea36-2023-06-29T160000.000Z,845,PubMed:18787637 +Patient cells,Functional Alteration Patient cells,"Cairo ER, et al., 2009, PMID: 19865785","Protein expression levels could be raised in both individuals’ cells by being cultured in hyper osmotic conditions but to a larger degree in the non-affected cells. The effect of the mutation on these physiological processes will affect magnesium balance by a mechanism we must learn more about. The hyper osmotic conditions also caused ATP hydrolyzing activity to increase, but more so in non-affected cells (1 point).",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_aef2e6fc-52d8-4077-a5c9-0f70bbebea36-2023-06-29T160000.000Z,845,PubMed:19865785 +Jin et al. Rescue of G6PD in Knock out HeLa Cells,Rescue Cell culture model,"Jin X, et al., 2022, PMID: 36243112","Knock out G6PD HeLa cells recapitulated several phenotypes associated with G6PD deficiency including loss of G6PD enzymatic activity, increased sensitization to oxidative stressors including hydrogen peroxide, and decreased NADPH. Transfection of WT G6PD including transfection of G6PD with variants observed in G6PD deficiency rescued the phenotype of increased susceptibility to hydrogen peroxide. Transfection of WT also rescued the enzymatic activity, while mutants observed in humans rescued enzymatic activity but to a lesser extent, while mechanistic variants failed to rescue G6PD enzymatic activity. Transfection of WT also rescued the phenotype of significantly decreased levels of NADPH and rescued the phenotype of increased susceptibility to oxidative stressors such as phenazine methosulfate and hypoxia.",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_153ae203-3ae5-4cb3-bbf8-d72467700d8c-2023-06-23T160000.000Z,848,PubMed:36243112 +Jin et al. Rescue of G6PD in Knock out HeLa Cells,Rescue Cell culture model,"Jin X, et al., 2022, PMID: 36243112","Knock out G6PD HeLa cells recapitulated several phenotypes associated with G6PD deficiency including loss of G6PD enzymatic activity, increased sensitization to oxidative stressors including hydrogen peroxide, and decreased NADPH. Transfection of WT G6PD including transfection of G6PD with variants observed in G6PD deficiency and variants observed in association to chronic nonspherocytic hemolytic anemia, rescued the phenotype of increased susceptibility to hydrogen peroxide. Transfection of WT also rescued the enzymatic activity, while mutants observed in humans rescued enzymatic activity but to a lesser extent, while mechanistic variants failed to rescue G6PD enzymatic activity. Transfection of WT also rescued the phenotype of significantly decreased levels of NADPH and rescued the phenotype of increased susceptibility to oxidative stressors such as phenazine methosulfate and hypoxia.",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_cb70a1c4-e861-4c45-adc6-9afc82f4a7a0-2023-06-23T160000.000Z,849,PubMed:36243112 +Forebrain selective KO,Model Systems Non-human model organism,"Ferguson C, et al., 2007, PMID: 17927825","Forebrain selective knockout mice have occasional absence-like and convulsive seizures. This study also tested Pan-neuronal knockout mice, which do not have observable seizures and is therefore not scored for this curation.",Score,1 (2),Downgraded because mouse model has seizures but does not have a consistent genotype with affected humans.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a9327dac-6f76-4881-8a23-ef2b210f92e7-2019-02-05T170000.000Z,853,PubMed:17927825 +Hernandez Functional Evidence,Functional Alteration Non-patient cells,"Hernandez CC, et al., 2017, PMID: 29162865","Peak GABA-gated current amplitudes were significantly reduced in cells expressing mutant β3 subunits with p.L170R, p.A305V, and p.T288N variants to ~80%, 50% and 60% of those expressing wildtype β3 subunits.",Score,1 (0.5),"Upgraded because p.L170R, p.A305V, and T288N were shown to have a pathogenic effect.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a9327dac-6f76-4881-8a23-ef2b210f92e7-2019-02-05T170000.000Z,853,PubMed:29162865 +CNS-specific KO mouse,Model Systems Non-human model organism,"Oh WJ, et al., 2010, PMID: 20333300",Found a complete cleft palate in 9 out of the 11 KO embryos as well as umbilical hernia in 6 of 11.,Score,1 (2),"The CNS-specific KO mouse also had the predominant phenotype of cleft palate, which has also been seen in 4/14 patients. The additional phenotypes in humans such as epilepsy and developmental delay are not reported in the mouse but these were studied only as embryos.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_20fdee08-81b0-4957-a18a-8f622e0ab054-2021-05-13T152239.014Z,857,PubMed:20333300 +MO Zebrafish,Model Systems Non-human model organism,"O'Connor MJ, et al., 2019, PMID: 30200754","Assessment of the cartilaginous head skeleton by Alcian blue staining in flat mount preparations at 7 dpf revealed defects in both the neurocranium and the pharyngeal skeleton in gad1b morphant larvae. The neurocranium includes the ethmoid plate, trabeculae and parachordal cartilages, and the pharyngeal skeleton includes cartilages of the segmented jaw, opercular, and gill-bearing skeleton",Score,0.5 (2),"gad1b morphant fish displayed abnormal craniofacial features, as reported in 6/14 patients. Additional features of the disease, such as epilepsy, were not reported.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_20fdee08-81b0-4957-a18a-8f622e0ab054-2021-05-13T152239.014Z,857,PubMed:30200754 +Mouse model,Model Systems Non-human model organism,"Zhu Y, et al., 2017, PMID: 28877911",The reduced plasma cholesterol is representative of the bleeding issues and thrombocytopenia observed in humans with GALE deficiency.,Score,1 (2),Bleeding complications is only one phenotype associated with GALE deficiency. It is not expected that a 56% reduction in protein product would adequately represent the severity of phenotypes demonstrated in humans.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ab7f5785-45a0-47dd-b646-6792c901d2d8-2023-09-29T160000.000Z,859,PubMed:28877911 +Hendriksz_FDA-approved ERT with elosulfase alfa,Rescue Human,"Hendriksz CJ, et al., 2014, PMID: 24810369","Enzyme replacement therapy with recombinant human GALNS (rhGALNS, elosulfase alfa, BMN 110, Vimizim®) represents the treatment option that was approved in the US by the Food and Drug Administration in February 2014. ERT replaces the deficient GALNS enzyme by a functioning enzyme, thus repairing the mechanism for degrading keratan sulfate and chondroitin sulfate. Elosulfase alfa increases KS and C6S catabolism and reduce the KS and C6S accumulation contributing to the clinical manifestations. Measures of 6-min walk test [6MWT], 3-min stair climb test [3MSCT]) and respiratory function were generally improved with therapy, and mean improvements were sustained over 2 years. Long-term effects of this treatment on the skeletal and non-skeletal features of MPS IVA are limited.",Score,4 (2),"ERT with elosulfase alfa is the first and only FDA-approved treatment for MPS IVA. Although the treatment with ERT is not curative, ERT could improve endurance and overall quality of life.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c58d08e9-dc6d-45fc-a21a-54be3bc438d9-2022-06-16T160000.000Z,862,PubMed:24810369 +Sawamoto_Biochemical Function B,Biochemical Function B,"Sawamoto K, et al., 2020, PMID: 32102177",Patients with MPS IV A display lysosomal storage of GAGs and elevated total GAG levels in urine. Accumulation of keratan sulfate and chondroitin sulfate in various tissues is also increased due to the lack of degradation of GAGs because of GALNS deficiency. This accumulation is the basis for the clinical features such as skeletal abnormalities observed in MPS IVA patients.,Score,2 (0.5),Increased score is awarded for the well-understood biochemical function.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c58d08e9-dc6d-45fc-a21a-54be3bc438d9-2022-06-16T160000.000Z,862,PubMed:32102177 +Encoding GALNT2,Biochemical Function B,"Antonucci A, et al., 2022, PMID: 35055114","Regulation of glycosylation caused by GALNT2 gene, is defined with patients presented with many human metabolic abnormalities, HDL-C",Score,1 (0.5),Expression in many tissues associated with genotypic-phenotypic relationship,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_8107f647-e731-44f5-ba38-46e648febab1-2024-02-06T170000.000Z,863,PubMed:35055114 +GAN expressed throughout the nervous system,Expression A,"Ganay T, et al., 2011, PMID: 21486449","Gigaxonin was expressed evenly throughout the nervous system but with very low levels of expression in muscle, heart, kidney and liver (Figure 2A-C). The high levels of gigaxonin detected in embryonic stages up to PO (postnatal), dropped by 50-56% in both tissues after birth, and then stayed constant in adults.",Score,0.25 (0.5),"Only expression in the murine tissue is investigated. In addition, the mouse GAN was shown to be ubiquitously expressed by RT-PCR, with a higher level in brain (PMID: 11062483, 2000).",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b9f65afa-5cb1-457e-abff-ab110145a32d-2022-02-10T021239.651Z,865,PubMed:21486449 +GANex3-5 mice show mild motor and sensory impairements,Model Systems Non-human model organism,"Ganay T, et al., 2011, PMID: 21486449","Severe alteration of cytoskeletal architecture was observed in GANex3-5 mice. In the absence of gigaxonin, NFs are abnormally distributed and lose their regular and parallel orientation along the axons. Neurofilament diameter is significantly increased in GAN mice. Expression level of the three subunits NF-L, NF-M and NF-H in mouse brain, spinal cord and sciatic nerves, was quantified in the three gigaxonin-null mice: (GANex3-5 mouse, the GANYY and the GANex1 mice). The analysis revealed an increased abundance of all three NF subunits, in all tissues and at all ages (fig6). The striking alteration of neurofilament architecture in gigaxonin-null mice closely resembles the human pathology.",Score,1 (2),"The alteration in NF content is comparable in the three GAN models: GANex3-5 mouse, the GANYY and the GANex1 mice. The absence of gigaxonin in mice has a striking impact on cytoskeletal architecture. However, the phenotype is mild and does not mimic the axonal defects that are hallmark of human GAN.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b9f65afa-5cb1-457e-abff-ab110145a32d-2022-02-10T021239.651Z,865,PubMed:21486449 +GAN depletion inhibits autophagosome synthesis,Functional Alteration Non-patient cells,"Scrivo A, et al., 2019, PMID: 30770803","GAN-/- neurons exhibited large perinuclear bundles of ATG16L1 within the soma at 4 div (days in vitro), with a pronounced increase in abundance. At 15 div, the ATG16L1 aggregates persisted but were not distributed in neurites, as in wild type cells. Similar to control cells, GAN-/- neurons were able to produce autophagic vesicules in basal condition and upon serum deprivation (Basal and EBBS conditions in Fig. 5a–c). However, in the presence of a blocker of autophagosome-lysosome fusion, autophagosome synthesis was severely altered (Fig 5a-d). +Gigaxonin overexpression totally cleared ATG16L1 bundles in GAN-/- neurons. This data identifies Gigaxonin-E3 ligase as the first regulator of ATG16L1 turn-over, essential in ensuring ATG16L1 functions in phagophore expansion and autophagosome production.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b9f65afa-5cb1-457e-abff-ab110145a32d-2022-02-10T021239.651Z,865,PubMed:30770803 +Bardhan mouse model,Model Systems Non-human model organism,"Bardhan T, et al., 2019, PMID: 31069810","A significant decrease in outer hair cells (OHC) numbers in heterozygous null mice shortly after birth, suggesting premature death of OHCs during embryonic development. Number of inner hair cells (IHC) was normal. Surviving OHCs matured normally, but IHCs failed to acquire the characteristic mature basolateral currents and to down-regulate the immature-type channels like to the cholinergic efferent systems. This shows gata3 affects all hair cell, but it affects OHCs and IHCs differently. +IHC numbers are maintained in gata3+/− mice, their biophysical differentiation is incomplete and could contribute to the observed hearing loss both in the mouse model and in HDR syndrome. +Adult gata3+/− mice (>1 month old) suffer general morphological degeneration of cochlear sensory cells, especially of OHCs, in young adults. +Absence of any effect in gata3+/fl otof-cre+/− mice suggests less sensitivity to gata3 haploinsufficiency in IHCs during early postnatal development. Results predict measurable hearing loss without loss of DPOAEs in gata3fl/fl otof-cre+/− mice. The ABR thresholds were largely elevated, although they were not as severe as for gata3+/− mice at a comparable age At 1.7 months, gata3fl/fl otof-cre+/− mice had about 20 dB of hearing loss across all frequencies, whereas the gata3+/− mice had a 30 dB loss. +Full knock-down of gata3 in IHCs led to progressive hearing loss, which becomes profound by 7 months. Such progression was not observed in gata3+/− mice, although it might have been masked by the background loss with age for the mouse strain. This shows gata3 is necessary in IHCs at least during early adult life. +Authors assert that hearing loss in patients with HDR syndrome is probably due to combined defects in both sensory hair cell types.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_afb6e0d5-81a5-439a-a498-9edc8505a367-2019-06-18T160000.000Z,870,PubMed:31069810 +EMSA in HeLa cells,Functional Alteration Non-patient cells,"Fang T, et al., 2019, PMID: 31322241","EMSA using wild-type and mutant GATA4 (p.H436Y) proteins from transfected HeLa cells, with a biotin-labeled probe showed that the mutant GATA4 protein decreased the ability to bind the conserved GATA-binding site on the HAND2 gene, which may contribute to abnormal expression of the HAND2 gene",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_005cf235-4d8d-4f12-9e75-59d3f7c4d933-2023-02-07T170000.000Z,871,PubMed:31322241 +Expression in HeLa cells,Expression B,"Fang T, et al., 2019, PMID: 31322241",RT-qPCR performed following extraction of total RNA from HeLa cells revealed that the mRNA expression levels of GATA4 were significantly lower in the mutant group compared with the wild-type group. Western blot analysis demonstrated that the GATA4 mutation significantly reduced GATA4 protein expression,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_005cf235-4d8d-4f12-9e75-59d3f7c4d933-2023-02-07T170000.000Z,871,PubMed:31322241 +Sharma cell culture modle,Model Systems Cell culture model,", , PMID: 33054971","Transcriptional and epigenetic analyses of differentiating cardiomyocytes from isogenic WT and mutant hiPSCs provide evidence that GATA6 functions as a pioneer factor that modifies chromatin accessibility and promotes the expression of gene networks involving HAND2, VEGFR and neural crest cells that enable second heart field development and patterning of the outflow tract and atria. GATA6 plays critical role in endodermal and retinoic acid signaling gene networks that gives rise to the pancreas and diaphragm. LoF GATA6 variants repress epigenetic modification and transcriptional activity, while an exon 4 GATA6 missense variant alters normal and also causes ectopic epigenetic effects that enhanced retinoic acid signaling resulting in profound deleterious consequences on gene expression",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a7a0fdd7-f796-4921-95b6-709fd859b6d3-2023-11-21T170000.000Z,872,PubMed:33054971 +SH-SY5Y cells stably overexpressing mutant GBA,Functional Alteration Non-patient cells,"Li H, et al., 2019, PMID: 30160596","Whereas WT GBA overexpression markedly increased both GBA protein levels and lysosomal GBA enzyme activity, the overexpression of mutant GBAL444P did not interfere with the normal lysosomal enzyme activity of endogenous WT GBA, although the total GBA protein levels significantly increased +(Figure 6(A)).",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9201c03f-10de-447c-9b84-194f14b549b6-2022-05-03T134810.206Z,874,PubMed:30160596 +GCase level in port mortem brain,Functional Alteration Patient cells,"Li H, et al., 2019, PMID: 30160596","GBA protein levels were decreased by ~30% in non-GBA-PD and ~60% in GBA-PD, suggesting an additive effect of PD status and heterozygous GBA mutations on reducing GBA protein levels. +GBA enzyme activity was significantly lower in GBA-PD, but was not different between controls and non-GBA-PD patients (Figure 7(A)).",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9201c03f-10de-447c-9b84-194f14b549b6-2022-05-03T134810.206Z,874,PubMed:30160596 +GCase in iPSC-derived dop. neurons and isogenic controls,Model Systems Cell culture model,"Kim S, et al., 2021, PMID: 33753743",reduced GCase levels have been repeadedly shown in patients,Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9201c03f-10de-447c-9b84-194f14b549b6-2022-05-03T134810.206Z,874,PubMed:33753743 +Gch1 null mouse,Model Systems Non-human model organism,"Douglas G, et al., 2015, PMID: 25557619","While the clinical phenotype of the Gch1 knock out mice (embryonic lethality) does not recapitulate the human phenotype (dystonia and other neurological symptoms), there are similarities in biochemical abnormalities including reduced BH4 and L-dopa (shown in whole embryos in mice and detected in body fluids e.g. CSF in humans).",Score,0.5 (2),"The phenotype of the Gch1 knock out mice (embryonic lethality) does not recapitulate the human phenotype (dystonia and other neurological symptoms). Some points were awarded, although reduced, due to similarities in biochemical abnormalities (decreased BH4 and L-dopa).",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ed6c1e6c-5856-48aa-aa8f-47328e6b09eb-2020-12-11T200937.286Z,875,PubMed:25557619 +Leung et al. Knock out Mice are embryonic lethal,Model Systems Non-human model organism,"Leung KY, et al., 2021, PMID: 33569080","Homozygous null mice (GCSH -/-) were embryonic lethal, specifically before E10.5, while heterozygous (GCSH -/+) mice had normal glycine levels and did not display neural tube deficits. While homozygous null mice fail to recapitulate many of the phenotypes seen in patients with glycine encephalopathy due to early embryonic lethality, mice with homozygous null alleles in AMT or GLDC, which are also genes associated with glycine encphalopathy, are also embryonic lethal. However, null homozygous AMT or GLDC mice survive later to the perinatal stage or until shortly after birth. The authors posit that embryonic lethality in GCSH mice may highlight additional roles of GCSH outside of the glycine cleavage system, such as in bioenergetic enzymes, and that perhaps why individuals with biallelic GCSH variants are less often reported in association with glycine encephalopathy than AMT or GLDC, is due to earlier stage lethality.",Score,1 (2),Downscored given an incomplete recapitulation of the disease phenotype in mice due to early embryonic lethality.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d360db9d-24e7-415e-b4bc-59a2c6231189-2023-02-10T170000.000Z,877,PubMed:33569080 +Arribas-Carreira et al. Biochemical function of H-protein,Biochemical Function B,"Arribas-Carreira L, et al., 2022, PMID: 36190515","The glycine cleavage system is the primary way the cell breaks down the amino acid glycine. In the central nervous system glycine serves as a major inhibitory neurotransmitter. Individuals with biallelic variants in GCSH present with elevated glycine levels in the cerebrospinal fluid and elevated CSF/plasma glycine levels. The glycine cleavage system is highly implicated in the development of glycine encephalopathy. Biallelic variants in the genes GLDC and AMT are responsible for most cases of nonketotic hyperglycinemia. The gene GLDC encodes for the P protein, while AMT encodes for the T protein, two subunits, in addition to the H protein, that make up the glycine cleavage system.",Score,1 (0.5),Upscored to 1 point given a strong link between the role of the H protien in the glycine cleavage system and glycine encephalopathy.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d360db9d-24e7-415e-b4bc-59a2c6231189-2023-02-10T170000.000Z,877,PubMed:36190515 +Arribas-Carreira functional alteration in COS7 cells,Functional Alteration Non-patient cells,"Arribas-Carreira L, et al., 2022, PMID: 36190515","In COS7 cells, co-transfection of P protein and the p.Glu58* variant led to near 0% glycine exchange activity compared to WT. Additionally, cotransfection of P protein and the p.Glu58* variant led to undetectable H protein expression in a western blot.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d360db9d-24e7-415e-b4bc-59a2c6231189-2023-02-10T170000.000Z,877,PubMed:36190515 +Niemann Functional Alteration 1,Functional Alteration Non-patient cells,"Niemann A, et al., 2005, PMID: 16172208","The mitochondria in COS-7cells with GDAP1 overexpression were shown to be more fragmented with less tubular forms (Fig. 4A), mitochondrial morphology was not significantly altered (Fig. 4A,b). This fragmentation was shown to not cause increase in apoptosis or mitochondrial activity or mitochondrial fusion - confirming that GDAP1 is a fission-inducing factor (Fig. 4B, Fig. 6, Fig. 7)",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c6d93637-02f5-4f5d-b7a9-17356f084149-2020-07-28T144211.873Z,878,PubMed:16172208 +Niemann Functional Alteration 2,Functional Alteration Non-patient cells,"Niemann A, et al., 2005, PMID: 16172208","GDAP1 expression reduced by 60% (Fig. 7A), caused an increase of cells with tubular mitochondrial morphology (Fig. 7B)",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c6d93637-02f5-4f5d-b7a9-17356f084149-2020-07-28T144211.873Z,878,PubMed:16172208 +Niemann Functional Alteration 3,Functional Alteration Non-patient cells,"Niemann A, et al., 2005, PMID: 16172208",Truncating variants shown to not be targeted to mitochondria and to have no fragmentation activity (Fig. 8); missense variant remained localized to mitochondria with significantly reduced fragmentation activity (Fig. 9),Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c6d93637-02f5-4f5d-b7a9-17356f084149-2020-07-28T144211.873Z,878,PubMed:16172208 +Niemann Expression,Expression A,"Niemann A, et al., 2005, PMID: 16172208","Western blot of neural tissues showed GDAP1 is predominantly expressed in regions of CNS (cortex, cerebellum, thalamus, olfactory bulb, spinal cord), expression also prominent in sciatic nerves and dorsal root ganglia (Fig. 1A). Analysis of cross sections of rat sciatic nerve confirmed GDAP1 expression in both neurons and Schwann cells of the PNS. GDAP1 was shown to localize to the mitochondrial as an integral membrane protein of the outer mitochondrial membrane via transfection of COS-7 cells (Fig. 2, Fig. 3).",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c6d93637-02f5-4f5d-b7a9-17356f084149-2020-07-28T144211.873Z,878,PubMed:16172208 +Niemann Mouse Model,Model Systems Non-human model organism,"Niemann A, et al., 2014, PMID: 24480485","Western blot confirmed loss of GDAP1 expression in Gdap1 -/- mice (Fig. 1B,C). Sciatic nerve crush was performed on 2mo mice which showed less effective remyelination in null mice (Fig. 1E). No pathological changes observed in null mice in first 13mo of age. In 19-month-old Gdap1−/− NCVs were reduced by 25% compared to controls (Fig. 2A,B), and CMAPs were reduced (Supplemental Table 1). Hypomyelination detected in morphometric analysis with no detectable axonal loss (Fig. 2C,E). Loss of GDAP1 expression in Schwann cells confirmed to be sufficient to cause hypomyelinating perpheral neuropathy in null mice through cre-mediated ablation (Fig. 2A,B,D,E). Analysis of peripheral nerve axons showed a slight increase of mitochondria in null mice, with intra-axonal mitochonria being larger (Fig. 2F), and mitochondrial transport in dorsal root ganglion neurons was mildly impaired (Fig. 3). Mitochondrial DNA biogenesis was shown to be increased in the PNS but not PCNS of Gdap1 -/- mice (Fig. 4). This oxidative stress in the PNS caused by GDAP1 loss was shown to be compensated by the GDAP1 paralogue, GDAP1L1 in the CNS (Fig. 5, 6, 7).",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c6d93637-02f5-4f5d-b7a9-17356f084149-2020-07-28T144211.873Z,878,PubMed:24480485 +transmammary delivered immunoblocking of BMP9 and BMP10,Model Systems Non-human model organism,"Ruiz S, et al., 2016, PMID: 27874028","Blocking of BMP9 and BMP10 induced HHT-like vascular defects in the postnatal retina of mice. Blocking both BMP9 and BMP10 is necessary to induce HHT-like defects given that BMP10 has been shown to be able to compensate for the loss of BMP9 in knock out mice, and serves as a functionally equivalent ligand in binding to ALK1. The authors found that blocking of both BMP9 and BMP10 led to significant vascular pathology in the retina of neonates, which included hypervascularization, defects in arteriovenous specification and the presence of multiple and massive AVMs.",Score,1 (2),Downscored to 0 points given that blocking of both BMP10 and BMP9 is required to induce HHT-like phenotypes.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_00608fb7-3483-495a-8f9e-76aabb4b1dc0-2023-04-03T160000.000Z,879,PubMed:27874028 +crystal structure of BMP9:ALK1 complex at 3.3 Å,Protein Interaction,"Salmon RM, et al., 2020, PMID: 32238803",ALk1 variants have been found in a number of probands with hereditary hemorrhagic telangiectasia. ALK1-mediated endothelial BMP9 and BMP10 signaling plays many important roles in angiogenesis and the maintenance of vascular quiescence. This paper demonstrated that the BMP9 GF-domain binds to the extra cellular domain of ALK1 with minimal conformational change. The entire ALK1 complex with pro-BMP9 is shown in figure 6.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_00608fb7-3483-495a-8f9e-76aabb4b1dc0-2023-04-03T160000.000Z,879,PubMed:32238803 +BMP9 ligand binding to ALK1,Biochemical Function B,"Salmon RM, et al., 2020, PMID: 32238803","The authors found that pro-BMP9 binds to ALK1 with a Kd of 48.1 pM. Additionally, it has been found that BMP9 and BMP10 are functionally equivalent in their ability to bind to ALK1 in in vitro endothelial cells. BMP9 ligand binding is important in the TGF-β Signaling Pathway, where BMP9 binding causes trans-phosphorylation of ALK1 which leads to the phosphorylation of R-Smads, which with Smad4 translocates into the nucleus and regulates transcriptional activity. Pathogenic mutations along this signaling pathway lead to HHT.",Score,1 (0.5),Upscored to 1 point given a detailed and well characterized understanding of the role of BMP9 in the TGF-β Signaling Pathway as well as the pathway being highly linked to HHT.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_00608fb7-3483-495a-8f9e-76aabb4b1dc0-2023-04-03T160000.000Z,879,PubMed:32238803 +BMP9 Knock out and BMP9/BMP10 double knock out,Model Systems Non-human model organism,"Bouvard C, et al., 2022, PMID: 34086873","Adult BMP9 single knock out mice had normal weight, viability, and appeared normal after dissection. Double knock out BMP9 and BMP10 mice showed cardiomegaly and increased cardiomyocyte size and increased ANP and BNP levels, leading to the progressive development of HOHF. Additionally, double knock outs showed decreased blood pressure, dilated blood vessel in the lungs, intestines, and brain, as well as the abnormal passage of fluorescent microbeads from pulmonary arteries to pulmonary veins and from systemic arteries to systemic veins in line with double knock out mice from PMID:33334130. The authors stated that possible AVMS or dilation was not limited to any single location. No mice spontaneously developed PH. Double knock out BMP9/10 mice from PMID:36348215, developed AVMs and lethality.",Score,0 (2),Downscored to 0 point given that BMP9 knock out mice showed no phenotypic differences to WT. BMP9 and BMP10 double knock out mice showed a number of vascular abnormalities including the potential formation of AVMS and the abnormal passage of fluorescent microbeads from arteries to veins. These results have been substantiated over multiple reports.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_00608fb7-3483-495a-8f9e-76aabb4b1dc0-2023-04-03T160000.000Z,879,PubMed:34086873 +BMP9 reverses pulmonary hypertension in Bmpr2+/R899X mice,Rescue Non-human model organism,"Long L, et al., 2015, PMID: 26076038","Reversed all indices of PAH in this chronic disease model, returning RVSP to the level seen in WT mice (Fig. 4a) and reversing the enhanced pulmonary arterial muscularization in these mice (Fig. 4c, d).",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_2d2e83fa-0af1-450f-af9c-5c61d4bc3106-2022-05-26T221514.154Z,880,PubMed:26076038 +shRNA-mediated knockdown of GEMIN5,Model Systems Non-human model organism,"Kour S, et al., 2021, PMID: 33963192","Loss of rigor mortis, a fly orthologue of human GEMIN5, due to RNAi-mediated knockdown in vivo lead to premature lethality, motor dysfunctions, and reduced life span, which replicates the neurological symptoms found in GEMIN5 patients.",Score,1 (2),"Although motor dysfunctions were noted, downgraded due to the simple Drosophila model, which could not adequately represent the complex (and variable) motor dysfunction observed in the human cohort.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_51809985-ee18-429f-b804-96e7decb3d08-2023-09-06T160000.000Z,881,PubMed:33963192 +SMN assembly proteins in iPSC-derived neuronal cells,Functional Alteration Non-patient cells,"Kour S, et al., 2021, PMID: 33963192","Immunofluorescence show a drastic decrease in the cytoplasmic distribution of GEMIN5 in the homozygous neuronal cells, p.His913Arg and p.Leu1068Pro, while neurons expressing heterozygous variants showed a normal physiological nuclear-cytoplasmic distribution of GEMIN5. Western blot showed the levels of GEMIN5 were drastically reduced by ~70–80% in Leu1068Pro and His913Arg patient neurons, and a significant reduction in the protein levels of other SMN complex subunits (GEMIN4, GEMIN3, GEMIN2, GEMIN6, SMN, and U1A).",Score,0 (0.5),Functional evidence was scored at case-level evidence.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_51809985-ee18-429f-b804-96e7decb3d08-2023-09-06T160000.000Z,881,PubMed:33963192 +In vitro culture of megakaryocytes from mk-specific ko mice,Model Systems Non-human model organism,"Beauchemin H, et al., 2017, PMID: 28082345","GFI1B deficiency increases megakaryocyte proliferation and affects their ploidy, but also abrogates their responsiveness towards integrin signaling and their ability to spread and reorganize their cytoskeleton. This is in line with defective aggregation of platelets from patients with platelet-type bleeding disorder 17. +Gfi1b-null megakaryocytes are also unable to form proplatelets. Some rare remaining platelets showed a larger perimeter and lower α-granule content, compatible with macrothrombocytopenia and deficiency of alpha-granules of platelets from patients with platelet-type bleeding disorder 17. +GFI1B-deficient megakaryocytes exhibit aberrant expression of +several components of both the actin and microtubule cytoskeleton, with +a dramatic reduction of α-tubulin. This has not yet been described in megakaryocytes or platelets from patients with platelet-type bleeding disorder 17.",Score,2 (2),"In this paper mice with a megakaryocyte-specific Gfi1b deletion exhibit +a macrothrombocytopenic phenotype along a megakaryocytic dysplasia +reminiscent of platelet-type bleeding disorder 17. They show prolonged bleeding time, macrothrombocytopenia and decrease of alpha-granules, all features compatible with the disorder.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_62841ea9-5bd8-4250-ab41-31d7cf82d2e3-2019-11-27T170000.000Z,884,PubMed:28082345 +Study of the Wnt/βcatenin signaling pathway in Mk,Functional Alteration Non-patient cells,"Shooshtarizadeh P, et al., 2019, PMID: 30894540","The authors show that Gfi1b forms complexes with β-catenin and other co-factors regulating the expression of Wnt/β-catenin target genes. +In Gfi1b-deficient mice the expression of numerous canonical Wnt/β-catenin target genes, co-occupied by Gfi1b, β-catenin and LSD1,was deregulated. +Gfi1b-deficient HSCs and MKs have decreased levels of canonical Wnt signaling in vivo, which can be reversed when Wnt/β-catenin signaling is stimulated externally by Wnt3A treatment: their normal cellularity is restored and Gfi1b-deficient MKs regained their ability to spread on integrin substrates.",Score,0.5 (0.5),This work shows that Gfi1b controls both the cellularity and functional integrity of HSCs and MKs by regulating Wnt/β-catenin signaling pathway,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_62841ea9-5bd8-4250-ab41-31d7cf82d2e3-2019-11-27T170000.000Z,884,PubMed:30894540 +rescue in non human model,Rescue Non-human model organism,"Trivigno C, et al., 2011, PMID: 21364917","When expressed ubiquitously with a combination of the armadillo and daughterless GAL4 drivers (arm+da-GAL4), the fly and human wild type transgenes are able to rescue close to 100% of ico mutant animals (Table 1, row 1, 2, and 6).",Score,0.5 (2),Minimal points applied for rescue of severe growth disruption and early lethality in Drosophila model.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_154a8f96-7062-49c7-9aaa-b23a98655f40-2019-12-19T185108.232Z,885,PubMed:21364917 +Brito 2015 patient cells,Functional Alteration Patient cells,"Brito S, et al., 2015, PMID: 25852744","Patient muscle histology and histochemistry showed no evidence of obvious subsarcolemmal mitochondrial accumulation (ragged-red fibers) or inclusions and mild variation in fiber size (Figure 2A). There was a generalized decrease in histochemical cytochrome c oxidase (COX) activity including a population of fibers (mosaic) that were COX-deficient (Figure 2B). The succinate dehydrogenase (SDH) reaction showed a population of pale fibers (Figure 2C), whereas the sequential COX/SDH reaction highlighted a population of weakly-reacting blue (COX-deficient) fibers (Figure 2D). In addition, the size of intracellular lipid droplets stained with Sudan Black appeared to be increased (not shown). Biochemical assessment of respiratory chain enzymatic function in fibroblasts confirmed impaired complex I (0.019 units; controls (mean ± SD) 0.197 ± 0.034) ,complex III (0.211units; controls (mean ± SD) 0.646 ± 0.192), and complex IV (0.165 units; controls (mean ± SD) 1.083 ±0.186) activities, with a low complex I:II ratio (0.071; range 0.58–0.90) consistent with a generalized defect of mitochondrial translation (Figure 2E). The activity of complex V was not assessed. Western blot analysis of patient fibroblasts showed a reduction in the steady-state levels of NDUFB8 (complex I subunit) and COXI (complex IV subunit), but similar levels of SHDA (complex II) compared to controls (Figure 3B), which corresponds well with the complex activity data (Figure 2E). A generalized impairment of de novo mitochondrial protein synthesis was also observed in patient fibroblasts (Figure 3C), consistent with a decrease in translation elongation due to the reduction of mtEFG1 protein levels.",Score,1 (1),Reduced OXPHOS protein expression and complex IV activity and reduced mito protein synthesis.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_154a8f96-7062-49c7-9aaa-b23a98655f40-2019-12-19T185108.232Z,885,PubMed:25852744 +Leigh map,Biochemical Function A,"Rahman J, et al., 2017, PMID: 27977873","There are three nuclear-encoded elongation factors: EFTu (TUFM; 602389), EFTs (TSFM; 604723), and EFG1 (GFM1; 606639); variants have been identified in all of these genes, and they result in combined respiratory chain deficiencies and severe phenotypes with an early fatal outcome (26937387: Ravn et al. 2015).",Score,1.5 (0.5),scored according to GCEP rubric,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_154a8f96-7062-49c7-9aaa-b23a98655f40-2019-12-19T185108.232Z,885,PubMed:27977873 +GgcxΔliver/Δliver mice,Model Systems Non-human model organism,"Azuma K, et al., 2014, PMID: 24520408","As in humans GgcxΔliver/Δliver mice displayed bleeding diathesis, which was accompanied by decreased activity of coagulation factors II and IX. Wild-type mice ceased bleeding within 10 minutes of tail incision, while GgcxΔliver/Δliver mice continued to bleed for more than 30 minutes. 60% of female GgcxΔliver/Δliver mice survived longer than 100 days indicating the small portion of residual Ggcx activity detected in the liver of GgcxΔliver/Δliver mice is sufficient to survive unless they got injured or pregnant. This is compatible with the clinical observation that patients with decreased carboxylase activity live several years before diagnosis.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_87ceae1d-b329-4c29-b6f2-8a94a127204e-2021-02-24T175200.635Z,888,PubMed:24520408 +Charizopoulou Animal Model and Rescue,Model Systems Non-human model organism,"Charizopoulou N, et al., 2011, PMID: 21326233","They examined the mice's auditory phenotype and their susceptibility to audiogenic seizures. In addition, they attempted to rescue the phenotype by creating transgenic mice to express the Gipc3 gene. The Gipc3 mutant mice exhibit progressive hearing loss and susceptibility to juvenile audiogenic seizures. They also noted abnormalities in the stereocilia bundles of the mutant mice a progressive degeneration of the organ of Corti in mutant mice. Transgenic rescue mice showed rescue of both the hearing loss and juvenile audiogenic seizure phenotypes.",Score,4 (2),Upgraded because this is a mouse model and a rescue,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e5feebe1-59a9-4e28-ad85-aec5cad6b54e-2017-08-22T160000.000Z,890,PubMed:21326233 +Charizopoulou Expression,Expression A,"Charizopoulou N, et al., 2011, PMID: 21326233","The researchers investigated the expression and localization of Gipc3 in WT mouse cochlea and spiral ganglion cells. Gipc3 was found to localize to the cytoplasm of IHCs, OHC's and spiral ganglion neurons.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e5feebe1-59a9-4e28-ad85-aec5cad6b54e-2017-08-22T160000.000Z,890,PubMed:21326233 +Charizopoulou Biochemical Function,Biochemical Function B,"Charizopoulou N, et al., 2011, PMID: 21326233",Same phenotype as observed in human patients.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e5feebe1-59a9-4e28-ad85-aec5cad6b54e-2017-08-22T160000.000Z,890,PubMed:21326233 +Fabry Outcome survey - ERT,Rescue Human,"Beck M, et al., 2015, PMID: 26937390","Compared with no treatment, patients treated with agalsidase alfa demonstrated slower decline in renal function and slower progression of left ventricular hypertrophy. Treated male patients with baseline eGFR < 60 mL/min/1.73 m2 had a mean (standard error of the mean [SEM]) annualized change in eGFR of − 2.86 (0.53) mL/min/1.73 m2/y compared with − 6.8 (1.5) in the published untreated cohort. The mean (SEM) rate of LVMI increase with treatment was 0.33 (0.10) g/m2.7/y in males and 0.48 (0.09) in females, compared with 4.07 (1.03) in untreated males and 2.31 (0.81) in untreated females. Morbidity occurred later in treated patients, with ~ 16% risk of a composite morbidity event (26% in males) after 24 months with ERT versus ~ 45% without treatment, with first events and deaths also occurring at older ages in patients administered ERT (e.g., estimated median survival in treated males was 77.5 years versus 60 years in untreated males). Findings from these retrospective comparisons of observational data and published literature support the long-term benefits of ERT with agalsidase alfa for Fabry disease in slowing the progression of renal impairment and cardiomyopathy. Treatment also appeared to delay the onset of morbidity and mortality. Interpretation of these findings should take into account that they are based on retrospective comparisons with previously published data.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_eb4bb6f4-89de-4586-af6b-3f218b8cb4dc-2019-01-23T170000.000Z,899,PubMed:26937390 +Chen_Rescue patient cells,Rescue Patient cells,"Chen JC, et al., 2020, PMID: 31481471","GM1 gangliosidosis is caused by the deficiency of the beta-galactosidase enzyme, which results in accumulation of the substrates such as glycosaminoglycans, which results in several systemic phenotypes. Authors in this study show that the expression of the wild-type enzyme clears substrate accumulation and rescues the cellular phenotype.",Score,1 (1),Default points are scored for rescue in patient cells.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0019c7ef-4e2f-4f32-ab42-decfa0b20c29-2023-04-28T160000.000Z,900,PubMed:31481471 +Chen_Rescue Mouse,Rescue Non-human model organism,"Chen JC, et al., 2020, PMID: 31481471","Using this method, authors showed that the enzyme gets precisely delivered to acidified lysosomes, where it exists as a stable dimer and results in substrate clearance in the brain tissue of affected mice. Authors suggest that once the uptake capacity of lysosomes was saturated, the remaining extracellular enzyme was likely cleared. rhbeta-gal activity levels in liver and bone marrow of ERT–treated KO mice were normalized, suggesting systemic exposure to the enzyme.",Score,2 (2),Default points are scored.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0019c7ef-4e2f-4f32-ab42-decfa0b20c29-2023-04-28T160000.000Z,900,PubMed:31481471 +Gorelik_Lysosomal multienzyme complex,Biochemical Function A,"Gorelik A, et al., 2021, PMID: 33980489","GLB1, CTSA and NEU1 form the lysosomal multienzyme complex together.",Score,1 (0.5),"GLB1 protein forms the lysosomal multienzyme complex with the products of two other genes, CTSA and NEU1. Increased points are awarded for the same function as two other genes causing lysosomal disorders.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0019c7ef-4e2f-4f32-ab42-decfa0b20c29-2023-04-28T160000.000Z,900,PubMed:33980489 +Gorelik_Interaction with CTSA,Protein Interaction,"Gorelik A, et al., 2021, PMID: 33980489","Authors show through cryo-electron microscopy that GLB1 forms a lysosomal multienzyme complex with CTSA and NEU1. While the direct interaction with NEU1 is not shown experimentally, electron microscopy reveals that the complex is composed of three GLB1 dimers and three CTSA dimers, adopting a triangular architecture maintained through six copies of a unique GLB1-CTSA polar interface.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0019c7ef-4e2f-4f32-ab42-decfa0b20c29-2023-04-28T160000.000Z,900,PubMed:33980489 +Nicoli_Beta-galactosidase activity,Biochemical Function B,"Nicoli ER, et al., 2021, PMID: 34539759","Bi-allelic mutations in GLB1 result in a reduction in β-GAL activity and the build-up of GM1 ganglioside in multiple tissues including the brain leading to severe neurodegeneration resulting in morbidity and premature mortality. More than 200 disease-causing mutations have been identified across the GLB1 gene, particularly in exons 2, 6, 15, and 16.",Score,2 (0.5),"This paper and several other review articles (PMID: 24156116, PMID: 33737400) describe the role of GLB1 in GM1 Gangliosidosis, warranting the maximum score for biochemical function.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0019c7ef-4e2f-4f32-ab42-decfa0b20c29-2023-04-28T160000.000Z,900,PubMed:34539759 +Gorelik_Lysosomal multienzyme complex,Biochemical Function A,"Gorelik A, et al., 2021, PMID: 33980489","GLB1, CTSA and NEU1 form the lysosomal multienzyme complex together.",Score,0.5 (0.5),"GLB1 protein forms the lysosomal multienzyme complex with the products of two other genes, CTSA and NEU1. Increased points are awarded for the same function as two other genes causing lysosomal disorders.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9e170fda-e08a-4fd3-a3e5-f08c5c0d55b8-2023-04-28T160000.000Z,901,PubMed:33980489 +Gorelik_Interaction with CTSA,Protein Interaction,"Gorelik A, et al., 2021, PMID: 33980489","Authors show through cryo-electron microscopy that GLB1 forms a lysosomal multienzyme complex with CTSA and NEU1. While the direct interaction with NEU1 is not shown experimentally, electron microscopy reveals that the complex is composed of three GLB1 dimers and three CTSA dimers, adopting a triangular architecture maintained through six copies of a unique GLB1-CTSA polar interface.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9e170fda-e08a-4fd3-a3e5-f08c5c0d55b8-2023-04-28T160000.000Z,901,PubMed:33980489 +Nicoli_Beta-galactosidase activity,Biochemical Function B,"Nicoli ER, et al., 2021, PMID: 34539759","Bi-allelic mutations in GLB1 result in a reduction in β-GAL activity and the build-up of GM1 ganglioside in multiple tissues including the brain leading to severe neurodegeneration resulting in morbidity and premature mortality. More than 200 disease-causing mutations have been identified across the GLB1 gene, particularly in exons 2, 6, 15, and 16. Morquio B disease results from the accumulation of keratan sulfate and is not characterized by neurological features.",Score,2 (0.5),"This paper and several other review articles (PMID: 24156116, PMID: 33737400) describe the role of GLB1 in GM1 gangliosidosis and Morquio B disease, warranting the maximum score for biochemical function.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9e170fda-e08a-4fd3-a3e5-f08c5c0d55b8-2023-04-28T160000.000Z,901,PubMed:34539759 +Stress Granules,Biochemical Function B,"Aditi, et al., 2015, PMID: 25694449","Here we show that hGle1 depletion results in SG-assembly defects and slows disassembly of SGs. Moreover, hGle1 is involved in regulating the exchange between SGs and translation in a manner similar to that reported for Ded1. Thus lack of proper hGle1-mediated control of DDX3 could lead to improper SG dynamics. Deregulation of SG assembly, disassembly, and their clearance is associated with various neurological diseases, including ALS. +The authors speculate that the ALS hGLE1 mutations could impact both mRNA export (by decreasing the pool of hGle1B available) and translation (by altering the pool of hGle1A and SG dynamics).",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0284b3cd-38af-4309-8ce4-054a0379e693-2023-10-10T160000.000Z,902,PubMed:25694449 +Li Zebrafish Expression,Expression A,"Li X, et al., 2012, PMID: 22815753","Figure 1: We generated transgenic zebrafish Tg (Gnat2:gal4-VP16/UAS:nfsB-mCherry) that express E. coli nitroreductase and mCherry in cone photoreceptor cells. By 48 hpf, mCherry was detected in the retina, at which time retinal cone photoreceptor cells were developed (Fig. 1B). The intensity of transgene expression in the pineal gland and retina increased during embryonic stages (between 56 and 120 hpf; Fig. 1C–F).",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6888747f-55ae-4f8e-a3a8-c77bcd543689-2022-11-03T160000.000Z,911,PubMed:22815753 +GNB4 Expression Induces Myelinaition in Mice,Functional Alteration Non-patient cells,"Pol SU, et al., 2017, PMID: 28793249","In the control shiverer/rag2 mice, very few hOPCs typically underwent differentiation into MBP-expressing oligodendrocytes consistent with the shiverer demylination phenotype. In contrast, MBP immunohistchemistry in mice transplanted with human GNB4-expressing hOPCs exhibited a greater than 3-fold increase in MBP staining within the corpus callosum. Consistent with improved myelination by GNB4-expressing transplanted cells, the density of ensheathed axons increased from 40.5 ± 5.1 fibers/mm by mCherry control cells to 71.8 ± 9.8 fibers/mm by GNB4-expressing cells, representing a >75% increase in axonal ensheathment. Thus, GNB4-expressing hOPCs more rapidly synthesized MBP and ensheathed host axons, consistent with accelerated donor-derived myelin synthesis.",Score,1 (0.5),"Gβ4 expression differentially regulates hOPC fate in vitro and in vivo and, importantly, GNB4/Gβ4 was sufficient to substantially improve the production of myelin proteins and axonal ensheathment by hOPCs in vivo. This provides a clear altered function in these hOPCs' differentiation when GNB4 is expressed vs. when it's absent, particularly since the myelin and axonal ensheathment is essential to the pathogenic mechanism of Charcot-Marie-Tooth phenotypes. Therefore, for conclusively demonstrating altered function in human hOPCs, this evidence earns 1.0 point.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a8cecdd7-06d8-4697-8cd9-32900c366371-2020-04-14T132010.930Z,912,PubMed:28793249 +Gnptg KO mouse neurological features,Model Systems Non-human model organism,"Idol RA, et al., 2014, PMID: 25314316","GNPTG KO mice exhibited mild-moderate sensorimoter deficits observed by results of locomotor activity tests, reduced vertical rearing frequency, impaired rotarod performance. +Histological analyses revealed mild to moderate atrocytosis and microgliosis. +Accumulation of GM2 in the cerebrum cerebellum and brainstem of 12 month old Gnptg KO mice was shown by mass spectrometry of brain tissues (Fig 10). +The authors also investigated the neurological features of Gnptab KO mice and concluded that Gnptab KO mice have more severe findings than Gnptg mice, as observed in humans with GNPTAB vs GNPTG biallelic variants.",Score,1 (2),Adding these point to an earlier study (PMID: 19261645) for a total of 2 points for Gnptg KO mice.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_71d1d916-4c96-4d09-a66b-1c7ccb55c353-2022-12-28T170000.000Z,915,PubMed:25314316 +Proplatelet Formation,Functional Alteration Patient cells,"Bury L, et al., 2019, PMID: 30655369","vWF bound to the surface of human PT-vWD megakaryocytes, co-localizing with GPIbα, was detected by confocal microscopy and flow cytometry on days 7, 10 and 14 of cell differentiation, while control megakaryocytes did not show bound vWF at any of the differentiation times. Probably due to the boosting role of vWF on proplatelet formation, PT-vWD megakaryocytes extended very long and branched proplatelets on fibrinogen and vWF, however, the number of proplatelet tips was reduced and tip diameter was larger in PT-vWD megakaryocytes. Additionally, immunohistochemistry showed an increased number of platelets in the bone marrow of the PT-vWD patient compared to healthy controls .",Score,1 (1),"Showed that constitutive binding of vWF to mutated GPIbα of PT-vWD megakaryocytes triggers dysregulated intracellular signaling leading to the loss of the physiological inhibition of proplatelet formation on type I collagen, and thus to ectopic platelet release in the bone marrow. This, together with the formation of a reduced number of large platelets by PT-vWD megakaryocytes and increased platelet clearance, causes thrombocytopenia.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_8fef91aa-8c41-4044-b601-da24c2bab351-2020-05-27T160000.000Z,919,PubMed:30655369 +Massberg_GPVI function,Biochemical Function B,"Massberg S, et al., 2003, PMID: 12515812","In GPVI-deficient mice, only few platelets tethered to the intact wall and there was no firm arrest of these platelets.",Score,0.5 (0.5),Patients with congenital GPVI deficiency show prolonged bleeding after minor trauma or surgery and the lack of platelet aggregation in response to collagen. The evidence is scored default points.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_76262cf5-f2cd-4466-b542-bf2334a96c73-2019-10-23T160000.000Z,921,PubMed:12515812 +Meehan2017,Model Systems Non-human model organism,"Meehan TF, et al., 2017, PMID: 28650483","Gp9tm1.1(KOMP)Vlcg null homozygotes have a decreased number of platelets with a larger cell volume, recapitulating key features of the disease and adding evidence that the point mutations associated with disease in humans lead to a functionally null complex.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_af66eb15-10fe-4c2b-bff2-b8c8bf813174-2019-11-27T170000.000Z,922,PubMed:28650483 +Knockout of GPC3 in mouse model by removing exon 1,Model Systems Non-human model organism,"Cano-Gauci DF, et al., 1999, PMID: 10402475","The mouse model shares the clinical features of developmental overgrowth, perinatal death, cystic and dysplastic kidneys, and abnormal lung development.",Score,1 (2),"The paper mentioned that other abnormalities observed in some SGBS patients, such as hernias, heart defects, polydactyly, and vertebral and rib malformations, are not present in the mutant mice. More importantly, no behavioral studies were performed regarding the neurological phenotypes.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5b8b02d6-1d60-4b4c-bb8a-b976907087c7-2019-12-31T175422.159Z,924,PubMed:10402475 +Gpr179 knock-out mouse,Model Systems Non-human model organism,"Orhan E, et al., 2021, PMID: 33922602","Gpr179−/− mice were lacking b-waves on their ERG responses, while a-waves were comparable in amplitude or implicit time to Gpr179+/+ and Gpr179+/−, leading to an electronegative ERG waveform",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_53ab184d-9f73-42b6-b407-7d72f7b44c8a-2022-06-02T160000.000Z,925,PubMed:33922602 +Mauriac 2017 Functional Alteration 1,Functional Alteration Non-patient cells,"Mauriac SA, et al., 2017, PMID: 28387217","At P5, scanning electron microscopy showed a ~40% decrease in IHC tallest stereocilia length and a ~25% increase in the number of stereocilia per IHC bundle. At P21, the average length of the tallest stereocilia was reduced by ~70% and the number of stereocilia per bundle was increased by ~60%.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_cd40cf49-a25c-450b-be6b-b80eef958f4c-2018-05-01T160000.000Z,926,PubMed:28387217 +Mauriac 2017 Mouse Model,Model Systems Non-human model organism,"Mauriac SA, et al., 2017, PMID: 28387217","Measuring of auditory brainstem responses showed Gpsm2 cKOs were profoundly deaf at 6 weeks of age. The mice also exhibited increased hyperactive behavior (413%) from controls, circling behavior, and tight swimming circles. The mice's behavior is indicative of vestibular dysfunction.",Score,1.5 (2),"Downgraded because no brain scans were performed, which reveal most symptoms of Chudley-McCullough syndrome.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_cd40cf49-a25c-450b-be6b-b80eef958f4c-2018-05-01T160000.000Z,926,PubMed:28387217 +Northern blot analysis,Expression A,"Namkoong H, et al., 2006, PMID: 16545136",Human gremlin 1 was expressed in normal tissue from colon.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9e702a1e-b700-4364-bf4b-9ad0d05af89f-2022-06-20T170000.000Z,928,PubMed:16545136 +Expression of GREM1 in patients colonic tissues,Expression B,"Jaeger E, et al., 2012, PMID: 22561515","Marked increased of GREM1 transcript levels in the normal epithelium of HMPS patients compared with the controls, but no significant differences in the expression of SCG5 or FMN1. +Allele-specific expression (ASE) analysis showed significantly increased expression of the duplicated allele in HMPS crypts (Mann-Whitney P = 0.0009).",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9e702a1e-b700-4364-bf4b-9ad0d05af89f-2022-06-20T170000.000Z,928,PubMed:22561515 +Mouse model of GREM1 overexpression,Model Systems Non-human model organism,"Davis H, et al., 2015, PMID: 25419707","Pan-intestinal polyposis (Supplementary Fig. 4c), with a median of 183 polyps per mouse. Small intestinal lesions had a mixed serrated, adenomatous and cystic phenotype characteristic of the lesions seen in HMPS.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9e702a1e-b700-4364-bf4b-9ad0d05af89f-2022-06-20T170000.000Z,928,PubMed:25419707 +GREM1 knockout,Rescue Non-human model organism,"Davis H, et al., 2015, PMID: 25419707",Mouse model of GREM1 knockout reduces polyp burden and size in Apc Min/+ mouse.,Score,0.5 (2),Downgraded: knockout in a gene that overexpression is the mechanism.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9e702a1e-b700-4364-bf4b-9ad0d05af89f-2022-06-20T170000.000Z,928,PubMed:25419707 +Expression Analyses by Droplet Digital PCR,Expression B,"Rohlin A, et al., 2016, PMID: 26493165",Six controls of normal colon mucosa and normal colon mucosa from two samples each from patient IV:2 and V:2 were analyzed by Droplet Digital PCR. The GREM1 gene is significantly higher expressed in samples from colon mucosa in the affected family members compared with controls (P < 0.013).,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9e702a1e-b700-4364-bf4b-9ad0d05af89f-2022-06-20T170000.000Z,928,PubMed:26493165 +"Novel open field, modified forced swim, elevated zero-maze",Model Systems Non-human model organism,"Fitzgerald PJ, et al., 2010, PMID: 20699120","GluA1 KO mice travelled significantly farther compared to WT in a novel open field, overal suggestive of locomotor hyperactivity in response to novelty and mild stress. KO mice showed decreased immobility and increased swimming compared to WT during forced swim and modified forced swim test. The profile of KO mice in the elevated zero-maze and stress-induced hyperthermia assays was more consistent with heightened anxiety-like behaviour. These behavioural abnormalities were however thought to resemble positive symptoms in schizophrenia or the manic-like component of schizoaffective disorder and to a lesser extent attention deficit hyperactivity disorder (ADHD). In line with the latter remark, treatment with psychostimulants like amphetamine and methylphenidate exacerbated (instead of reversing) open field hyperactivity of KO mice, although the effect of psychostimulant anti-ADHD drugs were observed over a short 10-minute session. Similar to previous reports, KO mice were otherwise commented to be normal in terms of physical health, neurological and sensory functions. The single affected individual reported to date, had behavioural issues although these were no further defined unless for self-injurious behaviour.",Score,0.5 (2),Homozygous mouse model (KO) only partially recapitulates human phenotype.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_84aaf490-76e2-4d87-a1bd-53ab6611236c-2024-02-08T070000.000Z,930,PubMed:20699120 +Review and T-maze rewarded alternation testing,Model Systems Non-human model organism,"Taylor AM, et al., 2011, PMID: 21641937","Abnormal spatial working memory observed in mouse model (limited impairement, still representing abnormal cognition). Cognitive impairement observed in humans.",Score,0.5 (2),"Highly specific impairment in mice, limited to spatial working memory.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_84aaf490-76e2-4d87-a1bd-53ab6611236c-2024-02-08T070000.000Z,930,PubMed:21641937 +Behavioural tests (incl.FMP Y-maze),Model Systems Non-human model organism,"Ismail V, et al., 2022, PMID: 35675825","A small subset of tadpoles (5 out of 50) presented behaviour similar to descriptions of seizures in Xenopus tadpoles in literature. Episodic periods of abnormal behaviour incl. C-shaped alternating axial contractions of the tail coupled with rapid changes in direction. “Manic bouts"" were followed by prolonged unusual period of immobility. The free-movement pattern (FMP) Y-maze behavioural model was developed to assess the effect of gria1 ko on cognitive function and was consistent with working memory deficit (significant decrease in alternations observed, as compared to WT). There was no evidence of hyperactivity. Brain morphology of gria1 crispants matched uninjected controls. Cognitive impairment, abnormal behaviour and seizures have been reported in the single affected individual reported to date. Brain MRI was also normal.",Score,0.5 (2),"A small subset of tadpoles exhibited behaviour similar to seizures. As commented by the authors of the study, the FMP Y-maze has been validated for assessing spatial working memory and cognitive flexibility in other model organisms (i.e. zebrafish) but has not been previously used in Xenopus.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_84aaf490-76e2-4d87-a1bd-53ab6611236c-2024-02-08T070000.000Z,930,PubMed:35675825 +Kainate receptor function in abDGCs,Model Systems Non-human model organism,"Zhu Y, et al., 2021, PMID: 34551304","Conditional knockout of GRIK2 in adult-born dentate granule cells (abDGCs) in 8-9 week mice resulted in impaired spatial discrimination, increased depolarization of EGABA, and elevated GABAergic synaptic events at 21 dpi, although the exact relevance to human clinical phenotypes is unclear.",Score,1 (2),The relevance to human clinical phenotypes is unclear.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1939b90b-f1e4-4426-9f8c-5526f9003f10-2022-02-10T070000.000Z,933,PubMed:34551304 +Functional studies of de novo het variants,Functional Alteration Non-patient cells,"Lemke JR, et al., 2016, PMID: 27164704",Expression in mutant cells and analysis of the dose-response curves for various mutations revealed a highly significant reduction in the affinities for both glutamate and glycine.,Score,0.5 (0.5),"Analyses of de novo mutations are consistent with a dominant negative effect resulting in a significant loss of receptor function. GRIN1 de novo mutations cluster within or in +direct proximity to the transmembrane domains of GRIN1. This dominant negative impact that is investigated with multiple variants and shows that certain variants that cause LOF to the transmembrane domain.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b98e5df5-8f39-4fd6-9715-bb8da7dc1806-2018-11-20T050000.000Z,935,PubMed:27164704 +A9D GRN mRNA Levels Are Decre ased Relative to WT GRN and V5,Functional Alteration Patient cells,"Pinarbasi ES, et al., 2018, PMID: 29874572","A9D mRNA is specifically degraded in patient-derived cells, and mRNA degradation is translation dependent +Disruption of SRP (Signal recognition particle) recruitment triggers GRN mRNA degradation (SRP recruitment is important for mRNA stability). A9D cannot recruit SRP efficiently. A9D signal sequence is sufficient to trigger mRNA degradation",Score,0 (1),Already added in the genetic evidence. (Disruption of SRP (Signal recognition particle) recruitment triggers GRN mRNA degradation (SRP recruitment is important for mRNA stability). A9D cannot recruit SRP efficiently. A9D signal sequence is sufficient to trigger mRNA degradation),https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e76545e6-2411-44c5-a458-99f02aa7ff44-2023-05-25T160000.000Z,942,PubMed:29874572 +Van Rossom Model,Model Systems Non-human model organism,"Van Rossom S, et al., 2012, PMID: 22848872",Mutant DFNA5 caused increase in reactive oxygen species and other signs of programmed cell death.,Score,1 (2),"More evidence available, Models & Rescue score maxed out.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9b0a844b-f968-48e0-8940-35584eb3454b-2017-11-21T170000.000Z,944,PubMed:22848872 +Hosoya Expression,Expression A,"Hosoya M, et al., 2016, PMID: 26915689","Expression observed in the stria vascularis, spiral ligament fibrocytes, inner and outer hair cells, supporting cells, and spiral ganglion neurons of common marmoset",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9b0a844b-f968-48e0-8940-35584eb3454b-2017-11-21T170000.000Z,944,PubMed:26915689 +Navarro-Gonzalez I,Model Systems Non-human model organism,"Navarro-González C, et al., 2017, PMID: 28732077","Mitochondrial dysfunction, fertility defects, embryonic and developmental arrest",Score,0.5 (2),"Recapitulates mitochondrial dysfunction, fertility defects, embryonic and developmental arrest, not full model",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0d1b0a47-e62d-48dd-8e0d-f2b1aff014a7-2020-02-12T203256.857Z,947,PubMed:28732077 +Asano I,Functional Alteration Non-patient cells,"Asano K, et al., 2018, PMID: 29390138","Fig 4 shows analysis of GTPBP3 KO HEK293T cells; severely reduced oxygen consumption rate, reduced complex 1 and IV activity but increased complex II activity, reduced levels of complex I proteins (ND2 and NDUFB8). Pulse labeling of mt protein synthesis showed a reduced rate.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0d1b0a47-e62d-48dd-8e0d-f2b1aff014a7-2020-02-12T203256.857Z,947,PubMed:29390138 +Chen I,Model Systems Non-human model organism,"Chen D, et al., 2019, PMID: 30916346","Biochemical recapitulation relevant to gene:disease association; reduced translation of mitochondrial proteins and reduced levels of complex I, -V. Abnormal mitochondrial morphology seen in cardiomyocytes is also consistent with disease (although abnormal heart development is not relevant to LSS).",Score,0.5 (2),"Biochemical recapitulation relevant to gene:disease association; reduced translation of mitochondrial proteins and reduced levels of complex I, -V. Abnormal mitochondrial morphology seen in cardiomyocytes is also consistent with disease (although abnormal heart development is not relevant to LSS).",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0d1b0a47-e62d-48dd-8e0d-f2b1aff014a7-2020-02-12T203256.857Z,947,PubMed:30916346 +GYS1 conditional KO mouse,Model Systems Non-human model organism,"Xirouchaki CE, et al., 2016, PMID: 26977394","Exercise intolerance was observed in multiple human GYS1 deficiency patients, and this was correlated with a loss of glycogen in skeletal and cardiac muscle. These phenotypes were fully recapitulated in mice with a muscle-specific, inducible GYS1 KO. Further, these mice showed signs of insulin resistance and impaired glucose uptake; a similar result was obtained in in vitro assays of glycogen synthase activity using patient fibroblasts (PMID: 19699667).",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_4b85c829-f66a-4c23-8a59-58f17bdaefb0-2024-02-12T190000.000Z,951,PubMed:26977394 +Marr et al. 2022,Protein Interaction,"Marr L, et al., 2022, PMID: 35690592",The interaction between GYS2 and GYG1 via the C-terminus is necessary in order for GYS2-mediated glycogen synthesis to occur.,Score,0 (0.5),GYG1 is localized to muscle and GYS2 is localized to the liver.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_fd645894-0fa6-4d63-8b8d-16731978ca6b-2024-03-22T160000.000Z,952,PubMed:35690592 +Wild-type H3.3 mRNA rescued the head skeletal defects,Rescue Non-human model organism,"Cox SG, et al., 2012, PMID: 23028350","increasing H3.3 levels by injection of wild-type H3.3 mRNA rescued the head skeletal defects of h3f3adb1092 mutants, showing that defects are indeed due to compromised H3.3 incorporation and not neomorphic effects of mutant D123N H3.3 on unrelated pathways (Figure 5a, 5b). H3.3-mRNA-injected h3f3adb1092 homozygotes (a) and +heterozygotes (b) exhibited a decrease in the severity of h3f3adb1092 craniofacial phenotypes over kikGR-RNA-injected controls (significant by Fisher’s +exact test: homozygotes, p = 7.7E-05; heterozygotes, p = 1.0E-04).",Score,0 (2),"The role of increasing H3.3 levels by injection of wild-type H3.3 mRNA in this study has rescued the head skeletal defects of h3f3adb1092 mutants but the aim is to confirm that defects seen in the h3f3adb1092 mutants are indeed due to compromised H3.3 incorporation and not neomorphic effects of mutant D123N H3.3 on unrelated pathways (Figure 5a, 5b). The panel feels that this piece of evidence is not for scoring after ClinGen Syndromic Group Discussion on 19 March 2024.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_92b54362-8c84-407b-bf92-5f67bee55ed3-2024-03-19T160000.000Z,954,PubMed:23028350 +A dominant H3.3 mutation disrupts CNC development,Model Systems Non-human model organism,"Cox SG, et al., 2012, PMID: 23028350","Like in other vertebrates, the facial skeleton and anterior skull of the larval zebrafish derive from cranial neural crest (CNC) ectomesenchyme, with the posterior skull being of mesoderm +origin. In db1092 homozygous mutants, nearly all of the CNC-derived cartilage, bone, and teeth were lost at 5 days-postfertilization (dpf), leaving only the mesoderm-derived skull +(Figure 1c, 1d). db1092 homozygous larvae die by around 7 dpf, presumably due to an inability to feed. Whereas some db1092 heterozygotes survived to adulthood, others exhibited variable reductions of the jaw-support skeleton (Figure 1e, 1f). Melanophore pigment cells and their dct-positive precursors were reduced in the cranial but not trunk regions of db1092 mutants, +and to a lesser extent so were xanthophore pigment cells and their xdh-positive precursors (Figure 1h, 1j and Figure S1). In contrast, foxd3-positive peripheral glia (Figure 1l), neurons of the cranial ganglia (Figure S1), and the dorsal root ganglia and sympathetic neurons derived from trunk NC (data not shown) were unaffected. db1092 mutants also displayed mild heart edema, consistent with a known CNC contribution to the heart [26], but had an otherwise +remarkably normal morphology at 5 dpf (Figure 1s). In summary, db1092 mutants have highly specific reductions of CNC derivatives, in particular the ectomesenchymal/skeletal components of the head. +Individuals/Patients reported with de novo germline mutations in H3-3A with neurological dysfunction may have microcephaly, Craniosynostosis/abnormal head shape (excluding plagiocephaly) that can be similar to the phenotype seen in the zebrafish model.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_92b54362-8c84-407b-bf92-5f67bee55ed3-2024-03-19T160000.000Z,954,PubMed:23028350 +Histone H3.3 is expressed in the neural stem cells,Expression A,"Xia W, et al., 2017, PMID: 28524856","Histone H3.3 Is expressed in the neural stem cells (NSC). Previous study has shown that the level of histone H3.3 is generally accumulated with age. However, the expression of H3.3 +during the embryonic development remains unexplored. The authors performed western blot to check the H3.3 expression pattern in brain tissue during different developmental periods. Our +results showed that the expression of H3.3 is dynamic during early brain development. The results showed that histone H3.3 was detectable at E10 in mice, and its expression was gradually +increased until E13.5. After that, the expression was reduced between E15.5 and P0 (Figure 1a). The expression pattern of H3.3 was similar with PAX6, which is a progenitor cell marker. +This result suggests that Histone H3.3 may play a key role in early embryonic brain development (Figure 1b). In the embryonic cortex, the immunostaining result showed that the histone H3.3 protein co-localized with NESTIN- and SOX2-positive neuronal progenitor cells residing in the +VZ/SVZ at E13.5 and E15.5 (Figures 1c and d). Moreover, the authors found that H3.3 co-localized with NESTIN- and SOX2-positive cultured NSCs (Supplementary Figure 1a). Since +H3.3 protein was encoded by h3f3a and h3f3b genes simultaneously, we generated two h3f3a-specific short hairpin RNA (shRNA) (h3f3a shRNA-1 and h3f3a shRNA-2) and two +h3f3b -specific short hairpin RNA (shRNA) (h3f3b shRNA-1 and h3f3b shRNA-2) plasmids. The knockdown efficiency was tested and the combination of h3f3a shRNA-1 with h3f3b shRNA-1 (H3.3KD#1) and h3f3a shRNA-2 with h3f3b shRNA-2 (H3.3KD#2) could efficiently silence H3.3 expression in vivo and in vitro (Figure 1e,Supplementary Figures 1b and 1c). The authors also constructed H3.3-overexpression plasmid to overexpress H3.3 expression in embryonic NSCs (Figures 1e and f). We found that H3.3 knockdown decreased the expression of neural stem cell markers PAX6 and SOX2, and increased the expression of neurogenesis marker TUJ1 +(Figure 1g). Also, H3.3 (h3f3a) overexpression could rescue the abnormal phenotype caused by H3.3 knockdown (h3f3a shRNA-2 targeting to UTR and h3f3b shRNA-2) (Figure 1h). These results suggest that H3.3 participates in the process of the early neurogenesis.",Score,0 (0.5),"Experimental evidence (Expression) with score 0.5 has been awarded to Funk et al 2022 PMID: 35930666). As per ClinGen Syndromic Group discussion on 19 March 2024, this piece of evidence is counted as extra piece of evidence for expression and will not be scored.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_92b54362-8c84-407b-bf92-5f67bee55ed3-2024-03-19T160000.000Z,954,PubMed:28524856 +Substantial Postmitotic H3.3 accumulation n cortical neuron,Expression A,"Funk OH, et al., 2022, PMID: 35930666","Substantial Postmitotic Accumulation of H3.3 in New Cortical Neurons. H3.3-encoding genes H3f3a and H3f3b are expressed in many tissues. To determine H3f3a and H3f3b expression +in the wild-type embryonic day (E)14.5 cortex, the authors used single-nuclei RNA-sequencing (snRNA-seq). We assayed 9,300 cells that met stringent quality control for snRNA-seq, with a +median of 2,642 genes detected per cell. Clustering by Seurat (38) revealed 19 groups that encompassed the full complement of known cell types in the embryonic cortex (Fig. 1A). Our +analysis revealed high H3f3a and H3f3b expression levels in all types of NPCs, including radial glial cells and intermediate progenitors, as well as postmitotic neurons at various stages of maturation (Fig. 1A). Each of the 19 cell types expressed H3f3a and H3f3b (Fig. 1A), which were detected, respectively, in 98.0% and 98.2% of cells. Consistent with RNA-seq of the +developing human cortex (39, 40), our data support that H3f3a and H3f3b are widely, likely ubiquitously, expressed in cortical development and throughout the cell cycle (21). +To directly quantify H3.3 levels from the time of neuronal birth, the authors labeled wild-type embryos by a pulse of thymidine analog 5-ethynyl-20-deoxyuridine (EdU) +at E13.5, and tracked labeled cells 2 h, 24 h, 3 d, 5 d, or 6 d later. They found that in S-phase cells labeled by a 2-h pulse of EdU, H3.3 was present only at low levels (Fig. 1C). Over the next 6 d following neuronal birth, H3.3 levels progressively increased in EdU-labeled neurons (Fig. 1C and D). Together, the data suggest that although H3f3a and H3f3b are expressed throughout the cell cycle, H3.3 histone accumulation in neurons significantly increases postmitotically over several days (Fig. 1E).",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_92b54362-8c84-407b-bf92-5f67bee55ed3-2024-03-19T160000.000Z,954,PubMed:35930666 +Defects in Cortical Axonal Projections w H3f3a & H3f3b del,Functional Alteration Non-patient cells,"Funk OH, et al., 2022, PMID: 35930666","Defects in Cortical Axonal Projections following H3f3a and H3f3b Codeletion. The authors analyzed cortical axon tracts (Fig. 5A). In P0 control, immunostaining of L1CAM revealed axons traversing white matter below the CP and corpus callosum (CC) (Fig. 5B). H3f3a/b codeletion +from neurons (dKO-N) or NPCs (dKO-E) led to a marked loss of white matter thickness, and agenesis of the CC (Fig. 5B). Leveraging the Cre-dependent reporters expressed from the +H3f3a and H3f3b floxed loci (SI Appendix, Fig. S1D), the authors found in both dKO-N and dKO-E that the anterior commissure (AC) failed to cross the midline and was misrouted toward the hypothalamus (Fig. 5C). Corticofugal tracts were also disrupted. In both dKO-N and dKO-E, corticofugal axons projected into the caudate putamen and innervated internal capsule (IC) (Fig. 5D). Beyond the IC, however, corticofugal axons showed deficits in reaching their targets in both dKO-N and dKO-E, including an absence of corticothalamic axons reaching the dorsal thalamus +(Fig. 5D) and an absence of corticospinal tract (CST) axons reaching the pons (Fig. 5E). We further analyzed the axons of hippocampal pyramidal neurons (SI Appendix, Fig. S6A). In both +dKO-N and dKO-E, hippocampal axons projected into fimbria, but failed to innervate fornix. These deficits accompanied alterations in hippocampal organization (SI Appendix, Fig. S6B and +C). Together, these findings revealed a requirement for H3.3 in the formation of both intracortical and corticofugal tracts, especially in enabling axons to reach their final targets. These axonal +defects were phenotypically indistinguishable between dKO-N and dKO-E, indicating that the requirement for de novo H3.3 in axon development is largely postmitotic.",Score,0 (0.5),This experimental evidence will not be scored - co-deletion of H3-3A/H3-3B genes. Does not fulfill criteria to be used for scoring. (ClinGen Syndromic Group discussion 19 March 2024),https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_92b54362-8c84-407b-bf92-5f67bee55ed3-2024-03-19T160000.000Z,954,PubMed:35930666 +Epigenetic regulation of gene expression in nervous system,Biochemical Function B,"Di Liegro CM, et al., 2023, PMID: 37446205","As described by the authors, H3.3 histone is important in the brain development as seen in H3-3A/H3-3B gene-related neurodevelopmental disorder. Experiments in which H3.3 expression that was silenced with RNA interference demonstrated profound alterations in both the structural and functional organisation of the brain, with clear effects on the mechanisms underlying memory processes (Maze et al 2015, PMID: 26139371; Xia et al 2017, PMID: 28524856). In the beginning of brain development, stage-dependent deletion of the two encoding H3.3 encoding genes led to genes involved in the proliferative stage of brain development are silenced, while a collection of genes are activated in order to drive neuronal differentiation, with even different genes involved in the specification of different layers of the developing cortex. (Funk et al 2022, PMID:35930666; Bedogni et al 2010, PMID: 20615956; Han et al 2011, PMID: 21285371; Tsyporin et al 2021, PMID: 34161768). Disruption to the structural and functional organisation of the brain lead to neurodevelopmental disorder/delay in human.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_92b54362-8c84-407b-bf92-5f67bee55ed3-2024-03-19T160000.000Z,954,PubMed:37446205 +HACD1 KO Mice Display Myopathic Phenotypes,Model Systems Non-human model organism,"Blondelle J, et al., 2015, PMID: 26160855","The HACD1 KO mouse model recapitulates many of the phenotypes seen in both the human probands and the canine splice-site model. Homozygous -/- mice displayed both a 29% reduction of tibialis anterior (TA) muscle mass and a 27.5% reduction of the muscle maximal force compared to the wild-type mice, similar to the muscle weakness and hypotonia seen in human/canine probands. Muscle biopsy displayed fiber-size disproportion and reduced myofiber diameter with necrosis and stunted regeneration, revealing muscle hypotrophy stemming from a defect in myoblast fusion to be the pathogenic mechanism for muscle-related phenotypes in HACD1 deficency. It is notable that both the canine and mouse myopathic phenotypes did not improve over time while the humans did, which may be due to residual protein activity in the human probands. There were also some specific phenotypes in humans not reported in this model, such as areflexia and intenrally-nucleated fibers.",Score,1.5 (2),"Although many of the important phenotypes are recapitulated in this model and the mechanism appears to be identical to human probands, the lack of progressive recovery and the absence of some phenotypes slightly downscore this model to 1.5.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_10c52aaf-cd58-4448-bac7-12b653bfa962-2021-06-28T160000.000Z,957,PubMed:26160855 +HACD1 Regulates VLCFAs and Myoblast Fusion,Biochemical Function B,"Blondelle J, et al., 2015, PMID: 26160855","Deficency in myoblast fusion likely directly causes the phenotypes seen in both the human and canine CNM diseases, namely muscle weakness, hypotonia, and the fiber-size variation. Observation of muscle fiber necrosis and resulting stunted regeneration supports this as the causal mechanism.",Score,0.5 (0.5),"Since the biochemical function of VLCFA regulation directly affects membrane flexibility and the resulting myotube fusion in development therefore easily causing the phenotypes displayed by probands, this evidence earns default points.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_10c52aaf-cd58-4448-bac7-12b653bfa962-2021-06-28T160000.000Z,957,PubMed:26160855 +HADH knock out mouse model,Model Systems Non-human model organism,"Schulz N, et al., 2011, PMID: 21990309",Reduced glucose levels and increased insulin secretion was observed.,Score,1 (2),Partly recapitulated human phenotype.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c2f238b9-4eb5-426c-a27a-ecb7b468d9e4-2018-06-26T160000.000Z,958,PubMed:21990309 +iPSCs,Expression B,"Kobayashi J, et al., 2014, PMID: 25050861",Decreased expression of HAND1 observed in cardiomyocytes differentiated from induced pluripotent stem cells from participants with hypoplastic left heart syndrome compared to those without congenital heart disease,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7a70bdb1-a3fc-45c5-aabb-4d2829fa6f29-2023-04-04T160000.000Z,961,PubMed:25050861 +Mouse single cell transcriptomics,Expression A,"de Soysa TY, et al., 2019, PMID: 31341279",Detection via single cell RNA sequencing,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7a70bdb1-a3fc-45c5-aabb-4d2829fa6f29-2023-04-04T160000.000Z,961,PubMed:31341279 +Patient iPSCs,Functional Alteration Patient cells,"Lewis-Israeli YR, et al., 2021, PMID: 34446706",Pluripotent stem cells from participants with hypoplastic left heart syndrome had decreased expression of HAND1 during differentiation to cardiomyocytes compared to those from participants without congenital heart disease,Score,0.5 (1),Observation in patient cells - no direct genetic manipulation of HAND1,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7a70bdb1-a3fc-45c5-aabb-4d2829fa6f29-2023-04-04T160000.000Z,961,PubMed:34446706 +CRISPR-based rescue of mice harboring an HBB variant,Rescue Non-human model organism,"Lu D, et al., 2022, PMID: 34706494","The rescue experiment resulted in significant reversal of prenatal death (Table 2), anemia (Table 1), low hemoglobin concentration (Table 1), anisocytosis and poikilocytosis (Figure 3), bone marrow proliferation (Figure 3), iron accumulation in the liver (Figure 3), and splenomegaly (Figure 4).",Score,2 (2),"The experiment has been scored at default levels due to the use of a targeted gene editing method to reverse the variant, with broadly successful results.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_10e10aac-d9cc-4422-8fb9-b206e642bb27-2023-04-26T160000.000Z,972,PubMed:34706494 +CRISPR/CAS9 correction of Beta Thalassemia in Mice,Model Systems Non-human model organism,"Lu D, et al., 2022, PMID: 34706494","Heterozygous βIVS-2-β654 mice recapitulate many of the core features of autosomal dominant Beta Thalassemia including the mode of inheritance and mimic phenotypes ranging from molecular to organ wide changes. Both the mouse model and probands display phenotypes such as anemia, inefficient erythropoiesis, increased hemolysis, and splenomegaly resulting from an imbalance in beta chain vs alpha chain synthesis. Additionally, this paper was able to rescue/improve clinical certain features of Beta Thalassemia including anemia, inefficient erythropoiesis, splenomegaly, and decreased survival rate by correcting the splice site variant.",Review,0 (2),"This model was scored at 0 due to the splice site variant being associated with recessive forms of the disorder, thus the molecular mechanism in this model differs from autosomal dominant Beta Thalassemia.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b52b6f04-67a6-4c4b-9765-2067e3b1e297-2023-03-22T160000.000Z,976,PubMed:34706494 +HCFC1 expression,Expression A,"Minocha S, et al., 2019, PMID: 31207118","HCFC1 is broadly expressed in the brain and other tissues; in the early postnatal mouse cortex, HCFC1 is expressed in neurons, astroglial cells, and oligodendrocytes (Fig. 1)",Score,0 (0.5),"Expression is consistent with a role for HCFC1 in ID and neurodevelopmental phenotype, but not specific so not scored.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_023defeb-36f4-4e54-ba8f-e2c9537e933c-2021-03-17T160000.000Z,978,PubMed:31207118 +HCFC1 conditional knockout mouse,Model Systems Non-human model organism,"Minocha S, et al., 2019, PMID: 31207118","The phenotype of the HCFC1 conditional knockout mouse includes reduced Nkx2.1-derived neurons and glia (Fig. 2), decreased migration to the neocortex and increased cell death (Fig. 4, 5). At early postnatal stages, CKO mice showed reduced Nkx2.1-derived cells (including GABAergic interneurons and glia) in the neocortex (Fig.6, 7), and results in commissural defects of the anterior commisure and corpus callosum, and alteration in cortical lamination (Fig. 7, 8, 9).",Score,1 (2),"Demonstrates a role for HCFC1 in the survival of GABAergic interneurons and glia, which have important functions in the neocortex and may be relevant to a human neurodevelopmental phenotype.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_023defeb-36f4-4e54-ba8f-e2c9537e933c-2021-03-17T160000.000Z,978,PubMed:31207118 +Merseburg Knock-in Mouse Model,Model Systems Non-human model organism,"Merseburg A, et al., 2022, PMID: 35972069",Heterozygous mice displayed spontaneous generalized tonic–clonic seizures.,Score,1 (2),Evidence is being scored at a full 2 points in combination with mouse model in (PMID:33822003).,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0932fa23-e0d2-4fa8-80ac-1ab9bfac974d-2023-01-03T080000.000Z,979,PubMed:35972069 +SMC3 overacetylation,Rescue Patient cells,"Deardorff MA, et al., 2012, PMID: 22885700","Purified wild type, but not mutant HDAC8, can rescue the SMC3 overacetylation seen in HDAC8 mutant LCLs.",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a7d29159-4c90-488e-a4e1-b006d70ae762-2018-09-11T160000.000Z,981,PubMed:22885700 +SMC3 deacetylation,Biochemical Function A,"Deardorff MA, et al., 2012, PMID: 22885700","Cohesin, containing nonacetylated SMC3, is loaded onto chromosomes under the direction of NIPBL and MAU2. Loading of cohesin containing nonacetylated SMC3 is required for cohesion establishment in S phase, when SMC3 is acetylated by ESCO1/ESCO2 to facilitate binding of Sororin. Cohesin is removed by either the prophase pathway or by separase-dependent cleavage of RAD21 at anaphase onset. Upon removal from chromatin, HDAC8 deacetylates SMC3 to facilitate release of RAD21 and Sororin, thereby efficiently “refreshing” cohesin “used” in the previous cell cycle. This allows reacetylation of SMC3 in the following cell cycle to ensure its full functionality in sister chromatid cohesion and transcriptional regulation.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a7d29159-4c90-488e-a4e1-b006d70ae762-2018-09-11T160000.000Z,981,PubMed:22885700 +Thijssen et al. siRNA knockdown in WT MEFs,Model Systems Cell culture model,"Thijssen PE, et al., 2015, PMID: 26216346","DNMT3B, ZBTB24, and CDCA7 in addition to HELLS are all associated with Immunodeficiency, Centromeric Instability and Facial Anomalies syndrome. Knock down of HELLS, Zbtb24, and Cdca7 and knock out of DNMT3B resulted in hypomethylation of centromeric repeats. Hypomethylation of these centromeric repeats may be responsible for the wide ranging phenotypes observed in ICF syndrome through a shared pathway involving methylation.",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9414c2ab-4eab-4ee0-9a68-ba78a5774f0a-2023-04-20T160000.000Z,984,PubMed:26216346 +He et al. HELLS conditional knock out mice,Model Systems Non-human model organism,"He Y, et al., 2020, PMID: 32727902","The central immunodeficient feature in patients with ICF4 is a reduction in types of immunoglobin such as IgG, IgM, and IgA. HELLS -/- mice die perinatally and display multiple organ and stem cell defects. Under two conditional HELLS knock out mouse models, there were normal levels of peripheral B cells, but a decrease in the expression of Immunoglobins in response to in vitro stimulation, suggesting biallelic variants in HELLS result in a deficiency underlying class switch recombination. The conditional knock out HELLS mouse models were independently able to recapitulate the core immunodeficient phenotype observed in humans of hypogammaglobulinemia, but other features of ICF4 such as facial abnormalities were either not observed or noted.",Score,1 (2),Downscored to 1 point given an incomplete recapitulation between ICF type 4 and LSH/HELLS conditional knock out mice.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9414c2ab-4eab-4ee0-9a68-ba78a5774f0a-2023-04-20T160000.000Z,984,PubMed:32727902 +He et al. Knock down HELLS in U2OS cells,Model Systems Cell culture model,"He Y, et al., 2020, PMID: 32727902","SiRNA targeting HELLS resulted in significantly decreased successful chromosomal repair in an reporter assay specifically designed to induce NHEJ that used CAS9 to cause double stranded breaks. This result suggests that HELLS may be important to the efficient functioning of NHEJ, which normally functions in class switch recombination to join the variable domain exon to the a specific constant domain exon in the heavy chain of antibodies. The authors suggest that a deficiency in this mechanism during class switch recombination may be an underlying cause of Ig deficiency observed in individuals with ICF4.",Score,0.25 (1),Downscored due to the assay suggesting a possible mechanistic interpretation of the disease phenotype rather than a recapitulation of the disease phenotype.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9414c2ab-4eab-4ee0-9a68-ba78a5774f0a-2023-04-20T160000.000Z,984,PubMed:32727902 +Peixoto et al. Review of HELLS function,Biochemical Function B,"Peixoto E, et al., 2022, PMID: 36012581","HELLS has been shown to play a role in genomic stability as well as a role in maintaining CpG methylation and DNA repair within heterochromatin. Individuals with ICF4 show evidence of genomic instability in addition to alpha satellite hypomethylation. Meanwhile, the observed decrease in immunoglobin G, A, and M in patients with ICF4 may reflect a deficiency in HELLS mediated DNA repair mechanisms specifically NHEJ, which is important to class switch recombination and the development of a diverse set of immunoglobin isotypes.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9414c2ab-4eab-4ee0-9a68-ba78a5774f0a-2023-04-20T160000.000Z,984,PubMed:36012581 +Rescue in HexA knock out mice,Rescue Non-human model organism,"Tropak MB, et al., 2016, PMID: 26966698","A challenge in developing gene therapy and enzyme replacement therapy for Tay-Sachs disease is the need to synthesize both the alpha- and beta- subunits of hexosaminidase. In this study, a single hybrid µ-subunit was engineered that contains the α-subunit active site, the stable β-subunit interface and the areas in each subunit needed to interact with GM2AP. Intracranial injections of scAAV9 vectors containing either the HexM gene (HEXM), HEXA, or HEXBMM into the left hemisphere of 4-month-old Tay-Sachs hexa-/- mice were performed. For mice injected with GFP vector alone, there was no decrease in the level of GM2 accumulation (Figure 5e) on the ipsilateral side of the brain compared to the contralateral side. In brain sections from mice injected with a mix of GFP and different Hex vectors, there was a visible reduction in the GM2 levels on the injected side of the brain compared to the contralateral side of the same section (Figure 5f–h), and this reduction overlapped with the area of peak GFP expression (Figure 5b–d).",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1f7530b5-af31-40f9-ac18-a1b4d404285a-2020-05-27T160000.000Z,987,PubMed:26966698 +Kuil_Zebrafish,Model Systems Non-human model organism,"Kuil LE, et al., 2019, PMID: 31140649","Zebrafish show loss of enzyme activity, accumulation of oligosaccharides, lysosomal abnormalities in glia and reduced locomotor activity, similar to the molecular, cellular, neuropathological, and motility aspects of Sandhoff disease in humans. Hexb deficient zebrafish seem to recapitulate early disease stages, but lack extensive neurodegeneration.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7f53d03d-f936-4628-ab75-351ae4da012a-2022-09-15T160000.000Z,988,PubMed:31140649 +Analysis of HGSNAT expression and splicing,Expression A,"Haer-Wigman L, et al., 2015, PMID: 25859010",RT-PCR of human and mouse WT retina showed expression of HGSNAT.,Score,0.5 (0.5),"The protein is expressed in the retina. Additionally, it can be seen in the human protein atlas. https://urldefense.com/v3/https://www.proteinatlas.org/ENSG00000165102-HGSNAT/tissue;!!NiUAmZJ8c1GNWg!SxopaRqUiHTaRPd_gIkwHkD8yxjr25Erxq0YeTS3JGj_pge_sEUA0rKsV7T1y9GPBUsvFB6LiMnpEMGlTPcRie_jCh2IxgD09kN_abixbl6O$",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_272a3322-e047-4b37-9bfc-eea3e65ddb57-2024-04-04T160000.000Z,991,PubMed:25859010 +Gene therapy in HGSNAT knockout mouse,Rescue Non-human model organism,"Tordo J, et al., 2018, PMID: 29788236","Gene therapy-treated MPS3C mice show corrected hyperactivity (assessed by total distance moved) and cognitive impairment (maze test), increased cerebral HGSNAT enzyme activity, and reduced neuronal heparan sulfate accumulation",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_943b7a75-eb7f-415b-ba80-de6b09cc5a43-2023-12-04T170000.000Z,992,PubMed:29788236 +Leigh map,Biochemical Function A,"Rahman J, et al., 2017, PMID: 27977873",0.5 points given shared function with one other LSS gene (ECHS1),Score,0.5 (0.5),0.5 points given shared function with one other LSS gene (ECHS1),https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_079ed613-0c28-494f-9852-9baf495f26ba-2021-06-14T142317.786Z,994,PubMed:27977873 +International Mouse Phenotyping consortium,Model Systems Non-human model organism,"Cacheiro P, et al., 2019, PMID: 31127358",Severe disease,Score,0.5 (2),"Homozygous knockout noted as having preweaning lethality, https://www.mousephenotype.org/data/genes/MGI:1923792",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_079ed613-0c28-494f-9852-9baf495f26ba-2021-06-14T142317.786Z,994,PubMed:31127358 +HINT1 Sumolayse Activity,Biochemical Function B,"Cortés-Montero E, et al., 2019, PMID: 31088288","The membrane and nuclear proteins targeted by HINT1 are essential for proper synaptic tonus and gene transcription regulation. Specifically, Teneurin1 has been implicated in processes such as neurite growth, axon guidance, and synaptogenesis. Without the proper ability to desumoylate proteins via activation of isopeptidase activity, this could certainly be related to the observed motor and sensory neuropathy phenotypes and the neuromyotonia.",Score,0.5 (0.5),HINT1's function as an essential signalling protein via isopeptidase activity in the CNS and peripheral nervous system supports both the primary motor neuropathy and neuromyotonia present in the majority of probands.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_170aae71-9b16-49b1-be29-44f98db2f72e-2021-03-22T201109.360Z,997,PubMed:31088288 +HL expression,Expression A,"Puisac B, et al., 2010, PMID: 20532825","HL mRNA and activity was measured in liver, kidney, pancreas, testis, heart, brain, and skeletal muscle. Expression and activity were significantly higher in liver than any other tissue.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_f4d084e5-a740-4bfd-a850-d6db900d4a4e-2018-06-26T160000.000Z,1000,PubMed:20532825 +Liver-specific KO in mice,Model Systems Non-human model organism,"Gauthier N, et al., 2013, PMID: 23861731","HLLKO mice died between 3 and 5 weeks and appeared normal until 1-3 hours before death. Progressive lethargy, hypoglycemia, and hyperammonemia occurred (Figure 3). Urine organic acids and plasma acylcarnitines were measured under non-stressed conditions, following KIC injection (a transamination product of leucine), and in samples available from spontaneous crises in HLLKO mice. Under stable conditions, HLLKO mice had elevated levels of leucine-related metabolites. In spontaneous crises of HLLKO mice, Krebs cycle and fatty acid derivatives were higher. Under stressed conditions, HLLKO mice showed elevated C5-hydroxylcarnitine, FA-derived acylcarnitines and decreased C4- and C3-acylcarnitines. In HLLKO hepatocytes, acetoacetate production was undetectable. Glucogenesis was measured in vivoby intraperitoneal pyruvate loading. The rapid increase of blood glucose occured in controls but not in HLLKO mice.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_f4d084e5-a740-4bfd-a850-d6db900d4a4e-2018-06-26T160000.000Z,1000,PubMed:23861731 +Dumbo (dmbo) mouse,Model Systems Non-human model organism,"Munroe RJ, et al., 2009, PMID: 19379485","Large/protruding ears found in humans. Microphthalmia is cardinal feature of human disease. No hearing loss or vestibular defects seen in mice - also not seen in humans. In some cases, bony differences also seen in humans.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ebf66ec9-77a4-4e48-83a4-970639ad5373-2021-05-06T160000.000Z,1004,PubMed:19379485 +Zebrafish ZFN mutants,Model Systems Non-human model organism,"El Fersioui Y, et al., 2021, PMID: 33465110",microphthalmia and lens anomalies seen in affected human patients.,Score,2 (2),Only assesses ocular phenotype,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ebf66ec9-77a4-4e48-83a4-970639ad5373-2021-05-06T160000.000Z,1004,PubMed:33465110 +Variants in MODY disrupt insulation secretion,Functional Alteration Non-patient cells,"Han EH, et al., 2012, PMID: 22952853","MIN6 cells expressing either control, wildtype HNF4A or the mutant HNF4A constructs D206Y (D215Y) or M364R (M373R). The transfected cells were cultured and incubated in medium rich with glucose. After incubation, the cell culture media was collected and the levels of secreted insulin was measured using ELISA. Expression of wildtype HNF4A constructs in the MIN6 cells increased insulin secretion over control, non-transfected cells, by 3 fold (Figure 5D). Addition of constructs expressing MED25 increased the insulin secretion further (solid black column). Expression of the mutant HNF4A construct D206Y (D215Y), in combination with the MED25 gene, showed the same level of secretion, indicating no changes compared to wildtype HNF4A+ MED25. However, expression of the M364R (M373R) variant (in combination with MED25) significantly reduced the insulin secretion compared to wildtype HNF4A+ MED25. The levels were reduced similar to HNF4A alone, indicating a mitigated response. These results suggest that the M364R (M373R) variant has reduced function in insulin secretion which would is consistent with perturbation of insulin secretion observed in individuals with MODY.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_98cb808e-02d3-4378-8e6b-9b1b2883cc65-2019-02-27T170000.000Z,1005,PubMed:22952853 +Mouse model,Model Systems Non-human model organism,"Korff A, et al., 2023, PMID: 37463454","Knock-in mice bearing two distinct pathogenic NLS mutations (P209L, R206W) in Hnrnph2 demonstrated a phenotypic spectrum highly similar to clinical features observed in human patients, including reduced survival in males, craniofacial abnormalities, impaired motor function, and increased susceptibility to audiogenic seizures.  +In contrast, two independent Hnrnph2 knockout (KO) mice showed no detectable phenotypes, arguing against a simple loss of hnRNPH2 function as the primary driver of disease. Importantly, Hnrnph2 KO mice showed significant upregulation of the paralogous gene Hnrnph1, whereas knock-in mice did not.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e303e734-0f37-4906-bc96-ca8e7f2d21b5-2024-06-13T160000.000Z,1006,PubMed:37463454 +RNA sequencing,Functional Alteration Patient cells,"Korff A, et al., 2023, PMID: 37463454","In human induced pluripotent stem cells, missense mutations (R206W, R206Q, P209L) as well as KO of HNRNPH2 showed altered global gene expression, with similar patterns observed for missense and KO, but more severe with the missense. HNRNPH1 transcript level was increased in KO neurons, but less so in missense-expressing neurons. +Kreienkamp et al. conducted RNA sequencing of patients' primary dermal fibroblasts harboring R114W, which showed aberrant splice patterns. +These two studies were combined and 1 point was awarded.",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e303e734-0f37-4906-bc96-ca8e7f2d21b5-2024-06-13T160000.000Z,1006,PubMed:37463454 +Fan 2015 Function 1,Biochemical Function B,"Fan X, et al., 2015, PMID: 26638989","As the phenotype involves skeletal abnormalities, including craniosynostosis, this may be relevant.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_f1adc74c-9bbc-48fc-bbbf-1159c0944108-2021-12-20T070000.000Z,1007,PubMed:26638989 +hnRNPs family members associated with NDD,Biochemical Function A,"Gillentine MA, et al., 2021, PMID: 33874999","The hnRNPs are a large family of RBPs consisting of 33 core and minor members implicated in many steps of RNA processing. Several, primarily through changes in expression or localization, have been associated with neurodegenerative disorders, and, more recently, five (HNRNPH1, +HNRNPH2, HNRNPK, HNRNPR, and HNRNPU) have been implicated in NDDs.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_457f4be2-fe32-4878-b367-7fa614f78c63-2023-05-03T160000.000Z,1008,PubMed:33874999 +Biochemical function,Biochemical Function A,"Gillentine MA, et al., 2021, PMID: 33874999","As reviewed in PMID 27215579, these genes encode members of the HNRNP family of RNA-binding proteins and share several functions including mRNA formation and processing, RNA splicing and stability, and transcriptional regulation.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b2c82248-c128-4d3e-802a-7f3295d14455-2022-10-11T060000.000Z,1009,PubMed:33874999 +Conditional knock-out,Model Systems Non-human model organism,"Sapir T, et al., 2022, PMID: 35864088","Mutant mouse brains were smaller and had abnormal morphology and cortical development, indicating abnormal neurodevelopment. Humans with HNRNPU pathogenic variants have neurodevelopmental phenotypes (intellectual disability, epilepsy), microcephaly, and abnormalities on brain MRI.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b2c82248-c128-4d3e-802a-7f3295d14455-2022-10-11T060000.000Z,1009,PubMed:35864088 +TALEN-based HPRT1 null hiPSCs,Functional Alteration Non-patient cells,"Frank S, et al., 2013, PMID: 24206569","Loss of HPRT1 function/ expression resulted in impaired neuronal differentiation, including reduced neuron numbers and reduced neurite length (figure 4E). The same results was found when human embryonic stem cells (hESs) went through the same TALEN based gene editing. The resulting cells showed reduced neurite length and growth.",Score,1 (0.5),"The effect on neurite length was shown in two different cell types that were differentiated into neurons, and is consistent with impaired neuronal differentiation observed in Lesch Nyhan patients, therefore I will increase the points.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_f60022bb-5679-4766-ac72-2ddfd0b752ee-2022-07-08T160000.000Z,1012,PubMed:24206569 +BLOC-2 complex cargo delivery,Biochemical Function B,"Dennis MK, et al., 2015, PMID: 26008744","Albinism in HPS patients reflects defects in the biogenesis of melanosomes in melanocytes of the skin, hair, and choroid of the eye and in pigment epithelial cells of the retina, iris, and ciliary body of the eye. While not addressed here, a similar cargo delivery mechanism may be involved in the bleeding and bruising which reflects the absence of detectable dense granules in platelets.",Score,0.5 (0.5),"Live-cell imaging analyses show that BLOC-2 is required for melanosome-destined tubular carriers to make stable contacts with maturing melanosomes. Consistently, BLOC-2 influences the melanosomal delivery of BLOC-1-dependent cargoes, including TYRP1, OCA2, ATP7A, and a cohort of TYR, from early endosomes in mouse melanocytes as observed in altered melanocytes from patients with HPS6. These results support a model in which BLOC-2 functions to direct recycling endosomal tubular transport intermediates to mature melanosomes and thereby promote cargo delivery and optimal pigmentation.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a761e746-824f-496c-8d9f-4f8cd50423c3-2020-10-28T160000.000Z,1016,PubMed:26008744 +BLOC-2 complex cargo delivery,Biochemical Function B,"Dennis MK, et al., 2015, PMID: 26008744","Albinism in HPS patients reflects defects in the biogenesis of melanosomes in melanocytes of the skin, hair and choroid of the eye and in pigment epithelial cells of the retina, iris and ciliary body of the eye. While not addressed here, a similar cargo delivery mechanism may be involved in the bleeding and bruising which reflects absence of detectable dense granules in platelets.",Score,0.5 (0.5),"Live cell imaging analyses show that BLOC-2 is required for melanosome-destined tubular carriers to make stable contacts with maturing melanosomes. Consistently, BLOC-2 influences the melanosomal delivery of BLOC-1-dependent cargoes, including TYRP1, OCA2, ATP7A, and a cohort of TYR, from early endosomes in mouse melanocytes as observed in altered melanocytes from patients with HPS6. These results support a model in which BLOC-2 functions to direct recycling endosomal tubular transport intermediates to maturing melanosomes and thereby promote cargo delivery and optimal pigmentation.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_602ae8f1-9e7f-4cc6-bf70-d572d98828c5-2020-11-25T170000.000Z,1017,PubMed:26008744 +HSD17B10 Conditional KO Mice,Model Systems Non-human model organism,"Rauschenberger K, et al., 2010, PMID: 20077426","Morphology of the mitochondria were analyzed in the locus coeruleus, which contains noraderenergic neurons. In the conditional KO mice, 30% of the mitochondria showed depletion of the cristae and appeared ""empty,"" >50% of the mitochondria were loosely packed and had swollen cristae, and normal morphology was found in 20%. Similar results were seen in the cerebellum and the PNS. This is consistent with the findings in fibroblasts from patients with the disease, suggesting that HSD10 is required for mitochondrial structural integrity.",Score,1 (2),KO mice were embryonic lethal. The conditional KO mice were not fully phenotyped.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9232b352-a845-4404-8a98-34cb6ad6ff0e-2018-10-09T160000.000Z,1019,PubMed:20077426 +Mitochondrial organization,Functional Alteration Patient cells,"Rauschenberger K, et al., 2010, PMID: 20077426","Mitochondrial morphology was analyzed by EM in fibroblasts derived from patients compred to controls. Control cells showed dense, dark morphology (WT), while Q165H fibroblasts maintained WT morphology in 45% of the mitochondria, 30% intermediate (loosely packed and/or swollen cristae) and 27% depletion of cristae. 65-86% of the mitochondria in D86G and R130C cells displayed an aberrant phenotype.",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9232b352-a845-4404-8a98-34cb6ad6ff0e-2018-10-09T160000.000Z,1019,PubMed:20077426 +morphological evaluation of neurons derived from Patient,Functional Alteration Patient cells,"Alderson TR, et al., 2021, PMID: 33644875",oligomer formation in patient-derived neurons,Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1bec365e-7832-41f1-89cc-48b8ab570c76-2022-08-03T160000.000Z,1023,PubMed:33644875 +Mutant HSPB8 induces neurite abnormalities in primary motor,Functional Alteration Non-patient cells,"Irobi J, et al., 2010, PMID: 20538880",Decreased neurite length and number and APP accumulation indicates axonal degeneration.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_044a2465-8e0a-44ff-8d00-1ec3a76183c8-2021-03-22T201855.441Z,1024,PubMed:20538880 +HSPB8 K141N knock-in mouse model,Model Systems Non-human model organism,"Bouhy D, et al., 2018, PMID: 28780615",Mouse model developed progressive motor deficits associated with severe axonal degeneration and muscle atrophy.,Score,1 (2),"Score was downgraded because the described model was homozygous, instead of heterozygous like the patients.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_044a2465-8e0a-44ff-8d00-1ec3a76183c8-2021-03-22T201855.441Z,1024,PubMed:28780615 +Mouse model,Model Systems Non-human model organism,"Costell M, et al., 1999, PMID: 10579729","Loss of perlecan results in disproportionate dwarfism with short limbs, neck and snout. Some homozygous have domed skull (-/-a), others lack the roof of skull and exhibit exencephaly (-/-b). The cartilage of homozygous mouse showed severe disorganization of the columnar structures of chondrocytes and shorter collagen fibrils.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b601b27a-7ba4-4111-a524-b55cbb86eaa5-2022-05-21T030011.112Z,1026,PubMed:10579729 +increased proteolytic processing,Functional Alteration Patient cells,"Oláhová M, et al., 2017, PMID: 27696117","The authors examined the levels of OPA1 in the HTRA2-deficient tissues and found differential proteolytic processing of OPA1. In both, skin fibroblasts and skeletal muscle derived from S1, they detected increased amounts of S-OPA1 cleavage products. The increased proteolytic processing of the L-OPA1 forms into S-OPA1 products in the subject samples suggest that HTRA2 may affect mitochondrial fusion and OPA1 proteolysis.",Score,0.5 (1),"While the disease mechanism is not fully elucidated, it is possible that the protease activity of HTRA2 could contribute to certain post-transcriptional modifications of proteins that are directly associated with inborn errors of metabolism with 3-MGA-uria as discriminative feature. These findings show that loss of HTRA2 influences the proteolytic processing of the mitochondrial dynamics regulator OPA1. The ubiquitously expressed OPA1 is processed into L- and S-OPA1 protein products, each of which have a distinct role in the control of mitochondrial fission and fusion processes, cristae morphology and apoptosis. Mutated HTRA2 caused differential proteolytic cleavage of OPA1 resulting in a marked increase of S-OPA1 forms that have been associated with fragmented mitochondria.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d0e86ea2-d848-442c-8bef-0818e39f3752-2022-07-11T160000.000Z,1027,PubMed:27696117 +C. elegans rescue,Model Systems Non-human model organism,"Madrigal I, et al., 2007, PMID: 18047645",Assay comments on protein function. Similarity between elegans phenotype and ID in humans is weak.,Score,1 (2),"I would use the lack of rescue in the point mutants as variant evidence to strengthen LOF as the molecular mechanism. They also show expression data of EEL-1/ HUWE1 in the worm, is expressed in non-neuronal tissue, but was strongly expressed in neurons, where it was shown to co-localize with synaptobrevin at the presynaptic terminal (Figure 4F, Fig S3). Assessment of eel-1/HUWE1 null worms showed no changes to GABAergic synapse formation or organization. Because there were changes to the synaptic transmission in these neurons, but no structural changes the authors conclude that the changes are not due to defective synapse formation or ""impaired aon guidance."" Also show that eel-1/ HUWE1 functions to inhibit ""ectopic axon branching,"" as loss of eel-1 caused the formation of ectopic axon branches called sprouts.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ded2ea2f-63ff-428a-8061-7c62c276163b-2017-10-20T160000.000Z,1029,PubMed:18047645 +K9149 Family Cell Studies,Functional Alteration Patient cells,"Friez MJ, et al., 2016, PMID: 27130160","p53 and Mcl-1 (known substrates of HUWE1) are upregulated in the affected, but not in the unaffected, male of family K9149, which carries the p.G4310R variant. HUWE1 protein expression is increased in an affected male in Family 3 (p.R4063Q variant), compared with unaffected male relatives.",Score,0 (1),"This evidence is variant evidence not experimental, as we do not know that reducetion of p53 (cancer gene) of Mcl-1 are responsible for the XLID.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ded2ea2f-63ff-428a-8061-7c62c276163b-2017-10-20T160000.000Z,1029,PubMed:27130160 +Proteomic analysis of a eukaryotic cilium,Biochemical Function B,"Pazour GJ, et al., 2005, PMID: 15998802","Cilia and flagella, are essentially identical organelles and hereafter referred to interchangeably. Homologues of HYDIN gene detected in flagellar proteome, along with other numerous proteins associated with diseases such as cystic kidney disease, male sterility, indicates its role in ciliary structure and/or function.",Score,0.25 (0.5),Proteomic analysis is performed on a model organism not on human cilia.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6c491ab7-496f-43b9-9bca-500901cb686d-2022-02-22T183411.247Z,1031,PubMed:15998802 +Hydin localizes to the CP.,Biochemical Function B,"Lechtreck KF, et al., 2007, PMID: 17296796","The experiment shows that HYDIN colocalizes in the CP cilium of Chlamydomonas. As human nodal cilium lacks CP, PCD5 patients do not have situs inversus. PCD5 patients show other manifestations related to defective ciliary structure and/ or motility.",Score,0.25 (0.5),Colocalization of HYDIN in CP illustrated in the flagellum of algae not in human cell.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6c491ab7-496f-43b9-9bca-500901cb686d-2022-02-22T183411.247Z,1031,PubMed:17296796 +Structural and functional role of Chlamydomonas hydin,Model Systems Non-human model organism,"Lechtreck KF, et al., 2007, PMID: 17296796","C. reinhardtii hydin is a CP protein required for flagellar motility and HYDIN knockdown causes flagellar paralysis and absent c2b projection. Similar human phenotypes have been subsequently identified in PMID 23022101. HYDIN mutant respiratory cilia lack the C2b projection of the central pair (CP) apparatus, markedly reduced beating amplitudes of respiratory cilia and stiff sperm flagella could be also identified.",Score,1.5 (2),Downscoring for non applicability of the model to match clinical phenotypes,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6c491ab7-496f-43b9-9bca-500901cb686d-2022-02-22T183411.247Z,1031,PubMed:17296796 +Mutations in Hydin impair ciliary motility in mice,Model Systems Non-human model organism,"Lechtreck KF, et al., 2008, PMID: 18250199","The paper provides evidence on lack of central pair projection and abnormal ciliary bending in HYDIN mutant mice. Both defects are observed in humans and are responsible for inefficient mucociliary clearance observed in PCD patients. Moreover, hy3/hy3 mice, situs abnormalities, as judged by the analysis of lung lobation as well as liver and stomach position in several dozen animals, were not observed which is also consistent with Ciliary dyskinesia, primary, 5(without situs inversus).",Score,3 (2),"The paper continued previous work by Davy and Robinson, 2003 where Two mutant alleles of Hydin (hy3 and OVE459) have been characterized with no transcripts have been detected. Both structural and functional defects in the brain and tracheal cells of HYDIN mutant mice. Phenotypes and (non phenotype) matches their human counterparts. PMID 23022101 explained the occurrence of hydrocephalus in HYDIN mutant mice by the fact that integrity of the cilia motility of ependymal cells is mandatory for maintaining patency of the aqueduct of Sylvii, which connects the third and fourth brain ventricles. Thus, disruption of ependymal flow regularly causes hydrocephalus in mice. In contrast, human PCD-affected individuals carry only an increased risk of developing hydrocephalus. Therefore, hydrocephalus in mice remains a supportive evidence of defective ciliary structure and/ or function.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6c491ab7-496f-43b9-9bca-500901cb686d-2022-02-22T183411.247Z,1031,PubMed:18250199 +Biochemical function,Biochemical Function A,"Boczonadi V, et al., 2018, PMID: 29980628","Variants in 19 mitochondrial aminoacyl-tRNA synthetases (mt-ARSs) have been linked to variety of pediatric and adult onset tissue specific disorder. More specifically, two mt-ARSs, NARS2 and PARS2 are associated with presentation of Leigh syndrome.",Score,2 (0.5),"Additionally, FARS2 is curated as moderate for Leigh syndrome. Points awarded based on GCEP rubric (10+ gene products).",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_50877212-c671-406b-8cb6-195c7369a96c-2019-11-25T154442.667Z,1033,PubMed:29980628 +Wang_ICOSL binding,Functional Alteration Non-patient cells,"Wang S, et al., 2002, PMID: 11956294","The ability of each ICOSIg mutant to bind to B7-H2 was determined by sandwich ELISA and by FACS analysis of the ICOSIg binding to CHO cells transfected to express B7-H2. In the capture ELISA, Q49S reduced the binding to B7-H2 only slightly. However, Q50S, D64S, and K69S displayed almost complete loss of binding. F51S, K67S, F114S, D115S, P117S, and F119S completely abrogated B7-H2 binding capacity. Only two variants, K52S and S76E, bound B7-H2 two- or threefold better than wild-type ICOSIg in both ELISA and FACS analysis.",Score,0.5 (0.5),"The study identified several critical residues in ICOS that likely have a role in ligand binding. While not many missense variants are reported in individuals with ICOS-related CVID, the functional evidence suggests an important mechanism for loss of protein function.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_51864ec9-27d9-4a94-9524-d6828b17361d-2022-11-29T170000.000Z,1035,PubMed:11956294 +Montes-Casado_NK cell response,Biochemical Function B,"Montes-Casado M, et al., 2019, PMID: 31283790","Individuals with ICOS-related CVID are reported with viral and opportunistic infections, in addition to the susceptibility to bacterial infections initially reported.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_51864ec9-27d9-4a94-9524-d6828b17361d-2022-11-29T170000.000Z,1035,PubMed:31283790 +Roussel- FA in HMEC1 cells,Functional Alteration Non-patient cells,"Roussel L, et al., 2018, PMID: 30498080","Similar to HEK293T cells transfected with the variant HMEC1 cells showed significantly reduced expression of ICOSL protein at the cell surface. Transendothelial migration of TNFα-activated Jurkat cells across the transfected HMEC1 cells was significantly reduced compared to wild type. HMEC-1 cells transfected with ICOSL WT significantly increased cell-surface expression of adhesion molecules involved in neutrophil recruitment, however this effect was significantly diminished with ICOSL p.N219K, implicating ICOSL on endothelial cells in the transmigration of neutrophils.",Score,1 (0.5),"Two pieces of functional alteration evidence, defective transendothelial migration of T cells and neutrophils, on HMEC1 cells have been scored together.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_312b156d-fc56-48da-9d10-1cd034afbb84-2023-04-25T160000.000Z,1036,PubMed:30498080 +Roussel -Absent expression,Functional Alteration Patient cells,"Roussel L, et al., 2018, PMID: 30498080",ICOS-ICOSL interaction is known for cytokine secretion through its effects on mature T cells. The author cocultured patient's LCL and Jurkat cells activated by TNFα to induce ICOS expression and measure gene responses of cytokines. It was shown that patients LCLs impaired their ability to release cytokines.,Score,1 (1),Experiments conducted in patient's EBV transformed LCL showed reduced release of cytokines.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_312b156d-fc56-48da-9d10-1cd034afbb84-2023-04-25T160000.000Z,1036,PubMed:30498080 +Rujas- Protein Interaction,Protein Interaction,"Rujas E, et al., 2020, PMID: 33033255","The authors determined the molecular basis of ICOS/ICOSLG interaction based on the three-dimensional structure elucidated by X-ray crystallography. ICOS-L is organized in two distinct domains: the most apical domain (D1) adopts a V-type fold, whereas the membrane-proximal domain (D2) adopts a C1-type fold. Authors report that ICOS/ICOS-L interact in a 1:1 receptor-ligand stoichiometry. The main binding interface is formed by the FDPPPFK motif (amino acids 114–120) located in the ICOS FG loop, which interacts with residues from strands C and C’ and loops CC’ and C’D of ICOSL. These residues form a network of interactions that are critical for receptor binding.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_312b156d-fc56-48da-9d10-1cd034afbb84-2023-04-25T160000.000Z,1036,PubMed:33033255 +Akbay 2014 knock-in mouse model,Model Systems Non-human model organism,"Akbay EA, et al., 2014, PMID: 24589777","Developed conditional knock-in transgenic mouse strains in which IDH2 R140Q (patient variant) or R172K (somatic, cancer) was expressed under the control of the chicken β-actin promoter and inducible by tamoxifen administration. +Global induction of mutant IDH2 expression in adults resulted in dilated cardiomyopathy, white matter abnormalities, muscular dystrophy, and elevated 2-HG in serum and brain tissue. Mutant heart tissue also showed evidence of mitochondrial dysfunction. +Embryonic activation of mutant IDH2 resulted in more pronounced phenotypes, including runting, hydrocephalus, and shortened life span. +Hearts from knock-in animals exhibited mitochondrial damage and glycogen accumulation. +Turning off expression of R140Q in knock-in mice with the inducible transgene lowered serum 2-HG levels, restored heart function, and improved survival.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_91787b5b-8185-48e6-a437-9162c039b454-2023-01-30T170000.000Z,1038,PubMed:24589777 +Wang 2016 knock-in mouse model,Model Systems Non-human model organism,"Wang F, et al., 2016, PMID: 27469509","Developed a heterozygous knock-in transgenic mouse strain in which the R140Q (patient variant) was introduced into the native Idh2 locus. +Knock-in mice showed higher pre- and peri-natal mortality, runting, facial dysmorphism and abnormal head shape, cardiomyopathy, cardiomyocyte hypertrophy, vacuoles in brain tissue, hydronephrosis, and functional renal obstruction. +Plasma, bone marrow, brain, spleen, and heart from knock-in animals showed elevated 2-HG. +Administration of the selective and potent small molecule inhibitor of IDH2 R140Q mutant enzyme, AGI-026, which crosses the blood-brain barrier inhibited 2-HG production, improved survival, reduced incidence of cardiac abnormalities, and reduced numbers of brain sites affected by vacuolation.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_91787b5b-8185-48e6-a437-9162c039b454-2023-01-30T170000.000Z,1038,PubMed:27469509 +Enzymatic assay,Expression A,"Sun P, et al., 2019, PMID: 31515270","NADP-IDH may actually be the principal catalyst of the isocitrate to α-ketoglutarate reaction in the citric acid cycle in all tissues, and IDH3 serves as an accessory enzyme that augments or regulates the reaction, with the retina being particularly sensitive to the loss of this accessory activity",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5617e337-aa89-44a0-afe0-e142ced68619-2022-12-01T170000.000Z,1039,PubMed:31515270 +Enzymatic activity of IDH3B,Biochemical Function B,"Zhu S, et al., 2022, PMID: 35985423","IDH3B is involved in the Krebs cycle, which is known to be important to retinal function",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5617e337-aa89-44a0-afe0-e142ced68619-2022-12-01T170000.000Z,1039,PubMed:35985423 +Behavioral studies,Model Systems Non-human model organism,"Gleitz HF, et al., 2017, PMID: 28207863",Cognitive decline was observed in MPSII mouse model where a few exons of Ids were deleted.,Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_753ba7a6-cef5-4665-81e9-306e11c618c5-2018-02-21T170000.000Z,1040,PubMed:28207863 +cultured fibroblasts patient 3,Functional Alteration Patient cells,"Alazami AM, et al., 2014, PMID: 24689072","Primary cilia in patient cells exhibit reduced frequency and length as compared with control cells. Primary cilia from serum-starved primary control (A) and patient (B) fibroblasts, stained with anti-acetylated tubulin (green) and counterstained with 4',6-diamidino-2-phenylindole (blue). (C) Patient cells show significantly decreased ciliogenesis versus control cells (P < 0.0001, Fisher's exact test). Figure 3",Score,1 (1),The number and morphology of cilia in this case are consistent with other reports.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6e4b420a-5df1-4c3c-aca8-a5359de25a5d-2021-10-21T040941.926Z,1043,PubMed:24689072 +Canine model of retinitis pigmentosa,Model Systems Non-human model organism,"Kaukonen M, et al., 2021, PMID: 33606121","At least one case of retinal dystrophy has been reported in cranioectodermal dysplasia 1 in humans +(PMID: 8695580). However, this phenotype may be more prevalent at an older age than the majority of the reported cases of CED1. The canine phenotype reported in this paper (PMID: 33606121) appears to match this retinal dystrophy.",Score,0.25 (2),This model gives an association between a homozygous missense IFT122 variant in canines that matches a rare phenotype in humans with IFT122 variants.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6e4b420a-5df1-4c3c-aca8-a5359de25a5d-2021-10-21T040941.926Z,1043,PubMed:33606121 +Cauli mouse homozygous Ift140 loss-of-function mutant,Model Systems Non-human model organism,"Miller KA, et al., 2013, PMID: 24009529","The mode of inheritance in this model matches the biallelic/homozygous mode of inheritance observed in human disease. While the defects in the mouse model are more severe than those of the human patients, shared features include rib cage anomalies (Figure 2), digit anomalies (Figure 4), disruption of eye development (fully penetrant, described in text only), and severe morphological anomalies of the primary cilia in the limb buds (Figure 1G). While the model was generated using a mutagen, it is important to note that the targeted homozygous null mutant in Ift140 recapitulates the features of the model, albeit with enhanced severity. This confirms that the model's mechanism of pathogenicity is incomplete loss of Ift140 function. The localization of Ift140 protein to the base and tip of primary cilia in the limb bud is also consistent with the known function in humans (Figure 5F).",Score,1.5 (2),"The model is a good match for the mode of inheritance of the human patients and affects the same areas of the body (the skeleton including the ribs and the digits, the eyes, and the primary cilia). However, Ift140 function appears to be more severely disrupted in the mouse model than in the human patients, resulting in more severe phenotypes that are difficult to compare.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b4bc5837-07d2-46e5-836e-500a978bbf25-2022-07-07T160000.000Z,1044,PubMed:24009529 +IFT140 variant rescue in Ift140 knockout cells,Rescue Cell culture model,"Zhu B, et al., 2017, PMID: 28207750","Wild-type IFT140 restored ciliogenesis in 11% of cells, while either variant restored ciliogenesis to 6%, despite the surprising continued absence of the frameshift variant at the protein level (Figure 3b). Wild-type IFT140 reduced the proportion of cells exhibiting IFT88 accumulation at the ciliary tip to 23%, while either variant partially reduced IFT88 localization to the ciliary tip to 50% or 56% (Figure 3d).",Score,0.25 (1),"The variants used for the rescue experiment were NM_014714.3(IFT140):c.992_993dup (p.Tyr332Valfs*18) (cannot be registered manually) and NM_014714.3:c.2767T>G (p.Tyr923Asp) (CA394227092). While only one variant is expressed at the protein level, both had similar rescue effects, leading to down-scoring for non-specificity.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b4bc5837-07d2-46e5-836e-500a978bbf25-2022-07-07T160000.000Z,1044,PubMed:28207750 +Chlamydomonas mutant model of IFT140 loss-of-function,Model Systems Non-human model organism,"Zhu B, et al., 2017, PMID: 28207750","The cellular defects of the model in flagellar regeneration/assembly (Figures 6A,6C) parallel the absence of cilia from a high proportion of patient fibroblasts. The model also helps explain this defect by showing the underlying cause; the absence of IFT-A complex components from the peri-basal body region (Figure 5E-5F).",Score,0.5 (2),The model recapitulates the cellular defects of the patient while helping to reveal the underlying cause; the absence of other IFT-A complex components from the region surrounding the basal body. The inability of the organism to model organ-level phenotypes motivated down-scoring.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b4bc5837-07d2-46e5-836e-500a978bbf25-2022-07-07T160000.000Z,1044,PubMed:28207750 +Mouse ciliated cell model of Ift140 loss-of-function,Model Systems Cell culture model,"Oud MM, et al., 2018, PMID: 30479745","The defect in ciliary formation induced by Ift140 knockout (Figure 3b) recapitulates one of the cellular features of human patients harboring IFT140 variants (absence of cilia from a high proportion of fibroblasts). This also matches the Chlamydomonas model of IFT140 loss described in PMID: 28207750, albeit with greater severity.",Score,1 (1),The defect in ciliary formation induced by Ift140 knockout recapitulates one of the cellular features of human patients harboring IFT140 variants and matches the Chlamydomonas model of IFT140 loss.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b4bc5837-07d2-46e5-836e-500a978bbf25-2022-07-07T160000.000Z,1044,PubMed:30479745 +IGF2 activates IR-A,Biochemical Function B,"Rajapaksha H, et al., 2015, PMID: 26217307","Binding of IGF2 to the IR-A causes a structural change, leading to activation of the tyrosine kinase domain and autophosphorylation. This promotes cell proliferation, survival, and migration. Mutations in the IGF2 gene can lead to inactivation of this pathway therefore causing severe growth delay.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_39e89185-94a4-4f94-ae80-63df06bece69-2023-10-04T160000.000Z,1046,PubMed:26217307 +cryo‐electron microscopy (cryo-EM),Biochemical Function B,"Xu Y, et al., 2020, PMID: 32459985",IGF2 mutations produce nonfunctional proteins that does not recognize and bind to IGF1-R therefore not causing the activation of cellular pathways required to promote mitogenic activities for growth. The clinical presentation is severe growth delay.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_39e89185-94a4-4f94-ae80-63df06bece69-2023-10-04T160000.000Z,1046,PubMed:32459985 +Mouse model( +/CHB),Model Systems Non-human model organism,"Liao J, et al., 2021, PMID: 33567274","Silver-Russel syndrome(SRS) mouse models were significantly smaller than that of their wild type siblings. The fetus and placenta were significantly smaller than the weights of their wild type siblings at 18.5 dpc and 13.5dpc. Additionally, the brain weight, heart, kidney, lung, and tongue were significantly smaller in SRS pups compared to the wild type pups.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_39e89185-94a4-4f94-ae80-63df06bece69-2023-10-04T160000.000Z,1046,PubMed:33567274 +QRT-PCR,Expression A,"Liao J, et al., 2021, PMID: 33567274","Igf2 transcript levels in the organs of the 18.5-dpc of wild type mice fetuses were measured using QRT-PCR. Igf2 levels were higher in the extraembryonic organs (placenta, yolk sac, and the amnion), than in the organs of the fetus body (liver, kidney, tongue, brain, heart, lung, muscle, and stomach).",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_39e89185-94a4-4f94-ae80-63df06bece69-2023-10-04T160000.000Z,1046,PubMed:33567274 +Rescue of nmd SMARD1 mouse with AAV9,Rescue Non-human model organism,"Nizzardo M, et al., 2015, PMID: 26601156","The AAV9 encoding wildtype IGHMBP2 was able to restore normal protein levels, rescue motor function and physiology, increase lifespan by 450%, and ameliorate pathological features in the CNS, muscles, and heart.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_2717b35a-87a4-4f24-a762-53388db1bcb5-2023-09-06T160000.000Z,1048,PubMed:26601156 +B-cell conditional KO,Model Systems Non-human model organism,"Pasparakis M, et al., 2002, PMID: 12235208",B lineage–specific disruption by deletion of NEMO leads to the disappearance of mature B lymphocytes. suggesting that maintenance of mature B cells depends on IKK-mediated activation of NF-κB.,Score,0.5 (2),"FACS analysis revealed a strong reduction of mature B cells in mice with B cell–specific ablation of NEMO which is consistent with a role of NEMO in immune response, however patients typically have normal B cell numbers but manifest dysgammaglobulinemia.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_2c9ee97a-ab3d-4747-b3fe-523578dd90e9-2022-09-15T160000.000Z,1053,PubMed:12235208 +Pericentromeric heterocrhomatin staining,Functional Alteration Non-patient cells,"Sriaroon P, et al., 2019, PMID: 31069201",NIH3T3 cells transfected with H195R variant can´t form punctual foci formation in the nucleus compared to the WT,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_be4b4555-477b-477b-bff9-7fcc8883806a-2022-09-13T170000.000Z,1055,PubMed:31069201 +Single cell RNA sequencing,Expression A,"Shahin T, et al., 2022, PMID: 34920454",The scRNAseq data showed that Helios is highly expressed in Treg and NK cells.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3c007dec-2ef6-49a6-ba07-5f495c7794ae-2023-03-21T170000.000Z,1056,PubMed:34920454 +DNA binding capacity,Biochemical Function B,"Shahin T, et al., 2022, PMID: 34920454","Helios has been shown to control lymphocyte development and T follicular helper (Tfh)– and natural killer (NK)–cell differentiation and to maintain the suppressive function of regulatory T (Treg) cells. Using Single RNA sequencing in the patient samples carrying the variant p.R291X, it was shown that there is a decrease of clusters corresponding to the NK cells and central memory T cells. Moreover, there is an upregulation of genes associated with inflammation, indicating an activated and effector state in both monocytes and T cells. In addition, the total numbers of NK cells and Tregs (FOXP3+ cells) were reduced in the patient sample compared to the healthy control.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3c007dec-2ef6-49a6-ba07-5f495c7794ae-2023-03-21T170000.000Z,1056,PubMed:34920454 +AIOLOS p.N159S mice,Model Systems Non-human model organism,"Kuehn HS, et al., 2021, PMID: 34694366","The B cell development was evaluated in Ikzf3 G159S knock-in mutant mice. Mature follicular B cells were significantly decreased in both hetero and homozygous mice. Serum IgG, IgA and IgM were also significantly decreased.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e9112f2c-325e-4363-8a37-e7a8862bf55b-2023-03-21T170000.000Z,1057,PubMed:34694366 +B cell proliferation and differentiation,Functional Alteration Patient cells,"Kuehn HS, et al., 2021, PMID: 34694366","The four patients carrying the AILOS p.N160S variant showed profound defects in B cell proliferation upon stimulation with anti-IgM, CD40L, and IL-4. In addition to that, the plasmablast differentiation was completely abolished in the patient´s cells.",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e9112f2c-325e-4363-8a37-e7a8862bf55b-2023-03-21T170000.000Z,1057,PubMed:34694366 +DSS-induced intestinal inflammation in IL-21RKO Mice,Model Systems Non-human model organism,"Wang Y, et al., 2016, PMID: 27545302","crypt damage, ulceration and infiltration of inflammatory cells were significantly aggravated in the colons of DSS-treated IL-21RKO mice, which resemble inflammatory changes seen in human IBD.",Score,1 (2),"The experiment demonstrated that IL-21/IL-21R signaling plays a protective role in the pathogenesis of DSS-induced acute colitis in mice mainly through regulation of Th cell responses. We downscored because the other phenotypes of IL21 deficiency reported in human, were not investigated in the model system.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_82664dca-783a-4ed9-abe5-c77b082a0684-2022-12-30T120000.000Z,1061,PubMed:27545302 +Impaired generation of memory B cells,Functional Alteration Patient cells,"Cagdas D, et al., 2021, PMID: 33929673","Within the contracted memory B cell population in IL-21R-deficient patients, proportions of IgG+ or IgA+ switched cells were significantly decreased",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_4dbeac16-997c-43c0-9fb6-eaa98d0816f9-2022-12-31T120000.000Z,1062,PubMed:33929673 +Functional defects in B and T cells,Functional Alteration Patient cells,"Cagdas D, et al., 2021, PMID: 33929673",undetectable levels of IgM as well as of the class-switched Ig isotypes IgG and IgA from IL21R deficient patients.,Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_4dbeac16-997c-43c0-9fb6-eaa98d0816f9-2022-12-31T120000.000Z,1062,PubMed:33929673 +Lentiviral rescue of IL2RB and STAT phosphorylation,Rescue Patient cells,"Zhang Z, et al., 2019, PMID: 31040185","Transduced cells had high levels of surface IL-2RB expression. +Transduced cells were able to phosphorylate STAT3 and STAT5 in response to IL-2. Did not restore to same level as a healthy control but significantly higher than non-transduced patient cells.",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9b6a2d8f-4ca0-42bb-9c1c-fbe59aac7b1f-2023-12-12T170000.000Z,1063,PubMed:31040185 +Organ of corti expression,Expression A,"Sang Q, et al., 2015, PMID: 25819842",ILDR1 was expressed in organ of corti including three lines of OHCs and a single line of IHCs.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e5e1a608-edc3-405c-805f-a7ed162c2bbc-2017-11-21T170000.000Z,1067,PubMed:25819842 +ILDR1 deficiency,Protein Interaction,"Sang Q, et al., 2015, PMID: 25819842",ILDR1 deficiency decreased expression of tricellulin (MARVELD2) in tight junctions in vivo.,Score,0.5 (0.5),MARVELD2 is associated with hearing loss,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e5e1a608-edc3-405c-805f-a7ed162c2bbc-2017-11-21T170000.000Z,1067,PubMed:25819842 +Mouse model with floxed exons 2-3,Model Systems Non-human model organism,"Sang Q, et al., 2015, PMID: 25819842",Probands with varians in this gene have had profound deafness like this mouse model did,Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e5e1a608-edc3-405c-805f-a7ed162c2bbc-2017-11-21T170000.000Z,1067,PubMed:25819842 +ILDR1 null mouse,Model Systems Non-human model organism,"Higashi T, et al., 2015, PMID: 25822906",Observed progressive OHC degeneration after P10. Presence of caspase-3 suggests degeneration is caused by apoptosis.,Score,2 (2),"ILDR1-null mouse had profound deafness. Mice had deletion of exons 3, 4, and 5. Observed progressive OHC degeneration after P10. Presence of caspase-3 suggests degeneration is caused by apoptosis.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e5e1a608-edc3-405c-805f-a7ed162c2bbc-2017-11-21T170000.000Z,1067,PubMed:25822906 +ILK gene transfer in DCM rat model,Model Systems Non-human model organism,"Gu R, et al., 2012, PMID: 22348065",see paper 22348065,Score,0.5 (2),Evidence that ILK is involved in DCM,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_540f2706-1c1a-452e-b5b9-334728b11e40-2020-09-04T160000.000Z,1068,PubMed:22348065 +Patient retinal organoid rescue by CRISPR/Cas9-based editing,Rescue Patient cells,"Mayerl SJ, et al., 2022, PMID: 36206764","Control retinal organoids with CRISPR/Cas9-based editing / rescue of both variants (Figure 2D) showed development of both the IPM and the outer segment, relative to the uncorrected retinal organoids (Figure 2A). This rescue argues for a role of IMPG2 in photoreceptor cell outer segment development / maintenance.",Score,0.25 (1),Down-scoring is recommended due to the use of retinal organoids to model a late onset disease in the context of IPM and photoreceptor development. The model may not be particularly physiological since it is missing the RPE (the other side of IPM where protein exerts its effect).,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_66bf5526-6f74-473b-b2f9-3e3270164bc8-2023-08-03T160000.000Z,1069,PubMed:36206764 +Morpholino knockdown and rescue in zebrafish,Rescue Non-human model organism,"Sun H, et al., 2014, PMID: 26086034",Normally developed zebrafish embryo,Score,1.5 (2),"Morpholino used, gross evaluation of zebrafish development",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5215f2cf-99c9-405a-b221-18f412abd1f0-2021-03-22T202012.410Z,1070,PubMed:26086034 +INF2 knockdown in fibroblasts,Biochemical Function A,"Bartolini F, et al., 2016, PMID: 27030671",These genes are involved in microtubule stabilization as well.,Score,0 (0.5),Relevant function involves domain different from the one carrying all CMT-associated variants,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5215f2cf-99c9-405a-b221-18f412abd1f0-2021-03-22T202012.410Z,1070,PubMed:27030671 +INO80 Knockdown,Functional Alteration Non-patient cells,"Kracker S, et al., 2015, PMID: 25312759","Knockdown of INO80 in murine CH12-F3 B cells reduced the percentage of IgA+ cells by an average of 30% compared with controls. Therefore, knockdown of INO80 impaired Immunoglobulin class-switch recombination (CSR). The authors also found that INO80 knockdown altered cell survival and DNA repair in the CH12-F3 B cells, suggesting that INO80 likely impacts the DNA repair step in CSR.",Score,0.5 (0.5),"Knockdown of INO80 using lentiviral shRNA in murine CH12-F3 B cells resulted in a 30% reduction of IgA+ cells, due to impaired Immunoglobulin class-switch recombination, altered DNA repair, and impacted sister chromatid cohesion",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_16d9f828-f6fa-4e35-bc23-c9f1b1138b9a-2021-01-22T014826.188Z,1071,PubMed:25312759 +Loss of exclusive ciliary localization in INPP5E mutant,Functional Alteration Non-patient cells,"Fansa EK, et al., 2016, PMID: 27063844","INPP5E(KS) mutant is not enriched in cilia but localized all over the cell including the cilium, while INPP5E(WT) is highly enriched in cilia with only a minor fraction in the cell body",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a50bbd87-4308-4272-83fc-21274d283e63-2023-05-30T160000.000Z,1072,PubMed:27063844 +Accumulation of Smo is dependent on Inpp5E's phosphatase act,Functional Alteration Non-patient cells,"Dyson JM, et al., 2017, PMID: 27998989",Reduced substrate hydrolysis and decreased accumulation of Smo on cilia,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a5fb970a-8747-4c3e-8465-d8cb007c1428-2021-09-08T160000.000Z,1073,PubMed:27998989 +Mouse Model Graft,Model Systems Non-human model organism,"Ma S, et al., 2018, PMID: 30503261","None of the 4 mice grafted with mutant cells showed detectable serum C-peptide, mice grafted with corrected cells showed detectable C-peptide at 3 weeks with levels increasing up to 19 weeks post transplantation (Fig. 4B), Corrected mice were fasted and human insulin levels were assessed before and after re-feeding at 11wks post transplantation and showed a decrease in C-peptide during fasting, and a large increase after re-feeding (Fig. 4C), all mice were treated with 150 mg/kg STZ after human C-peptide reached a threshold of >400 pM or at 19 weeks post transplantation and this resulted in elimination of insulin secretion from mouse beta cells (Fig. 4D), mutant mice were diabetic 7 days post STZ treatment (Fig. 4E), but corrected mice retained normal blood glucose levels (Fig. 4E) +Blood glucose levels and serum C-peptide in corrected mice normalized after fasting and intraperitoneal glucose tolerance test (Fig. 4F), mutant mice did not normalize (Fig. 4G) +The grafted human tissues was removed from all mice and stained for NKX6.1 and insulin, NKX6.1 positive cells were present from both mutant and corrected cell grafts (Fig. 4I), only correct grafts were positive for insulin (Fig. 4I)",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9c21ba4d-785f-486f-84f8-511b9c89c137-2020-05-13T160000.000Z,1074,PubMed:30503261 +Patient derived iPSCs,Model Systems Cell culture model,"Ma S, et al., 2018, PMID: 30503261","both insulin mutant and corrected cells differentiated into definitive endoderm, 96% of cells positive for SOX17 and FOXA2 (Fig. 2B, S2A, S2B), 40% of both cells types were positive for PDX1 and NKX6.1 at the pancreatic progenitor stage (Fig. 2C, S2C, S2D), mutant cells lacked C-peptide positive cells while corrected cells showed 53.7% ± 9.8% insulin-positive cells (Fig. 2D,E), both cell lines expressed pancreatic endocrine and beta-cell markers (CHGA, NKX6.1, PDX1, MAFA) (Fig. 2F-I) +No mutant cells showed insulin protein expression however quantitative RT-PCR confirmed expression of insulin locus with expression of mutant insulin mRNA reduced 800-fold compared to corrected cells, suggesting reduced stability of non-translated transcript, this was confirmed via gel electrophoresis (Fig. 3), the insulin-negative mutant cells also had a lower amount of spliced XBP1 than corrected cells (Fig. 3C,D) +Insulin contents shown to be restored from 0-0.6pmol/cell in corrected cells in vitro via ELISA (Fig. 3E), pro-insulin was absent in mutant cells, while corrected cells had 0.14 ± 0.03 pmol/L pro-insulin (Fig. 3F, S2F), when treated with KCl, mutant cells did not secrete insulin and corrected cells secreted 0.027 ± 0.002 pmol after KCl stimulation (Fig. 3G)",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9c21ba4d-785f-486f-84f8-511b9c89c137-2020-05-13T160000.000Z,1074,PubMed:30503261 +Knockdown Iqsec2 in mouse neuronal culture,Model Systems Cell culture model,"Hinze SJ, et al., 2017, PMID: 28463240","Knockdown and overexpression of Iqsec2 leads to the disruption of dendritic morphology, indicating that dosage sensitivity for IQSEC2 is critical. Animal models of neurodevelopmental disorders seen in the patients have shown abnormal dendritic morphology.",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0916cda1-5213-4f88-9835-34c3931526a2-2019-06-05T160000.000Z,1078,PubMed:28463240 +Knockout mouse model for IQSEC2,Model Systems Non-human model organism,"Hinze SJ, et al., 2017, PMID: 28463240","Knockdown and overexpression of Iqsec2 leads to the disruption of dendritic morphology, indicating that dosage sensitivity for IQSEC2 is critical. Animal models of neurodevelopmental disorders seen in the patients have shown abnormal dendritic morphology.",Score,0.5 (2),"This paper only showed the gross morphological changes in the cortical neuronal culture instead of a comprehensive characterization of the knockout mouse, such as a battery of behavioral assays. The paper mentioned at the very end that the behavioral and phenotypic characterization of this knockout mouse is ongoing.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0916cda1-5213-4f88-9835-34c3931526a2-2019-06-05T160000.000Z,1078,PubMed:28463240 +Specific expression in the brain,Expression A,"Mignot C, et al., 2019, PMID: 30206421",IQSEC2 isoforms across multiple tissues was quantified using two different methods: Cap Analysis of Gene Expression (CAGE) data and isoform specific intron-spanning RNA-seq reads quantification.,Score,0.5 (0.5),"In addition to human tissue, similar brain-specific expression were also found in the mouse. PMID 18164504_Fig 3: RT-PCR showed brain-specific expression of IQSEC2 in mouse. PMID 17045249_ Fig 3: Immunostaining showed that IQSEC2 colocalizes with postsynaptic density marker, PSD-95, in mouse hippocampal neuronal culture. PMID 17045249_ Fig 2: Immunoblot showed that IQSEC2 is enriched in the postsynaptic density fractions of mouse forebrain homogenate.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0916cda1-5213-4f88-9835-34c3931526a2-2019-06-05T160000.000Z,1078,PubMed:30206421 +A350V IQSEC2 knockin mouse model,Model Systems Non-human model organism,"Rogers EJ, et al., 2019, PMID: 30842726",Reduced surface GluA2 AMPA receptors and synaptic transmission in hippocampal tissue as well as impaired cognitive function found in mice may reflect intellectual disability in patients. Hyperactivity in mice may reflect attention deficit hyperactivity disorder seen in some patients. Abnormal social interactions in mice may reflect autistic behaviors in some patients.,Review,0 (2),"For the two social interaction tests: three-chamber social preference test showed no statistical significance between knockin and wildtype mice; social novelty test showed that knockin mice have increased preference for social novelty, which is in contrast to what has +been described in autism patients and other autism mouse models. The Morris water maze used to evaluate cognitive function in mice used the heterozygous knockin female mice instead of the male mice which were used throughout the paper (without any explanation). Also the mouse number for Morris water maze is n=5, which is well below what most literature published.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0916cda1-5213-4f88-9835-34c3931526a2-2019-06-05T160000.000Z,1078,PubMed:30842726 +Sheftel_Functional alteration (non-patient cells),Functional Alteration Non-patient cells,"Sheftel AD, et al., 2012, PMID: 22323289","There was altered mitochondrial morphology (swollen, enlarged mitochondria devoid of cristae membranes) and decreased activities of [4Fe-4S] mitochondrial proteins.",Score,1 (0.5),"There was altered mitochondrial morphology (swollen, enlarged mitochondria devoid of cristae membranes) and decreased activities of [4Fe-4S] mitochondrial proteins.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ac2a091c-b7da-4268-b2f4-0fbf9231a5fb-2023-08-21T160000.000Z,1083,PubMed:22323289 +Alaimo_Functional alteration (non-patient cells),Functional Alteration Non-patient cells,"Alaimo JT, et al., 2018, PMID: 29297947",There were decreased activities/amount of MRC complexes and lipoic-acid bound proteins.,Score,1 (0.5),There were decreased activities/amount of MRC complexes and lipoic-acid bound proteins.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ac2a091c-b7da-4268-b2f4-0fbf9231a5fb-2023-08-21T160000.000Z,1083,PubMed:29297947 +Rawcliffe_Mouse,Model Systems Non-human model organism,"Rawcliffe DF, et al., 2016, PMID: 27783661",Expression is recapitulated.,Score,0.5 (2),0.5 (recapitulated expression),https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_636c0bfd-1dfd-4eb8-af33-3cbb652a2634-2023-10-19T040000.000Z,1084,PubMed:27783661 +2.5P-Cre; ITGA3fl/fl mice,Model Systems Non-human model organism,"Sachs N, et al., 2006, PMID: 17015618",Similar to renal phenotype in human disease,Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3dc277da-52f8-4f64-91a8-cd6c4f68db3a-2022-05-09T023000.000Z,1087,PubMed:17015618 +ITGA3-null mice,Model Systems Non-human model organism,"DiPersio CM, et al., 1997, PMID: 9151677",Similar model phenotype to human EB disease,Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3dc277da-52f8-4f64-91a8-cd6c4f68db3a-2022-05-09T023000.000Z,1087,PubMed:9151677 +JAK3 Inhibition Diminishes Human ILC proliferation,Model Systems Cell culture model,"Robinette ML, et al., 2018, PMID: 28513593","Both expanded iILC1 (Figure 5A–B) and ILC3 (Figure 5C–D) were substantially less proliferative in the presence of tofacitinib. Both iILC1 and ILC3 incorporated significantly less BrdU in a dose-dependent manner, and their proliferation almost completely blocked at high dose (Figure 5A–D).",Score,1 (1),"To test if the proliferative defect caused by tofactinib was truly JAK3 mediated, authors tested the effect of the JAK3-specific inhibitor PF-06651600 on iILC1 (Figure 5E) and ILC3 (Figure 5F) proliferation compared to tofactinib. Mirroring tofacitinib, authors found that PF-06651600 abrogated ILC proliferation. Thus, human ILC proliferation is JAK3 dependent, at least in culture conditions.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_669dcacf-8423-4507-a36c-feab049737b3-2020-12-18T200520.841Z,1096,PubMed:28513593 +WLVRN phenotype caused by JAK3 frameshift mutation,Model Systems Non-human model organism,"Robinette ML, et al., 2018, PMID: 28513593","This defect phenocopied littermates from intercrossed Jak3tm1Ljb/+ mice, which are on a mixed 129S4 and C57BL6/J background (some data not shown). Authors noted a phenotype characterized by lack of lymphoid tissue development that emerged in the F1 from original Jackson breeders and that segregated independently from Nr1d1tm1Ven alleles, which were then called Wolverine (WLVRN). Grossly, mice with the WLVRN phenotype lacked Peyer’s patches (PPs) and peripheral lymph nodes as measured by inguinal lymph node presence or absence, and also demonstrated thymic aplasia compared to littermates. To test directly if Jak3 deficiency caused these WLVRN phenotypes, authors intercrossed Jak3tm1Ljb/+ and Jak32067insC/+ and found that Jak32067insC/ tm1Ljb mice had reductions in ILCs and lacked lymphoid tissue development, while there was no difference between WT and either heterozygous allele (some data not shown). From these data, authors conclude that the WLVRN phenotype is caused by a spontaneous loss-of-function mutation in Jak3, leading to the first C57BL6/J Jak3 deficient mouse line. Authors also conclude that Jak3 is critically important for the development and/or maintenance of all ILCs.",Score,1 (2),"Mouse phenotype not as closely related to the human SCID phenotype, but evidence for JAK3 impact on ILCs.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_669dcacf-8423-4507-a36c-feab049737b3-2020-12-18T200520.841Z,1096,PubMed:28513593 +JPH overexpression and knockdown Drosophila model,Model Systems Non-human model organism,"Calpena E, et al., 2018, PMID: 29208631","Mean survival was reduced from 47 days in control flies to 27 days in OE flies and only 17 days in KD flies. +Cardiac chamber parameters for both OE en KD (fig 3): +Increased end-systolic diameter (ESD) and end-diastolic diameter (EDD). +Decreased fractional shortening (FS) =>DCM phenotype. +Sections show that the thickness of the heart wall in the mutant flies does not show any statistically significant difference from control flies, discounting hypertrophy of cardiomyocytes (Fig. 3E). +The cardiac fibers in the mutant flies were clearly more disorganized and less compact than in control flies.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_242181ea-8909-4b38-a6bd-9a6552935c74-2020-10-09T160000.000Z,1097,PubMed:29208631 +A405S pseudo-knockin,Model Systems Non-human model organism,"Quick AP, et al., 2017, PMID: 28393127","A399S mice exhibited various features typically associated with HCM, including a hypertrophic interventricular septum, an increased LV mass, asymmetric LV hypertrophy with a reduced diastolic filling and myofiber disarray.",Score,3 (2),"Generated transgenic mouse with corresponding mutation A399S in mice (human A405S): expressed only in heart, but increased globally so crossed with cardiac-specific JPH2 KD mice. This generated pseudo-KI (PKI) mouse that express JPH2 levels similar to control mice. Cardiac JPH2 levels were similar in WT-PKI and A399S-PKI mice. Studied intracellular calcium handling in ventricular myocytes from A399S mice. Higher SERCA2 activity consistent with faster calcium re-uptake into the SR in mutant myocytes, altered transverse tubule organization.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_378a727d-0c5b-4563-9c96-ac18a2902742-2022-10-12T160000.000Z,1098,PubMed:28393127 +Calpena Drosophila Model (JPH2 Overexpression),Model Systems Non-human model organism,"Calpena E, et al., 2018, PMID: 29208631","PCR confirmed increase in jp transcript levels (Fig. 1D), reduction of lifespan from 53 days in control flies to only 35 days (Fig. 3A), increased end-systolic diameter (ESD) and end-diastolic diameter (EDD) and decreased fractional shortening (FS) percentage (Fig. 3B), thickness of the heart wall in the mutant flies does not show any statistically significant difference from control flies (Fig. 3E), cardiac fiber in mutant flies were more disorganized and less compact than in control flies (Fig. 3G)",Score,0 (2),"This model more closely resembles DCM, so it receives a score of 0 since the curation is for the relationship with HCM.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_378a727d-0c5b-4563-9c96-ac18a2902742-2022-10-12T160000.000Z,1098,PubMed:29208631 +Calpena Drosophila Model (JPH2 Knockdown),Model Systems Non-human model organism,"Calpena E, et al., 2018, PMID: 29208631","quantitative PCR confirmed decrease in jp transcript levels (Fig. 1D), reduction of lifespan from 53 days in control flies to only 35 days (Fig. 3A), increased end-systolic diameter (ESD) and end-diastolic diameter (EDD) and decreased fractional shortening (FS) percentage (Fig. 3B), thickness of the heart wall in the mutant flies does not show any statistically significant difference from control flies (Fig. 3E), cardiac fiber in mutant flies were more disorganized and less compact than in control flies (Fig. 3G)",Score,0 (2),"This model more closely resembles DCM, so it receives a score of 0 since the curation is for the relationship with HCM.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_378a727d-0c5b-4563-9c96-ac18a2902742-2022-10-12T160000.000Z,1098,PubMed:29208631 +Kansl1+/- mice cultured hippocampal neurons,Functional Alteration Non-patient cells,"Arbogast T, et al., 2017, PMID: 28704368","KANSL1 regulates global transcription through chromatin remodeling. +Epigenetic profiling in the hippocampus of Kansl1+/- mice showed changes in H3K4me3 pattern, indicating misregulation of promoters of target genes.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e89a0e87-314a-49b1-bb50-6b26aeaa1037-2022-02-18T120936.714Z,1099,PubMed:28704368 +KANSL1 knockout mouse,Model Systems Non-human model organism,"Arbogast T, et al., 2017, PMID: 28704368","Kansl1+/- mice showed similar phenotypes observed in KdVS patients: recognition memory deficit, abnormal locomotor activity, reduced body weight. In addition, Kansl1+/- showed similar phenotypes observed in Del/+ models (the 17q21.31-homologous Arf2-Kansl1 genetic interval in mice) for KdVS, supporting the critical importance of KANSL1 in KdVS.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e89a0e87-314a-49b1-bb50-6b26aeaa1037-2022-02-18T120936.714Z,1099,PubMed:28704368 +Moz Deficiency,Model Systems Non-human model organism,"Voss AK, et al., 2012, PMID: 22921202","overlaps some of the phenotypes observed in humans, however not scored due to lack of assessment for neurodevelopmental phenotypes.",Score,0 (2),Downgrading this score to 0 points because none of the phenotypes reported are associated with a neurodevelopmental disorder.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_86ec74ba-6b12-42ea-bc06-58af4fd6b7a4-2021-10-05T160000.000Z,1101,PubMed:22921202 +Human Katnip binds to MTs and regulates MT stability,Biochemical Function B,"Sanders AA, et al., 2015, PMID: 26714646","Consistent with ciliopathy phenotypes, as primary cilium is a microtubule-based structure and alterations of microtubule architecture is well described mechanism in ciliopathies.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0ec67a40-fd4c-4eb8-b90d-e0b3fc4f0133-2023-07-10T160000.000Z,1105,PubMed:26714646 +Ultrastructural expression,Expression A,"Sanders AA, et al., 2015, PMID: 26714646","Human RNA expression in relevant tissues (PMID: 27245168). +IF staining (protein atlas)",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0ec67a40-fd4c-4eb8-b90d-e0b3fc4f0133-2023-07-10T160000.000Z,1105,PubMed:26714646 +Katnip associates with katanins and with ciliary components,Protein Interaction,"Sanders AA, et al., 2015, PMID: 26714646","IFT172 associated with several ciliopathies (AR retinitis pigmentosa, Bardet-Biedl and Short-rib thoracic dysplasia with or without polydactyly)",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0ec67a40-fd4c-4eb8-b90d-e0b3fc4f0133-2023-07-10T160000.000Z,1105,PubMed:26714646 +KATNIP-ortholog disrupted C.elegans possess defects in MT,Model Systems Non-human model organism,"Sanders AA, et al., 2015, PMID: 26714646",Ultrastructural analysis showed significant microtubule defects - in line with ciliopathy-Joubert phenotype in humans,Score,1 (2),mild and only structural phenotype (no functional phenotype),https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0ec67a40-fd4c-4eb8-b90d-e0b3fc4f0133-2023-07-10T160000.000Z,1105,PubMed:26714646 +Katnip KO mouse model,Model Systems Non-human model organism,"Sanders AA, et al., 2015, PMID: 26714646",morphological brain phenotypes,Score,0 (2),Phenotype discordant with human disease - no ciliary phenotype,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0ec67a40-fd4c-4eb8-b90d-e0b3fc4f0133-2023-07-10T160000.000Z,1105,PubMed:26714646 +Ciliary defects in patient derived fibroblasts,Functional Alteration Patient cells,"Sanders AA, et al., 2015, PMID: 26714646",Significant reduction in the number of ciliated cells compared with controls. Average cilium length was abnormally long.,Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0ec67a40-fd4c-4eb8-b90d-e0b3fc4f0133-2023-07-10T160000.000Z,1105,PubMed:26714646 +Cell Culture Model System.4,Functional Alteration Non-patient cells,"Syrbe S, et al., 2015, PMID: 25751627",p.Leu298Phe variant expressed in Xenopus oocytes; co-expressed with WT Kv1.2 channels. Current amplitudes measured via patch clamp. Mean current amplitudes significantly increased compared to WT. Activation curve of WT + Leu298Phe channels significantly shifted to more hyperpolarized potentials. Resting membrane potential ~40mV more negative than WT. Consistent with constituitively open channels and GOF.,Review,0 (0.5),"scored as variant level evidence, not functional evidence for gene",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1a825f85-585a-4086-8118-ce912d4c1469-2022-05-18T130146.911Z,1106,PubMed:25751627 +Cell Culture Model System.1,Functional Alteration Non-patient cells,"Syrbe S, et al., 2015, PMID: 25751627","p.Pro405Leu variant expressed in Xenopus oocytes; co-expressed with WT Kv1.2 channels in increasing ratios (1:1; 1:2; 1:4). Current amplitudes recorded via patch clamp. Showed increasing loss-of-function, consistent with dominant-negative effect",Review,0 (0.5),"Scored as variant level evidence, not functional evidence for gene",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1a825f85-585a-4086-8118-ce912d4c1469-2022-05-18T130146.911Z,1106,PubMed:25751627 +Cell Culture Model System.2,Functional Alteration Non-patient cells,"Syrbe S, et al., 2015, PMID: 25751627","p.Ile263Thr variant expressed in Xenopus oocytes; co-expressed with WT Kv1.2 channels in increasing ratios (1:1; 1:2; 1:4). Current amplitudes recorded via patch clamp. Showed increasing loss-of-function, consistent with dominant-negative effect",Review,0 (0.5),"This was scored as variant-level evidence, not functional evidence for the gene",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1a825f85-585a-4086-8118-ce912d4c1469-2022-05-18T130146.911Z,1106,PubMed:25751627 +Cell Culture Model System.3,Functional Alteration Non-patient cells,"Syrbe S, et al., 2015, PMID: 25751627",p.Arg297Gln variant expressed in Xenopus oocytes; co-expressed with WT Kv1.2 channels. Current amplitudes measured via patch clamp. Mean current amplitudes significantly increased compared to WT. Activation curve of WT + Arg297Gln channels significantly shifted to more hyperpolarized potentials. Resting membrane potential ~40mV more negative than WT. Consistent with constituitively open channels and GOF.,Review,0 (0.5),"Scored as variant-level evidence, not functional evidence for gene",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1a825f85-585a-4086-8118-ce912d4c1469-2022-05-18T130146.911Z,1106,PubMed:25751627 +Firing of cortical neuron cultures expressing Kv3.1b,Biochemical Function B,"Carpenter JC, et al., 2021, PMID: 33735526","This result shows that KCNC1 plays a role in maintaining high frequency firing of neurons by rapid repolarization. If the neurons' ability to fire high frequency action potentials, the balance of brain's electrical activity is expected to be inbalances, leading to seizures, which is an uncontrolled electrical activity in the brain.",Review,0 (0.5),Expression in the brain tissues is not enough for the experimental points.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_35d2beba-40f6-472d-842c-41925f486ba9-2022-11-07T200000.000Z,1108,PubMed:33735526 +p.R320H reduced the firing frequency of cortical neurons,Functional Alteration Non-patient cells,"Carpenter JC, et al., 2021, PMID: 33735526","As expected, expression of KV3.1bWT enabled high-frequency firing and prevented depolariza- tion block in response to current injections greater than 200 pA. In contrast, KV3.1bR320H significantly reduced AP frequency compared to GFP across a range of current steps. There were no significant dif- ferences in the current threshold, AP threshold, input re- sistance, or capacitance. To assess the impact of KV3.1bR320H channels on high- frequency firing in response to rapid current inputs, we delivered 5-ms suprathreshold current pulses at frequen- cies of 10–100 Hz. Neurons overexpress- ing KV3.1WT had significantly higher AP success rates at 100 Hz compared to GFP control neurons. Overexpression of KV3.1bR320H, on the other hand, had no effect on spike fidelity at 100 Hz compared to GFP controls. The lack of effect of KV3.1bR320H on firing in response to stimulus trains may be due to the repolarization after the end of the step being sufficient to support firing at this rate, or to low functional expression of endogenous KV3.1b at this developmental stage in cul- ture . The somatic expression level of KV3.1b was not found to differ for the wild-type (WT) and mutant channel.",Review,0 (0.5),This is a variant-level functional study.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_35d2beba-40f6-472d-842c-41925f486ba9-2022-11-07T200000.000Z,1108,PubMed:33735526 +Neuronal cell death by p.R320H,Functional Alteration Non-patient cells,"Carpenter JC, et al., 2021, PMID: 33735526","In addition to compromised dendritic development, a higher proportion of neurons expressing KV3.1bR320H were positive for a marker of programmed cell death (termi- nal deoxynucleotide transferase-mediated deoxyuridine triphosphate nick-end labeling [TUNEL]) after 72 h, with respect to GFP and KV3.1bWT. At 72 h post- transfection, KV3.1bR320H neurons had rounded cell bodies and blebbing of neuronal processes, consistent with pro- grammed cell death. KV3.1bR320H neurons were still viable 48 h after transfection as indicated by the TUNEL assay, but there were early proapoptotic nuclear changes, such as chromatin condensation and morphologi- cal irregularities, reflected in a significantly reduced nuclear area factor.",Review,0 (0.5),Variant-level functional evidence,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_35d2beba-40f6-472d-842c-41925f486ba9-2022-11-07T200000.000Z,1108,PubMed:33735526 +Effect of p.R320H on dendritic and axonal growth,Functional Alteration Non-patient cells,"Carpenter JC, et al., 2021, PMID: 33735526","Interneurons expressing KV3.1bR320H had clear morpho- logical defects at 14–16 DIV. To quantify this, we transduced neurons at 1 DIV, when neurons un- dergo a rapid period of neuritogenesis, and performed dendritic analysis at 7 DIV. A significantly higher percentage of neurons expressing KV3.1bR320H had undetectable processes at 7 DIV (85.7% ± 1.1%, n = 6) compared to WT (27.8% ± 2.6%, n = 6) and GFP controls (30.9% ± 4.0%, n = 6; p < .001, one-way ANOVA fol- lowed by Bonferroni multiple comparison test). Of those neurons with clearly detectable processes, KV3.1bR320H ex- pression had no significant effect on dendritic arborization, but significantly reduced total dendritic length when com- pared to GFP and KV3.1bWT controls. In contrast, overex- pression of KV3.1bWT had no effect on either total dendritic length or dendritic arborization compared to GFP control. When KV3.1b variant was introduced by plasmid transfection at 4 DIV, a time point at which the dendritic arbor is partly established, dendritic land axonal length was significantly reduced. Dendritic arborization was also significantly reduced. Dendritic length did not decrease between 24 and 48 h after transfection with KV3.1bR320H, suggesting that reduced length at 48 h is due to impaired outgrowth and not col- lapse.",Review,0 (0.5),Variant-level functional evidence.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_35d2beba-40f6-472d-842c-41925f486ba9-2022-11-07T200000.000Z,1108,PubMed:33735526 +change in time constant by p.R320H,Functional Alteration Non-patient cells,"Carpenter JC, et al., 2021, PMID: 33735526","In contrast to reported complete or partial reductions in expression in some experi- mental conditions, KV3.1bR320H produced WT-like current amplitude in our conditions. Voltage dependence of activation also did not differ from the WT channels. However, KV3.1bR320H activation was slower than WT channels. The reduced rate of activation persisted in the simulated heterozygous condition with RNA for mutant and WT subunits injected at a 1:1 ratio. Finally, WT channels showed a rapid but small decay in currents in response to pulses positive to 0 mV, and this inactivation was not seen in oocytes expressing KV3.1bR320H. Simulated heterozygous channels were inactivated at volt- ages more positive than WT channels. Overall, KV3.1bR320H conferred dominant loss-of-function due to a reduced rate of channel activation.",Review,0 (0.5),Variant-level functional evidence,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_35d2beba-40f6-472d-842c-41925f486ba9-2022-11-07T200000.000Z,1108,PubMed:33735526 +Current analysis,Functional Alteration Non-patient cells,"Cameron JM, et al., 2019, PMID: 31353855","Current traces obtained from a set of depolarizing pulses from − 60 to + 60 mV revealed a clear loss of function for all but the Ala513Val variant, being the variant observed once in gnomAD (not scored or assessed as causative by authors). To determine potential dominant‐negative effect, we performed coexpression experiments, where both WT and mutant cRNA of the same concentration were injected at a 1:1 ratio. Two variants that showed very small or no currents, (Arg317His and Arg339X) caused a significant reduction compared to the WT current amplitude indicating a dominant‐negative effect (Fig. ​(Fig.3A3A and ​and3).3). For the coexpression of the Gln492X with the WT, the normalized current amplitudes were as follows: WT + H20 – 1.00 ± 0.03 (n = 111) and WT + Gln492X – 1.02 ± 0.12 (n = 21). In both cases, the injected amount of WT cRNA was the same, so that the resulting current amplitude of the coexpression should be the sum of the expressed WT + H2O (1.00 ± 0.03) and half of the amplitude recorded for the Gln492X alone (0.7 ± 0.1; Fig. ​Fig.2C),2C), that is, with a value of about 1.3. Since this predicted value is larger than the recorded one this might suggest the dominant‐negative effect of the Gln492X. The conductance‐voltage relationships for Ala421Val + WT, Arg317His + WT, Gln492X + WT, and Arg339X + WT did not differ from the wild type alone. With no changes seen in the voltage dependence of activation, the observed reduction in current amplitudes may be explained by other mechanisms such as reduced number of mutant channels reaching the membrane or reduced open probability of these channels.",Review,0 (0.5),This is variant-level experimental evidence.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5146494e-71e7-4e06-b10f-cc126429e3fb-2022-11-07T200000.000Z,1109,PubMed:31353855 +Current analysis,Functional Alteration Non-patient cells,"Park J, et al., 2019, PMID: 31353862","Current amplitudes recorded in oocytes expressing either of the three mutant channels were barely detectable and similar to water‐injected controls (Fig. ​(Fig.2A2A and ​and2).2). Coexpression of wild type (WT) with mutant channels indicated dominant‐negative loss‐of‐function effects with a significant decrease in K+ current amplitudes of approximately 68% and 48% for Thr399Met and Ala421Val mutant channels compared to WT alone (Fig. ​(Fig.2C2C and D), whereas coexpression of Cys208Tyr mutant and WT channels did not cause a significant amplitude reduction. The activation curve showed a hyperpolarizing shift when WT channels were coexpressed with Ala421Val mutant channels in comparison to WT channels alone (Fig. ​(Fig.2E),2E), whereas Cys208Tyr channels did not show any significant difference. Thr399Met showed a strong dominant‐negative effect on the WT which impeded the evaluation of further gating parameters.",Review,0 (0.5),This is a variant level experimental evidence.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5146494e-71e7-4e06-b10f-cc126429e3fb-2022-11-07T200000.000Z,1109,PubMed:31353862 +Firing of cortical neuron cultures expressing Kv3.1b,Biochemical Function B,"Carpenter JC, et al., 2021, PMID: 33735526","This result shows that KCNC1 plays a role in maintaining high frequency firing of neurons by rapid repolarization. If the neurons' ability to fire high frequency action potentials, the balance of brain's electrical activity is expected to be inbalances, leading to seizures, which is an uncontrolled electrical activity in the brain.",Review,0 (0.5),"In the Epilepsy GCEP meeting, we decided that we do not need this evidence.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5146494e-71e7-4e06-b10f-cc126429e3fb-2022-11-07T200000.000Z,1109,PubMed:33735526 +Human-induced pluripotent stem cell-derived cardiomyocytes,Functional Alteration Patient cells,"El-Battrawy I, et al., 2018, PMID: 29574456",Increased rapidly activating delayed rectifier potassium channel current (IKr) density and shortened action potential duration,Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6b033c3f-04de-4806-a9f3-0b318082b32e-2020-08-03T160000.000Z,1115,PubMed:29574456 +Wangemann,Expression B,"Wangemann P, et al., 2004, PMID: 15320950","SLC26A4-null mice, which had EVA and were deaf, lacked KCNJ10 protein in the stria vascularis, however Kcnj10 mRNA were present. This was reported to result in loss of endocochlear potential",Score,0 (0.5),This is not scored because it is a weak argument for the interaction of KCNJ10 and SLC26A4.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_09f81c95-1213-4029-a6bd-279e52f240c7-2018-02-20T170000.000Z,1117,PubMed:15320950 +Whole-cell patch-clamp,Functional Alteration Non-patient cells,"El Harchi A, et al., 2009, PMID: 19285083",Augmentation of outward current,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9111653a-7d9c-4d0e-94d9-daaa208a0b05-2020-10-27T160000.000Z,1123,PubMed:19285083 +Kcnma1 knockout (BK KO) mice,Model Systems Non-human model organism,"Yao Y, et al., 2022, PMID: 35095492","The phenotype in the knockout mouse model recapitulates the phenotype in humans with autosomal recessive KCNMA1 disorders, including seizures, developmental delay, EEG abnormalities. The knockout mouse model is also suspected to have cognitive impairment, although further research would be needed to confirm these findings",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9aabc05e-8452-4b72-bd07-ae1a1fc40dfc-2022-03-08T114915.435Z,1128,PubMed:35095492 +KCNQ1 -/- Rescue,Rescue Non-human model organism,"Chang Q, et al., 2015, PMID: 26084842","Conducted ABR testing and found that the varial constructs were able to rescue the hearing in the mice. They also monitored circling behavior, head tilt and swimming ability of injected mice and concluded that ""deafness phenotypes were rescued"".",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_2cb5cd32-6663-48bc-b8b0-3b9ca34e2cb7-2017-12-19T050000.000Z,1129,PubMed:26084842 +Cochlear expression of KCNQ1,Expression A,"Chang Q, et al., 2015, PMID: 26084842",Used immunolabeling in WT mice to show that there was KCNQ1 expresssion and also showed that the KCNQ1 -/- mice did not have any expression of KCNQ1,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_2cb5cd32-6663-48bc-b8b0-3b9ca34e2cb7-2017-12-19T050000.000Z,1129,PubMed:26084842 +Whole-cell patch-clamp,Functional Alteration Non-patient cells,"Wu ZJ, et al., 2015, PMID: 26346102",Increase in peak current density and deactivation shift,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5000dde0-156c-45b0-87db-35a935c69cb7-2020-10-27T160000.000Z,1130,PubMed:26346102 +Whole-cell patch-clamp,Functional Alteration Non-patient cells,"Lee HC, et al., 2017, PMID: 29213224",Acceleration of channel activation and slowing of deactivation,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5000dde0-156c-45b0-87db-35a935c69cb7-2020-10-27T160000.000Z,1130,PubMed:29213224 +S3 mutations and channel function,Functional Alteration Non-patient cells,"Eldstrom J, et al., 2010, PMID: 20421371","IKs made up from D202H mutants showed smaller currents with a similar activation +time course to WT over the physiological range of voltages. The activation time constants did not decrease significantly at more positive potentials,unlike WT (Fig. 3 B), and this was accompanied by a positive shift in the V1/2 of activation of 17 mV from WT. The combination of the positive displacement of the activation relationship and the lower overall expression resulted in much reduced peak currents in D202H in the physiological +range of plateau potentials, 0 and +20 mV. +The D202H mutation accelerated the rate of channel deactivation compared with WT.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_dff8874e-98a1-472b-9cc2-3f441b1c1064-2018-09-25T040000.000Z,1131,PubMed:20421371 +Functional study for Y266C,Functional Alteration Non-patient cells,"Yang ND, et al., 2022, PMID: 35857840",The antiepileptic drug retigabine rescued KCNQ3 currents that were abolished suggesting that modulating the E-M coupling in KCNQ channels presents a potential strategy for antiepileptic therapy.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_875415b6-877e-4a99-8591-f3de963a7920-2023-08-01T170000.000Z,1137,PubMed:35857840 +HEK293 dominant negative on WT channel,Functional Alteration Non-patient cells,"Gao Y, et al., 2013, PMID: 23750663","Cell surface expression, but not conductance, could be rescued by overexpression of a gene that controls KCNQ4 biogenesis",Score,1 (0.5),1 point given for strong functional evidence,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_88196c6d-4bd7-4aff-ba98-c7b4411c562d-2017-11-21T170000.000Z,1138,PubMed:23750663 +zebrafish KCNQ4 homolog expression,Expression A,"Wu C, et al., 2014, PMID: 24555524",Zebrafish found to have two KCNQ4 homologs that produce distinct mRNAs. Expression was detected in the ear,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_88196c6d-4bd7-4aff-ba98-c7b4411c562d-2017-11-21T170000.000Z,1138,PubMed:24555524 +KCNT1 Gain-of-Function Mouse Model of Childhood Epilepsy,Model Systems Non-human model organism,"Shore AN, et al., 2020, PMID: 33113364",The pattern of motor cortex hyperexcitability and early-onset seizures provide a phenotype that is strikingly similar to those of human patients.,Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_f1fe70b9-1f8b-4fbf-b79f-9f05dfbcf01c-2022-08-16T160000.000Z,1139,PubMed:33113364 +mouse KO model,Model Systems Non-human model organism,"Hart NS, et al., 2019, PMID: 30820446","The loss of both Kv8.2 (KCNV2) as well as Kv2.1 (KCNB1) is assessed in a KO mice. a boulbe KO mouse was also created. Only in the Kv8.2 KO mice, the b-wave is present/higher than in the other two KO mice, recapulating more or less the human abnormal electrophysiological response is.",Score,1.5 (2),"The recapitulation was not complete, therefore degraded with .5",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b260eab0-c2ff-405c-b720-c223ed6307e9-2023-09-07T160000.000Z,1140,PubMed:30820446 +KCTD7 knockout mouse model exhibits myoclonic seizures,Model Systems Non-human model organism,"Liang JH, et al., 2022, PMID: 35972048","The knockout mice exhibited spontaneous epileptiform activity lasting several seconds to 1-2 minutes, consisting of interictal multifocal fast cortical spike and polyspike discharges in 8 of 10 animals recorded. The spikes triggered episodes of single myoclonic head jerks with sudden head/shoulder drop. Behavioral myoclonic seizures were also noted with high-frequency runs of repetitive discharges with a myoclonic head drop and clonic truncal and limb movements, followed in some instances by abnormal tremor and repetitive grooming movements of the forelimbs. The mice were noted to have some gait abnormalities but did not exhibit the more pronounced ataxia or progressive features noted in humans.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e6068b08-413e-4105-b8dc-97426d64c6c4-2022-09-07T160000.000Z,1141,PubMed:35972048 +Transcirptiojnal profiling using RNA seq in PAH patients,Expression B,"Saygin D, et al., 2020, PMID: 32166015",RNA analysis showed differential expression of KDR in PAH vs control lung explants,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_07a11f06-0904-4a38-9fd3-0aec2bece699-2021-05-12T165601.478Z,1148,PubMed:32166015 +Inducible knock out,Model Systems Non-human model organism,"Winter MP, et al., 2020, PMID: 32880713","Endothelial cell-specific conditional deletion of the kinase insert domain protein receptor (kdr) gene, coding for VEGFR-2, in C57/BL6 mice (Kdr∆end) and held them in an environmental chamber with 10% FiO2 or under normoxia for 6 weeks. Kdr knockout led to a mild PH phenotype under normoxia that worsened under hypoxia. Kdr∆end mice exhibited a significant increase in pulmonary arterial wall thickness, muscularization, and VEGFR-3+ endothelial cells obliterating the pulmonary artery vessel lumen.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_07a11f06-0904-4a38-9fd3-0aec2bece699-2021-05-12T165601.478Z,1148,PubMed:32880713 +Proplatelet Formation,Rescue Patient cells,"Bariana TK, et al., 2019, PMID: 30467204",Increased proplatelet formation resulted by 24 hours for the rescued versus the non-rescued iMK. The rescue also resulted in a significant reduction in 3-ketodihydrosphingosine levels.,Score,1 (1),Aberrant size and proplatelet formation in patient megakaryocytes was was normalized upon rescue of the propositus’s iMK with a KDSR transcript carrying the reference allele. Additionally the increased level of 3-ketodihydrosphingosine in patient-derived iMKs was also normalized.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0a5d1542-feb7-4aaf-9079-55da7fb99a4a-2020-07-22T160000.000Z,1149,PubMed:30467204 +Zebrafish knockdown,Model Systems Non-human model organism,"Bariana TK, et al., 2019, PMID: 30467204","KDSR knockdown by morpholino in the zebrafish model was associated with impaired thrombocyte formation. The fish also displayed curved tails, which is a typical feature for embryos with thrombocytopenia. Additionally, there was elevated 3-ketodihydrosphingosine in the MO zebrafish.",Score,1 (2),KDSR knockdown in a zebrafish model is associated with impaired thrombocyte formation and elevated 3-ketodihydrosphingosine. This is consistent with observations in patients with thrombocytopenia however does not address the severe skin disorder also associated with KDSR.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0a5d1542-feb7-4aaf-9079-55da7fb99a4a-2020-07-22T160000.000Z,1149,PubMed:30467204 +Kif1a knockout mouse model,Model Systems Non-human model organism,"Yonekawa Y, et al., 1998, PMID: 9548721","Kif1a-mediated transport of synaptic vesicle precursor plays a critical role in viability, maintenance, and function of neurons.",Score,0.5 (2),Heterozygous knockout mice showed no obvious morphological or behavioral abnormalities. No animal behavioral assays performed.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1d586d93-7066-4db0-b623-8b7e3eafdc06-2020-09-24T134254.893Z,1153,PubMed:9548721 +Morpholino knockdown of KIF1B in zebrafish,Model Systems Non-human model organism,"Lyons DA, et al., 2009, PMID: 19503091",Antisense morpholino oligonucleotide (MO) knockdown of the common start region of kif1b and blocking a splice junction specific to kif1b β cause truncation of the posterior lateral line nerve and a reduced axonal outgrowth in spinal cord motoneurons.,Score,1 (2),Score reduced due to morpholino- instead of stable knockdown.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ae6ffeae-9609-47bf-89a9-4863cf6ef05c-2020-10-05T161930.420Z,1154,PubMed:19503091 +Fluorescent micrograph of cultured mouse hippocampal neurons,Biochemical Function B,"Xu F, et al., 2018, PMID: 30126838",Disturbances of axonal transport and reduced axonal outgrowth are typical pathomechanisms of axonal neuropathies.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ae6ffeae-9609-47bf-89a9-4863cf6ef05c-2020-10-05T161930.420Z,1154,PubMed:30126838 +KIF20A Zebrafish model,Model Systems Non-human model organism,"Louw JJ, et al., 2018, PMID: 29357359","A congenital heart defect is any heart disease present at birth. This model has several heart defects noted, suggesting that kif20a is required for proper heart function and development. This is similar to the phenotype in the humans in the paper who were were born with heart defects that progressed and resulted in their demise.",Score,0.5 (2),"The score was reduced due to the model being a zebrafish, which is not a great model for cardiomyopathies as any change may result in a cardiac phenotype. Additionally, the model phenotype was not very specific.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6933da23-6904-43da-bd0e-5a4b65ad323d-2024-06-27T160000.000Z,1155,PubMed:29357359 +KIF20A Zebrafish Rescue Model,Rescue Non-human model organism,"Louw JJ, et al., 2018, PMID: 29357359","Zebrafish were evaluated at 3dpf and those with the KIF20A WT cDNA showed approximately 20% reduction in phenotype compared to the kif20a-MO only zebrafish (p<0.05), whereas the fish injected with KIF20A R182W cDNA showed no significant difference in phenotype.",Score,0.5 (2),"Although the injection of WT KIF20A cDNA resulted in a statistically significant result, the score was reduced since WT only partially (roughly 20%) rescued the cardiac phenotype in the model.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6933da23-6904-43da-bd0e-5a4b65ad323d-2024-06-27T160000.000Z,1155,PubMed:29357359 +exogenous KIF26A corrects neuronal migration defect,Rescue Cell culture model,"Qian X, et al., 2022, PMID: 36228617",Introduction of exogenous KIF26A restores neuronal migration to wildtype levels.,Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3056587d-5d40-4bef-bac8-4e84c3f657bf-2024-03-12T190000.000Z,1157,PubMed:36228617 +KIF26A KO disrupts hiPSC-derived neurites,Model Systems Cell culture model,"Qian X, et al., 2022, PMID: 36228617","Disrupted neuronal migration observed in CRISPR-Cas9-mediated KIF26A KO hiPSC lines illustrate that normal Kif26a function is required for corpus callosum development and this dependence establishes a strong association between KIF26A LoF and the corpus callosum abnormalities seen in +patients.",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3056587d-5d40-4bef-bac8-4e84c3f657bf-2024-03-12T190000.000Z,1157,PubMed:36228617 +shRNA depletion of kif26a in mouse day E13.5 embryos,Model Systems Non-human model organism,"Qian X, et al., 2022, PMID: 36228617","migration defect and impaired localization localization, morphology, and corpus callosum development in knockdown mouse brain illustrate that normal Kif26a function is required for corpus callosum development, consistent with the agenesis of the corpus callosum seen in patients.",Score,1.5 (2),"despite demonstrated differences in development, overall morphology of the corpus callosum appeared normal in the mouse brains electroporated with Kif26a shRNA",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3056587d-5d40-4bef-bac8-4e84c3f657bf-2024-03-12T190000.000Z,1157,PubMed:36228617 +KIF26A expression in human mid-gestation fetal cortex,Expression A,"Qian X, et al., 2022, PMID: 36228617","Data from the BrainSpan Atlas of the Developing Human Brain shows KIF26A expression is enriched in the developing cerebral cortex in the first and second trimesters of embryonic development with expression decreasing rapidly entering the third trimester and becoming undetectable after birth. Single-cell RNA-seq from human GW17-18 fetal cortex shows preferential expression by migrating excitatory neurons suggesting a reduction in KIF26A expression as +cortical neurons mature after completing migration.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3056587d-5d40-4bef-bac8-4e84c3f657bf-2024-03-12T190000.000Z,1157,PubMed:36228617 +KIF5A_KO_mouse_phenotype_clinical,Model Systems Non-human model organism,"Xia CH, et al., 2003, PMID: 12682084",Progressive paralysis and weight loss are both symptoms of ALS,Score,0 (2),Full KO of gene does not properly represent variation that is thought to cause ALS.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5e7d2674-bce3-469c-b1e4-5cf57f5780a8-2022-05-26T110000.000Z,1159,PubMed:12682084 +KIF5A_KO_mouse_phenotype,Model Systems Non-human model organism,"Karle KN, et al., 2012, PMID: 22466687",Motor neuron degeneration is a feature of ALS,Score,0 (2),Full KO of gene does not properly represent variation that is thought to cause ALS.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5e7d2674-bce3-469c-b1e4-5cf57f5780a8-2022-05-26T110000.000Z,1159,PubMed:22466687 +C. elegans exon skipping,Model Systems Non-human model organism,"Nakano J, et al., 2022, PMID: 35430760",Degeneration and death of motor neurons in C. elegans with mutant KIF5A as seen in humans,Score,1 (2),Decision of GCEP to downgrade C. elegans model for ALS.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5e7d2674-bce3-469c-b1e4-5cf57f5780a8-2022-05-26T110000.000Z,1159,PubMed:35430760 +KIRREL3-/- mice display behavioral abnormalities,Model Systems Non-human model organism,"Choi SY, et al., 2015, PMID: 26283919","A battery of behavioral assays were performed on wild type littermates and Kirrel3-/- (homozygous null) mice, including open field, elevated plus maze, social novelty recognition (three chamber assay), self grooming repetitive behavior, novel object recognition, Morris water maze (spatial learning and memory), contextual fear conditioning and extinction, contextual discrimination test, buried food test, and radial arm maze. +Kirrel3-/- mice showed significant differences compared to wildtype controls in the: (1) open field, where the Kirrel3-/- mice showed hyperactivity in their familiar cage compared to WT littermates. Note that this was not observed in a novel environment. (2) novel object, in which Kirrel3-/- mice showed showed a reduced capability to recognize the new object. For all the other assays tested, the Kirrel3 -/- performed similar to the control, wildtype +littermate mice.",Score,0 (2),"The mouse model is not scored because there is no genetic evidence supporting the relationship of the gene with ID or autism, and there is no evidence that the disease mechanism is LOF (which this mouse model represents). In addition, mice studied are homozygous, whereas the variants reported in humans are heterozygous.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_55fd22eb-792f-4e84-926d-846aae0f4733-2023-11-08T170000.000Z,1163,PubMed:26283919 +Kirrel3 homozygous mouse social deficits and hyperactivit,Model Systems Non-human model organism,"Hisaoka T, et al., 2018, PMID: 29362445","wildtype and Kirrel3 -/- littermates were tested in a battery of behavioral tests including: the three-chambered social test, ultrasonic vocalizations, open field test for anxiety, repetitive behavior, rotarod, elevated plus maze, light-dark test, resident-intruder test for aggression, acoustic startle response, olfactory habituation/dishabituation test (buried food test), foot shock test for pain sensitivity, Morris water maze for spatial learning and memory, and passive avoidance test of short-term fear memory. +Kirrel3-/- mice showed significant differences (or deficits) compared to wildtype littermates in the following: (1) reduced preference for a novel mouse and (2) reduced social investigation, suggesting deficits in social investigation and recognition memory. (3) reduced ultrasonic vocalization in adult Kirrel3+/- mice when mating or same sex intruder paradigm. (4) Hyperactivity in the open field including increased rearing behavior. (5) reduced aggressive behavior towards same sex intruder mouse. (6) increased amplitude of startle response with no change in pre-pulse inhibition. +Some of these behaviors including the reduced aggression and hyperactivity are consistent with another model of Kirrel3 knockout mice.",Score,0 (2),"The experimental evidence is not scored due to a lack of compelling genetic evidence. Furthermore, this model does not provide support for a dominant disorder as the mouse model is a homozygous knockout.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_55fd22eb-792f-4e84-926d-846aae0f4733-2023-11-08T170000.000Z,1163,PubMed:29362445 +SenBanerjee Biochemical Function Experiment,Biochemical Function B,"SenBanerjee S, et al., 2004, PMID: 15136591","Proinflammatory stimuli such as cytokines induce endothelial dysfunction and lead to a proadhesive and prothrombotic phenotype. KLF2 inhibits the proinflammatory stimuli, which in turn, inhibits endothelial dysfunction.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1544c7bb-410b-4340-ab70-0bd431426c04-2022-11-03T160000.000Z,1167,PubMed:15136591 +SenBanerjee Protein Interaction Experiment,Protein Interaction,"SenBanerjee S, et al., 2004, PMID: 15136591",KLF2 induction of the eNOS promoter is dependent on DNA binding. Transient transfection studies performed in BAECs and COS-7 cells demonstrate that KLF2 but not mutant constructs (DBD–DNA binding domain; ZnF–DNA binding domain alone; KLF2ΔZnF–non-DNA binding domain) can induce the eNOS promoter.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1544c7bb-410b-4340-ab70-0bd431426c04-2022-11-03T160000.000Z,1167,PubMed:15136591 +Sindi Functional Alteration (Patient Cells) Experiment,Functional Alteration Patient cells,"Sindi HA, et al., 2020, PMID: 32132543","HPAH patients with c-terminal (p.H288Y) KLF2 mutation (n = 3) also showed a marked up-regulation of Notch4 and ETS-1 in the remodeled pulmonary vasculature, identified by endothelial vWF and a prominent α-SMA staining in the small, normally non-muscularised arterioles.",Score,0.5 (1),"The evidence provided in the paper was suggestive, not definitive. The data that was provided in the graph had no p-value, which suggested a data trend only.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1544c7bb-410b-4340-ab70-0bd431426c04-2022-11-03T160000.000Z,1167,PubMed:32132543 +Sindi Biochemical Function Experiment,Biochemical Function B,"Sindi HA, et al., 2020, PMID: 32132543","Endothelial damage followed by proliferation of vascular endothelial and smooth muscle +cells underlie the disease pathology and hypoxia and inflammation are known contributory factors. Formation of angioobliterative vascular lesions, driven by vascular endothelial growth factor (VEGF), is a hallmark of severe PAH.",Score,1 (0.5),"This particular experiment was very comprehensive, as it covered three different experimental conditions (hypoxia, TNF-stimulation, and VEGF-stimulation) and three gene functions (apoptosis, NFkB activity, and cell proliferation).",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1544c7bb-410b-4340-ab70-0bd431426c04-2022-11-03T160000.000Z,1167,PubMed:32132543 +Lu et al. Biochemical function of KMO in KP pathway,Biochemical Function B,"Lu Y, et al., 2020, PMID: 32148781","KMO normally functions to convert L-kynurenine to 3-hydroxy-L-kynurenine using NADPH. Loss of KMO function shunts the kynurenine pathway towards either kynurenine acid (KYNA) catalyzed by kynurenine aminotransferase (KAT) or anthranilic acid (AA) catalyzed by KYNU. The resulting phenotypes from complete loss of KMO are not well understood. KMO may play a role in a number of neurological disorders including schizophrenia. Indeed, patients with schizophrenia display a significant reduction in KMO gene expression. However, inhibition of KMO is also a candidate therapeutic for other disorders such as Alzhiemer's disease, Parkinson's disease, and acute pancreatitis.",Score,1 (0.5),Upscored to 1 point given the role of KMO in the KP pathway in tryptophan catabolism is well characterized and understood,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_47847642-c495-43ac-92d4-854ecdd773ba-2023-05-12T160000.000Z,1172,PubMed:32148781 +Knock-down of KMT2C ortholog in Drosophila,Model Systems Non-human model organism,"Koemans TS, et al., 2017, PMID: 29069077",Functional evidence shows trr is important for the normal function of short term memory in flies.,Score,0.5 (2),"Functional evidence downgrade to 0.5 for non-mammalian system, observed phenotypes in flies can be difficult to translate into human characteristics.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e1dcdd6c-30e0-4d06-8df5-f120b1b02477-2022-03-02T170000.000Z,1175,PubMed:29069077 +KMT2C is part of the COMPASS complex,Protein Interaction,"Lavery WJ, et al., 2020, PMID: 31924266","KMT2C is a subunit of the core nuclear regulatory structure known as KMT2C/D COMPASS complexes (COMPASS complex stands for complex of proteins associating with Set1), which methylate the histone 3 lysine 4, and regulate gene expression. COMPASS complexes contain one of the two lysine demethylases KDM6A and KDM6B (also known as UTX and JMJD3, respectively). Mutations in UTX (OMIM 300128) are associated with Kabuki syndrome 2 (OMIM 300867). Physical interaction is supported by immunoprecipitation of endogenous KMT2C, and immunoblot with the core COMPASS subunit RBBP5 and UTX [PMID: 29785026].",Score,0.5 (0.5),KTM2C directly interacts with proteins such as UTX with implications in intellectual disability. Impaired intellectual development was reported in 93% of 80 patients with pathogenic KDM6A variants and diagnosed with Kabuki syndrome [PMID: 33674768].,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e1dcdd6c-30e0-4d06-8df5-f120b1b02477-2022-03-02T170000.000Z,1175,PubMed:31924266 +Biochemical function 1,Biochemical Function A,"Stessman HA, et al., 2017, PMID: 28191889","KMT5B as one of a group of epigenetic modifier genes that are critical for typical neurodevelopment, such as EHMT1 and ARID1B, which are associated with Kleefstra syndrome (OMIM: 610253) and Coffin-Siris syndrome (OMIM: 135900). KMT enzymes (KMT5A, B, anc C) play an epigenetic role by acting as histone methyltransferases and 'writing' H4K20 methylation marks. Another gene family of H4K20 writers, the NSD family, are also associated with neurodevelopmental disorders (NDD): NSD1: Sotos syndrome andNSD2: Wolf-Hirschhorn syndrome. De novo variants have also been identified among individuals with NDD for many of the other writers, erasers and readers of the H4K20 mark (Table S1, which includes cited PMIDs to support the associations).",Score,0.5 (0.5),Shares a function with other genes associated with neurodevelopmental disorders.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_885d56b0-a2b0-4a3d-9f11-4034298e074e-2022-04-08T072351.945Z,1177,PubMed:28191889 +Drosophila model,Model Systems Non-human model organism,"Stessman HA, et al., 2017, PMID: 28191889","Knockdown flies were subjected to an ASD- and ID-relevant behavioral assay measuring light-off jump habituation, which has been shown to be affected in a number of ASD- or ID-related Drosophila models. The KMT5B knockdown flies were overall healthy but showed specific and significant habituation deficits (Fig. 5a,c). Habituation defects following knockdown of fly homologs were observed for several other genes significantly enriched for de novo variant in neurodevelopmental disorder cohorts, including SYNGAP1, GRIN2B, and SRCAP (Fig. 5c, Supplementary Table 23) as well as for genes with borderline significance (NCKAP1, WDFY3, and GIGYF2; Fig. 5c, Supplementary Table 23).",Score,0.5 (2),"Fly KMT5B knockdown model shows impaired habituation in behavioral assay, similar to other genes associated with neurodevelopmental disorders. Reduced points since it is a lower model organism and phenotype not highly specific.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_885d56b0-a2b0-4a3d-9f11-4034298e074e-2022-04-08T072351.945Z,1177,PubMed:28191889 +Eve and Smith 2017 zebrafish KD,Model Systems Non-human model organism,"Eve AMJ, et al., 2017, PMID: 29417095","Lamc3 is enriched in endothelial cells during zebrafish development, but it is also expressed by other tissues (Figure 1). Antisense morpholino oligonucleotides or CRISPR/Cas9 were used to create zebrafish F0 embryos in which lamc3 expression is compromised. Transgenic imaging, immunofluorescence, and in situ hybridisation reveal that Lamc3 loss-of-function affects the development of muscle pioneers, endothelial cells, and motoneurons. Lamc3 knockdown embryos (n=10) show a reduction in γ3 protein in the vasculature and horizontal myoseptum (Figure 2b). These embryos lacked a parachordal chain (PAC) formation (Figure S3C). The parachordal chain is the source of lymphatic endothelial cells that form the thoracic duct. Accordingly, thoracic duct development was also affected in knockout embryos (Fig 2M,N,O,P). CRISPR/Cas9 genetically modified F0 embryos recapitulate the MO knockdown phenotype (Fig 3).",Review,0 (2),"Not relevant for autism, and possible mechanism of disease not established.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0ff89702-c97e-4ef9-91ce-2e37b66efd84-2020-09-01T160000.000Z,1184,PubMed:29417095 +LAS1L Interaction with Genes to Regulate Ribosome Biogenesis,Protein Interaction,"Castle CD, et al., 2012, PMID: 22190735","LAS1L complexes purified from HEK293T cells - to identify interacting proteins using a proteomic approach. The authors demonstrate that LAS1L interacts with PELP1, TEX10, and WDR18, the mammalian homologues of the budding yeast Rix1 complex, along with NOL9 and SENP3, to form a novel nucleolar complex that cofractionates with the 60S preribosomal subunit.",Score,0 (0.5),The ID/Autism GCEP has decided not to score this line of evidence because there is no mention DD/ID/autism.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c5b85dbb-3d49-4924-8294-e518ff56f048-2021-09-21T160000.000Z,1187,PubMed:22190735 +Subretinal AAV8-hLCA5 rescue,Rescue Non-human model organism,"Uyhazi KE, et al., 2020, PMID: 32428231","The Lca5gt/gt mouse has a similarly severe and rapid photoreceptor degeneration comparing to human patients. The ONL became progressively thinner and was undetectable by P60. Rod- and cone-mediated ERGs were severely reduced in amplitudes at P30 and became nondetectable by P60. Subretinal AAV8-hLCA5 administered to Lca5gt/gt mice at P5 and P15, but not at P30, resulted in structural and functional rescue.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ece57d88-4307-420a-aedb-4b5900248ea1-2021-10-07T160000.000Z,1191,PubMed:32428231 +J14 reconstitution,Functional Alteration Non-patient cells,"Lev A, et al., 2023, PMID: 36474126","reduced MAPK signaling, CD69 upregulation and Ca flux following TCR stimulation",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3f14a481-2d4c-4cd0-a930-03db5bff6b9b-2024-02-15T180000.000Z,1193,PubMed:36474126 +Immunoprecipitation ZASP,Expression A,"Faulkner G, et al., 1999, PMID: 10427098",Immunoprecipitation experiments showed ZASP is expressed in both fetal and adult hearts. Myosin was used as the control.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7756e3c0-5a16-49b8-ac0f-220e79a4fa99-2020-09-25T160000.000Z,1194,PubMed:10427098 +Yeast two hybrid screen ACTN2,Protein Interaction,"Faulkner G, et al., 1999, PMID: 10427098",Yeast two hybrid screen found 23 clones with fragments of the ACTN2 gene. The only other seven clones were false positives (mitochondrial genes and transcription factors).,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7756e3c0-5a16-49b8-ac0f-220e79a4fa99-2020-09-25T160000.000Z,1194,PubMed:10427098 +Northern and Western Blot,Expression A,"Faulkner G, et al., 1999, PMID: 10427098",Northern blot analysis revealed LDB3 is expressed in the heart and skeletal muscle. Western blot analysis was also consistent with this finding.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7756e3c0-5a16-49b8-ac0f-220e79a4fa99-2020-09-25T160000.000Z,1194,PubMed:10427098 +Cypher KO mice,Model Systems Non-human model organism,"Zhou Q, et al., 2001, PMID: 11696561",Knockout mice developed dilated left and right ventricles with abnormal histology consistent with DCM.,Score,1 (2),Human data has shown a heterozygous phenotype while this experimental data is only for knockout of both alleles.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7756e3c0-5a16-49b8-ac0f-220e79a4fa99-2020-09-25T160000.000Z,1194,PubMed:11696561 +Pull down Assay Cypher and ACTN2,Protein Interaction,"Zhou Q, et al., 2001, PMID: 11696561","The authors introduced mutations within the PDZ domain via PCR-based mutagenesis. +""Mutant PDZ domains, and a control wild-type PDZ domain were fused to GST, and pull-down assays were performed to evaluate the interaction between mutant PDZ domains and -actinin 2. Mutation of either L76 or L80 to K significantly reduced binding of the Cypher PDZ domain to - actinin 2, and mutation of L78 to K completely abolished the binding."" +For part 2, the authors introduced mutations into the EF hands of ACTN2. ""Results from GST pull down assays demonstrated that EF3–4, containing the last two EF hands, retained the ability to bind to the PDZ domain, whereas EF1–2, lacking the last two EF hands, 4EF-del3, and -actinin 2-del3, lacking only the last three amino acids, no longer bound the PDZ domain.""",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7756e3c0-5a16-49b8-ac0f-220e79a4fa99-2020-09-25T160000.000Z,1194,PubMed:11696561 +LDLR function to internalize LDL from plasma,Biochemical Function B,"Benito-Vicente A, et al., 2018, PMID: 30388787","Hypercholesterolemia is caused by excess amounts of low density lipoprotein (LDL) in plasma. LDL and cholesterol clearance occurs through the binding and internalization of LDL in the liver. Low density liproprotein receptor (LDLR) is one of the protein responsible for binding and internalizing LDL, thus perturbation of its function would be expected to, and in fact does, lead to increased cholesterol in plasma.",Score,1 (0.5),"Due to the amount of data, understanding of the mechanism, and repeated confirmations of the biochemical and metabolic pathway, the points have been increased.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_81788cfe-7520-4821-b80b-3ee0b2018909-2021-02-24T170000.000Z,1196,PubMed:30388787 +Knock out Mouse,Model Systems Non-human model organism,"Chabrol E, et al., 2010, PMID: 20659958","Created KO mice with deletion exons 6-7 and confirmed by Western blot. Homozygous KO mice developed frequent spontaneous seizures, some with tonic clonic seizures. Heterozygotes did not show spontaneous seizure activity but did mimic ADLTE. At age postnatal day 28, auditory stimulation induced seizures in a significantly higher percentage of LGI1+/− than wild-type littermates (52% versus 18%, P < 0.03) (Fig. 6A). Typically, audiogenic seizures began suddenly at 5–20 s after the onset of the tone, with wild running, followed by a tonic phase and sudden death in 23% of mice.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_662936d4-11a7-43f3-9daf-4ba1a7c92ffe-2020-07-07T183907.849Z,1200,PubMed:20659958 +Gene therapy in a mouse model,Rescue Non-human model organism,"Lam P, et al., 2022, PMID: 36092360","Treatment dramatically lowered hepatosplenomegaly, liver and spleen triglyceride and cholesterol levels, and serum expression of markers of liver damage. Measures of liver inflammation and fibrosis were also reduced and reduced LAL activity was corrected.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1691be18-3aa2-46e7-b6a6-e7acafb9f998-2023-04-28T160000.000Z,1207,PubMed:36092360 +LIPT1 transfection in pt and ctrl FCL,Rescue Patient cells,"Soreze Y, et al., 2013, PMID: 24341803","""PDH and α-KGDH activities increased moderately after LIPT1 transfection (PDH: 90 and 93 to 210 and 215 pmoles/min/mg protein; α-KGDH: 0.9 to 3 nmoles/min/mg protein). "" +""Lactate (L) and pyruvate (P) levels were significantly increased in fibroblast supernatants compared to controls and they were dramatically decreased after LIPT1 transfection (Figure 2A-B).""",Score,1 (1),"Rescue in patient cells, default score. Patient met criteria for LSS.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_55d66b81-fe31-4965-b5fc-483393af820d-2021-04-09T142912.496Z,1208,PubMed:24341803 +Biochemical parameters - pt fibroblast enzyme activities,Functional Alteration Patient cells,"Soreze Y, et al., 2013, PMID: 24341803","α-KGDH (patient: 900 pmol/min/mg protein; control 7000) +PDH (patient: 90 mol/min/mg protein; control 1117) +reduced oxygen production using pyruvate as substrate (2.2 nmol O2/min/mg of protein, reference range from 3.3 to 6.8 nmol) by polarography; low CO2 production by the +Krebs cycle and mitochondrial respiratory chain after administration of fatty acid, ketone body, and glucose (showing Krebs cycle and PDC defect",Score,2 (1),"Performed in cells from patient meeting all criteria for Leigh syndrome spectrum phenotype, also directly correlated with known enzyme function",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_55d66b81-fe31-4965-b5fc-483393af820d-2021-04-09T142912.496Z,1208,PubMed:24341803 +Leigh map,Biochemical Function A,"Rahman J, et al., 2017, PMID: 27977873",Table 1,Score,0.5 (0.5),1 gene product associated with Leigh syndrome spectrum (LIAS),https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_55d66b81-fe31-4965-b5fc-483393af820d-2021-04-09T142912.496Z,1208,PubMed:27977873 +Lipt1N44S/N44S mice (prenatal lethal),Model Systems Non-human model organism,"Ni M, et al., 2019, PMID: 31042466","0.5 points: embryonic lethal, found to die between 10.5 dpc and 11.5 dpc (""Initially, breeding between heterozygous Lipt1N44S/+ mice failed to yield any viable homozygous Lipt1N44S/N44S mice (260 pups from >25 litters) (Figure 3A). About 70% of the progeny were heterozygous for N44S and the rest were homozygous WT, consistent with prenatal loss of Lipt1N44S/N44S embryos."") +0.5 points: biochemical deficiency (""Immunoblotting [of 10.5 dpc embryos] revealed defective lipoylation of both PDH and AKGDH in the Lipt1N44S/N44S embryos, although LIPT1 protein was expressed in all genotypes (Figure 3C). Lipt1N44S/N44S embryos also had decreased PDH activity compared to Lipt1+/+ and Lipt1N44S/+ embryos (Figure 3D). +0.5 points: growth retardation (""Lipt1N44S/N44S embryos collected at 10.5 dpc were pale and small compared to Lipt1+/+ or Lipt1N44S/+ littermates (Figure 3B)."")",Score,1.5 (2),"1.5 points per mito GCEP scoring guidance +0.5 points: embryonic lethal, found to die between 10.5 dpc and 11.5 dpc (""Initially, breeding between heterozygous Lipt1N44S/+ mice failed to yield any viable homozygous Lipt1N44S/N44S mice (260 pups from >25 litters) (Figure 3A). About 70% of the progeny were heterozygous for N44S and the rest were homozygous WT, consistent with prenatal loss of Lipt1N44S/N44S embryos."") +0.5 points: biochemical deficiency (""Immunoblotting [of 10.5 dpc embryos] revealed defective lipoylation of both PDH and AKGDH in the Lipt1N44S/N44S embryos, although LIPT1 protein was expressed in all genotypes (Figure 3C). Lipt1N44S/N44S embryos also had decreased PDH activity compared to Lipt1+/+ and Lipt1N44S/+ embryos (Figure 3D). +0.5 points: growth retardation (""Lipt1N44S/N44S embryos collected at 10.5 dpc were pale and small compared to Lipt1+/+ or Lipt1N44S/+ littermates (Figure 3B)."")",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_55d66b81-fe31-4965-b5fc-483393af820d-2021-04-09T142912.496Z,1208,PubMed:31042466 +Pt cells transduced with vectors expressing WT,Rescue Patient cells,"Ni M, et al., 2019, PMID: 31042466","Phenotype prior to rescue: Compared to five normal controls, patient’s fibroblasts had lower levels of lipoylation on both proteins (the lipoylated E2 subunits of the PDH (DLAT) and AKGDH (DLST) complexes), whereas total DLAT, DLST, and LIPT1 were similar. +WT LIPT1 increased lipoylation of both DLAT and DLST. +Ectopic expression of WT LIPT1 more than doubled PDH activity (neither of the mutants had this effect).",Score,1 (1),1 is default. No additional evidence to up-weight.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_55d66b81-fe31-4965-b5fc-483393af820d-2021-04-09T142912.496Z,1208,PubMed:31042466 +LITAF Δ114–139 shows Mislocalization and Decreased Stability,Functional Alteration Non-patient cells,"Ho AK, et al., 2016, PMID: 27927196","The altered LITAF constructs showed mislocalization in the soluble fraction as opposed to the membrane pellets after fractionation. The LITAF altered constructs also displayed a decreased ability to coordinate zinc atoms and therefore was more succeptible to improper folding. Removing this domain also caused the wild-type's interaction with PE-head groups to decrease in the mutant leading to protein instability. The V144M mutant construct also decreases the protein's stability significantly, pointing towards misfolding and deleterious effects on intracellular membranes.",Score,0.5 (0.5),"This experiment shows a clearly altered protein when the hydrophobic helical region or the known pathogenic mutant V144M is expressed in the cells. This altered stability and mislocalization can lead to dysfunctional membrane trafficking and eventually to the phenotypes observed in CMT1. Therefore, this evidence earns default points.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e7106097-314c-487a-9770-b7dea3f25f37-2020-04-07T160000.000Z,1209,PubMed:27927196 +LITAF as an Integral Membrane Component,Biochemical Function B,"Ho AK, et al., 2016, PMID: 27927196","According to PMID:31173589, many schwann cell proteins responsible for maintaining the stability and function of compact myelin have variants that can cause Charcot-Marie-Tooth disease or other related neuropathies. Without the ability to functionally transmit materials or form the proper structures in the schwann cells, myelin sheaths can begin degrading and cause the phenotypes that we observe in CMT Type 1.",Score,0.5 (0.5),"Since the predicted function of LITAF as a membrane trafficking protein with disrupted function could feasibly cause the phenotypes we see in CMT1, this evidence earns default points.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e7106097-314c-487a-9770-b7dea3f25f37-2020-04-07T160000.000Z,1209,PubMed:27927196 +ABCD4 Accessory Protein,Biochemical Function A,"Kawaguchi K, et al., 2016, PMID: 27456980","LMBD1 associates with ABCD4 on the ER membranes and supports the translocation of ABCD4 to lysosomes. Membrane-bound LMBD1 and ABCD4 are hypothesized to facilitate the vectorial delivery of lysosomal vitamin B(12) to cytoplasmic MMACHC, thus preventing cofactor dilution to the cytoplasmic milieu and protecting against inactivating side reactions. If either protein is deficient then delivery is disrupted leading to methylmalonic aciduria and homocystinuria similar to the MMACHC associated methylmalonic aciduria and homocystinuria type cblC.",Score,1.5 (0.5),"LMBRD1 function in transport of ABCD4 for delivery of lysosomal vitamin B(12) to cytoplasmic MMACHC is consistent with the elevated methylmalonic acid and homocysteine, which are the biochemical hallmarks of this disorder.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_14c077fe-c0ff-43d5-8436-041db18b20b1-2021-03-26T160000.000Z,1211,PubMed:27456980 +PB-Mutated LMOD3 KO Mice,Model Systems Non-human model organism,"Tian L, et al., 2015, PMID: 26035871","The homozyogus mutants from this mouse model display a marked similarity to the phenotypes exhibited by patients with this disorder. The primary phenotype, the presence of nemaline bodies combined with the disorganized sarcomeric structure, is directly reflected in the model. The muscle weakness is also almost always present in the human probands, indicating that the loss of function from the LMOD3 gene is related to the disorder.",Score,2 (2),"The nemaline bodies and muscle weakness recapitulate the phenotype of the nemaline myopathy with relatively high accuracy. Combined with the disorganized sarcomeric structure, it seems clear that the loss of function in LMOD3 is related to the appearance of these signs in the mice. Thus, this model earns default points.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_af248a78-5ef6-4c0b-b174-f43cc4688ec9-2019-09-09T160000.000Z,1215,PubMed:26035871 +KO Mouse model,Model Systems Non-human model organism,"De Gaetano A, et al., 2020, PMID: 32521756","The homozygous Lonp-/- mouse is embryonic lethal at day 7.5 p.c. +Characterisation of the heterozygous mouse: +Het mice show no gross phenotypic abnormalities(fig1) MtDNA levels were also similar between WT and het mice +Fig 3. EM analysis of enterocytes showed structurally abnormal mitochondria in the heterozygous mice, mitochondria were swollen, on average longer and with less organised cristae. +Fig 4, MEFs: The ultrastructure analysis revealed an increased number of mitochondria in heterozygous MEFs compared with wildtype MEFs. +Using glucose free galactose media, Basal and non-mitochondrial oxygen consumption were significantly lower in het cells, while maximal respiration, despite lower than controls, did not reach statistical significance (Figure 7B and Figure 7 C). +Figure 7D demonstrates than expression of respiratory complexes was reduced in the heterozygous MEFs, activity of specific complexes was not assessed.",Score,0.5 (2),Scored 0.5 for embryonic lethality (default).,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3da0a308-3a7e-4101-b40b-1f23db106aea-2021-04-09T140215.539Z,1217,PubMed:32521756 +Phosphatidic acid phosphatase activity,Functional Alteration Patient cells,"Pelosi M, et al., 2017, PMID: 28986436",Reduced phosphatidic acid phosphatase activity in patients' cells compared to controls,Score,0.5 (1),In adipose tissue not muscle,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_642c8d4a-d498-4739-957d-a4e0d457362a-2018-09-25T160000.000Z,1219,PubMed:28986436 +Lipin-1 protein levels in adipose tissue,Expression B,"Pelosi M, et al., 2017, PMID: 28986436",Reduced Lipin-1 protein levels in samples from patients with LPIN1 pathogenic variants by western blot (Figure 4A).,Review,0 (0.5),In adipose tissue not muscle,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_642c8d4a-d498-4739-957d-a4e0d457362a-2018-09-25T160000.000Z,1219,PubMed:28986436 +Lorden P2X7 receptor activation,Biochemical Function B,"Lordén G, et al., 2017, PMID: 28031477","Systemic inflammation via fevers, elevated acute phase reactants; increased inflammsome activity",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6ebe7cb7-3855-465d-ab11-dcde27f1e737-2024-05-15T160000.000Z,1220,PubMed:28031477 +Bhuyan 2021 Pit Assay,Model Systems Cell culture model,"Bhuyan F, et al., 2021, PMID: 33314777",Patients with Majeed experience sterile osteomyelitis due to altered osteoclastogenesis. Pit assay demonstrated increased bone resorption in cells from patients with Majeed syndrome.,Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6ebe7cb7-3855-465d-ab11-dcde27f1e737-2024-05-15T160000.000Z,1220,PubMed:33314777 +Bhuyan 2021 Osteoclast Differentiation,Functional Alteration Patient cells,"Bhuyan F, et al., 2021, PMID: 33314777",More osteoclasts were produced in patient/Majeed cells compared to healthy control,Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6ebe7cb7-3855-465d-ab11-dcde27f1e737-2024-05-15T160000.000Z,1220,PubMed:33314777 +Bhuyan 2021 Monocyte IL-1B expression,Functional Alteration Patient cells,"Bhuyan F, et al., 2021, PMID: 33314777","Increased Il-1B production in majeed cells compared to healthy controls. Additionally increased CXCL1, TNF, CCL2, CXCL10 in M2 (mediators of osteoclastogenesis)",Score,1 (1),Need to add large deletion as well; since patient cells were used and this is a compound heter patient,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6ebe7cb7-3855-465d-ab11-dcde27f1e737-2024-05-15T160000.000Z,1220,PubMed:33314777 +Baggio Drosophila KD model,Model Systems Non-human model organism,"Baggio F, et al., 2014, PMID: 25428350",biochemical/mitochondrial dysfunction and growth retardation (early death),Score,1 (2),Biochemical/mitochondrial dysfunction (0.5) and growth retardation (early death) (0.5) in Drosophila co-ortholog KD model. Scored according to GCEP rubric.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_79691365-1911-423c-ab14-73a1f509ed22-2019-12-19T190157.942Z,1225,PubMed:25428350 +Burelle functional alteration patient cells,Functional Alteration Patient cells,"Burelle Y, et al., 2015, PMID: 25835550","Characterized mitochondrial dysfunction in fibroblasts from patients with the French Canadian type of Leigh syndrome. Despite maintaining normal ATP levels (Fig. 1), LSFC fibroblasts present several mitochondrial functional abnormalities under normal baseline conditions, which likely impair their capacity to respond to stress. This includes reduced COX enzyme activity (Fig. 1F), mitochondrial network fragmentation, impaired oxidative phosphorylation capacity, and lower membrane potential (Fig. 2). Increased sensitivity to Ca2+-induced permeability transition but no changes in reactive oxygen species production were also observed. LSFC fibroblasts also display enhanced susceptibility to cell death when exposed to palmitate, an effect that is potentiated by high lactate, while high glucose or acidosis alone or in combination were neutral (Fig. 3).",Score,1 (1),Evidence of mitochondrial dysfunction in patient cells.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_79691365-1911-423c-ab14-73a1f509ed22-2019-12-19T190157.942Z,1225,PubMed:25835550 +Olahova functional alteration patient cells,Functional Alteration Patient cells,"Oláhová M, et al., 2015, PMID: 26510951","Steady-state levels of LRPPRC in patients’ fibroblasts and muscle protein extracts were evaluated by western blot analysis and confirmed a marked decrease in the steady-state levels of LRPPRC protein compared to age-matched controls (Fig. 3A).Mitochondrial protein extracts from muscle of Patient 2 also showed a marked decrease in the steady-state levels of the mutant LRPPRC protein (Fig. 3B). A significant decrease in basal oxygen consumption rate was observed in Patient 2 fibroblasts compared to the control cell line (Fig. 4A). Steady-state protein levels of subunits of mitochondrial respiratory chain complexes in LRPPRC patient samples were analysed by SDS-PAGE and immunoblotting. Homozygous mutant LRPPRC (Patients 1 and 2) fibroblasts showed an almost complete loss of mitochondrial (COXI and COXII) and nuclear-encoded (COXIV) subunits of Complex IV (Fig. 5A). The steady-state levels of Complex I subunit proteins NDUFB8, NDUFA9 and NDUFA13 were also decreased in Patient 2 fibroblasts. Consistent with the reduced steady-state levels of Complex IV subunits in LRPPRC patient fibroblasts, mitochondrial protein extracts from muscle homogenates also revealed a significant decrease in the steady-state levels of COXI and COXII (Fig. 5B). In addition, slightly decreased levels of Complex I subunit proteins NDUFB8 and NDUFA9 were found in LRPPRC patients’ muscle homogenates, whilst the levels of Complex V and Complex III subunits remained unchanged (Fig. 5B). The assembly of OXPHOS complex subunits into mitochondrial respiratory chain complexes was subsequently analysed by blue native PAGE in LRPPRC patient fibroblasts and skeletal muscle. Blue native PAGE analysis showed a slight decrease of fully assembled Complex IV in Patient 1 and 2 fibroblasts and an almost complete lack of Complex IV in the muscle of Patient 2 (Fig. 5C). Patient muscle homogenates displayed decreased levels of Complex I, similar to previously published studies (Fig. 5C). Fibroblast and muscle samples from patients also showed decreased steady-state levels of mitochondrial mRNA transcripts (MTCO1, MTCO2, MTND1 and RNA14) (Fig. 6A). Pulse labelling experiments showed a mild decrease in synthesis of COX1 in patients 1 and 2 (Fig. 6C).",Score,1 (1),Evidence of mitochondrial dysfunction in homozygous patient cells.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_79691365-1911-423c-ab14-73a1f509ed22-2019-12-19T190157.942Z,1225,PubMed:26510951 +Leigh map,Biochemical Function A,"Rahman J, et al., 2017, PMID: 27977873","According to Leigh Map, LRPPRC is one of 13 nuclear genes involved in mitochondrial translation (Table 2).",Score,1.5 (0.5),scored in accordance with GCEP rubric,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_79691365-1911-423c-ab14-73a1f509ed22-2019-12-19T190157.942Z,1225,PubMed:27977873 +LRRC10 Mouse Model,Model Systems Non-human model organism,"Brody MJ, et al., 2012, PMID: 23236519",Beginning at 1 month of age the mice developed left ventricular enlargement and fractional shortening which are both signs of DCM in humans.,Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7403d325-ff12-4c92-a308-b2054e9861c5-2020-09-04T160000.000Z,1226,PubMed:23236519 +Pull Down experiment ACTC1,Protein Interaction,"Brody MJ, et al., 2012, PMID: 23236519",Pulled down protein with immunoblotting showed co-localization with alpha actin.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7403d325-ff12-4c92-a308-b2054e9861c5-2020-09-04T160000.000Z,1226,PubMed:23236519 +LRRC10 and actin Yeast hybrid screen,Protein Interaction,"Brody MJ, et al., 2012, PMID: 23236519",Yeast two hybrid screen indicates alpha-actinin is a binding partner for LRRC10.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7403d325-ff12-4c92-a308-b2054e9861c5-2020-09-04T160000.000Z,1226,PubMed:23236519 +quantify LRRK2 kinase pathway activity by measuring LRRK2-me,Functional Alteration Patient cells,"Fan Y, et al., 2018, PMID: 29127255",increased phosphorylation with high evidence. multiple studies have shown this effect including West et al. 2005,Score,0 (1),Results could not be confirmed by the authors for this variant in a follow-up study (https://www.medrxiv.org/content/10.1101/2021.01.28.21249614v1),https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_2728e13a-b95a-4c55-8cba-082260094ecd-2021-05-03T160000.000Z,1229,PubMed:29127255 +KO mouse mice with increased sensitivity to neurotxic agents,Model Systems Non-human model organism,"Bogdanik LP, et al., 2013, PMID: 23519028",Mice had compromised peripheral axons and therefore provide a reasonable model for human CMT2P.,Score,1 (2),"Mice were generally healthy and only show mild symptoms of peripheral neuropathy. The phenotype is mild even in aging mice. This is a LOF model with intermediate phenotypes in heterozygous mice. Nevertheless, mice lacking Lrsam1 have compromised peripheral axons and therefore provide a reasonable model for human CMT2P.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_82dac4c0-801f-4704-b59d-0a9441423d5a-2023-11-28T170000.000Z,1230,PubMed:23519028 +LRSAM1 is expressed in the nervous system,Expression A,"Bogdanik LP, et al., 2013, PMID: 23519028","Using lacZ reporter expression analysis, the authors show that Lrsam1 is expressed at a high level in peripheral motor and sensory neurons. +Lrsam1 in situ hybridization on embryonic (15.5 days post-fertilization) transverse sections revealed broad low-level expression with particular enrichment in the dorsal root ganglion (arrow) and throughout the spinal cord.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_82dac4c0-801f-4704-b59d-0a9441423d5a-2023-11-28T170000.000Z,1230,PubMed:23519028 +Overexpression rescue the cell KO phenotype,Rescue Cell culture model,"Minaidou A, et al., 2018, PMID: 29845787",growth recovery with formation of early neurites. Patient variant failed to rescue the phenotype,Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_82dac4c0-801f-4704-b59d-0a9441423d5a-2023-11-28T170000.000Z,1230,PubMed:29845787 +Impaired nerve regeneration in C698R KI mice,Model Systems Non-human model organism,"Moiseev D, et al., 2022, PMID: 35842440","Knock-in mice did not appear to differ from Lrsam1+/+ mice in appearance and body weight. No behavioral abnormalities were identified. Following crush nerve injuries, nerve regeneration was mildly impaired in the Lrsam1+/C698R mice. Additionally, in homozygous C698R mice, CV and CMAP were not significantly different from that of heterozygous C698R mice after injury.",Score,1 (2),Milder phenotype than that observed in patients with the C694R mutation. Peripheral neuropathy not seen even in older mice.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_82dac4c0-801f-4704-b59d-0a9441423d5a-2023-11-28T170000.000Z,1230,PubMed:35842440 +Kuehn_Domestic cat,Model Systems Non-human model organism,"Kuehn MH, et al., 2016, PMID: 27149523","One-hundred-forty-seven cats in an expanded pedigree were examined for ocular phenotype. No systemic or reproductive abnormalities were observed. All affected cats had bilateral mild to moderate globe enlargement. At 8wo, IOP was significantly higher in cats with PCG that unaffected cats. No signs of episcleral vascular congestion, ocular pain, intraocular inflammation were seen. Gonioscopy revealed features consistent with goniodysgenesis, supported by the extreme narrowing of the ciliary cleft. Additional clinical features noted in affected animals include prominent, elongated ciliary processes, spherophakia, iris hypoplasia and iridodonesis (iris trembling) in cats older than 4mo. Mild to pronounced optic nerve head cupping was noted in all affected cats from 6mo. In the anterior segment, a paucity of intra-scleral blood vessels, and hypoplasia of iris stroma and ciliary body, was evident at birth in affected cats. Elongation of the ciliary processes was a consistent finding in affected cats by 3 weeks of age. Uveal and corneo-scleral trabecular meshwork, angular aqueous plexus (analogous to Schlemm’s canal in human eyes), and associated vascular channels are rudimentary in affected animals and when visible, appear collapsed. They also perform pedigree analysis to show autosomal recessive inheritance.",Score,3 (2),Authors identify the causative variant (frameshift variant in exon 8 resulting in truncation of protein) for spontaneous primary congenital glaucoma in domestic cats. Increased score is awarded for recapitulation of phenotype and thorough experiments and analysis.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_8f3a9450-53ca-4e64-99c8-4cc195e851d5-2023-03-16T160000.000Z,1231,PubMed:27149523 +WT rescue in null yeast,Rescue Cell culture model,"Fernández-Vizarra E, et al., 2015, PMID: 25914718","S. cerevisiae yeast strains lacking Mzm1 (Δmzm1) show defective growth on non-fermentable carbon sources due to a defect in respiration linked to a CIII deficiency, which is much more marked at 37 °C. The human allele encoding the 104 amino acid LYRM7-001 was introduced in the Δmzm1 cells. As can be seen in Fig. 1B, human LYRM7 restored the ability of the mutant yeast strain to grow on non-fermentable media at 37 °C, as did transformation with the yeast MZM1. Another yeast protein included in the LYR motif family, SDH6 (human ortholog SDHAF1), failed to restore the growth in Δmzm1 cells.",Score,1 (1),The human protein can functionally complement the respiratory defect of a Mzm1-deleted yeast strain.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ac7b4d77-f1e5-4b7a-a7c4-e37db6c49026-2022-04-04T160000.000Z,1232,PubMed:25914718 +Zebrafish expression,Expression A,"Deml B, et al., 2015, PMID: 25719200","This was a study done in zebrafish. At 18-hpf (hours post fertilization) expression in the eye region and midbrain is clear. At 24-hpf MAB21L2 is expressed in the retina, lens, spinal cord, midbrain. At 48-72 hpf, there is expression in the inner nuclear layer, ciliary marginal zone, and ganglion cell layer of retina, and the optic fissure of the eye.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d89e935d-55fe-43f1-b2a3-d1f0eca74928-2023-07-25T160000.000Z,1234,PubMed:25719200 +Treg defect,Model Systems Non-human model organism,"Brüstle A, et al., 2017, PMID: 26405015",Mice with MALT1 deficiency show a defect in Foxp3+ regulatory T cell generation and maintenance. Patients with MALT1 deficency show a reduction in Treg cell frequency compared to control patients.,Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_537efc87-5f45-489b-9aa0-6bd3e029754e-2022-07-21T160000.000Z,1239,PubMed:26405015 +Tian Cleft Palate Rescue,Rescue Human,"Tian Q, et al., 2023, PMID: 35637269",,Score,0 (2),"This cleft palate surgery could be performed on anyone regardless of disease, so does not show that it is correction of the MAN2B2 deficiency that is driving recovery.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ccfe9ebc-087e-4cdd-bb49-9cdc1f12e3ef-2024-01-18T180000.000Z,1243,PubMed:35637269 +Tian Glycan degradation & N-Glycan Synthesis Functional 1,Functional Alteration Patient cells,"Tian Q, et al., 2023, PMID: 35637269","serum N-glycan profiles by MALDI-TOF Mass Spectromy showed increase in the under-sialylated, mono-sialylated N-glycans and Man5/Man6",Score,0 (1),Same functional data reported in Verheijen. Downscored to not double count it.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ccfe9ebc-087e-4cdd-bb49-9cdc1f12e3ef-2024-01-18T180000.000Z,1243,PubMed:35637269 +Allogeneic hematopoietic cell transplantation in MANSB,Rescue Human,"Lund TC, et al., 2019, PMID: 31115173","UCBT resulted in restored leukocyte beta-mannosidase activity, increased plasma beta-mannosidase activity, and decreased urinary oligosaccharides; and stable neurocognitive trajectory (versus neurocognitive decline seen pre-treatment)",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d70d38aa-f7e9-4c93-8160-58dec9cec010-2022-08-02T160000.000Z,1245,PubMed:31115173 +Willmann_Fibroblast rescue,Rescue Patient cells,"Willmann KL, et al., 2014, PMID: 25406581",Expression of WT-NIK reactivated non-canonical NF-κB signalling manifesting in nuclear translocation of p52.,Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3952c8fc-29f9-4c29-be1d-258bb2cd90fc-2023-07-18T180000.000Z,1248,PubMed:25406581 +heterozygous mouse knockout model,Model Systems Non-human model organism,"Gowrishankar S, et al., 2017, PMID: 28784610","MAPK8IP3 has been shown to be part of the axonal transport machinery, which is essential for the function and maintenance of neurons. It supplies the synapse with newly synthesized proteins and lipids while damaged or misfolded proteins are cleared. Defects in axonal transport can lead to progressive neuronal cell death and have initially been associated with a wide range of neurodegenerative diseases, for example hereditary spastic paraplegia, Parkinson disease, Alzheimer disease, and other forms of dementia. But certain components of the axonal transport machinery, such as the dynein +heavy chain 1 (DYNC1H1) and BICD2 have also been implicated in childhood-onset neurodevelopmental disorders comprising ID and a spectrum of malformations of cortical development (MCD), such as lissencephaly and (bilateral perisylvian) polymicrogyria. In addition, the disruption of proteins (such as CDK517 and NTRK228 [alternative name TRKB]) that directly interact with MAPK8IP3 has been shown to cause childhood-onset phenotypes of ID, lissencephaly, and cerebellar hypoplasia. Taken together, these overlapping phenotypic effects of ID and variable brain anomalies due to the disruption of other parts of the axonal transport machinery provide another line of evidence for the causal role of MAPK8IP3 in the genesis of ID and variable brain anomalies.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7af4bd87-1d3d-4e52-929f-c3893f81c38a-2022-05-22T063958.942Z,1249,PubMed:28784610 +gene expression in tissues,Expression A,"GTEx Consortium, et al., 2017, PMID: 29022597",GTex data,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7af4bd87-1d3d-4e52-929f-c3893f81c38a-2022-05-22T063958.942Z,1249,PubMed:29022597 +Drosophila model,Model Systems Non-human model organism,"Bayat V, et al., 2012, PMID: 22448145","Aats-met is the homolog for MARS2 in Drosphila with 44% identityand 75% similarity. HV and FB Drosophila mutants identified via forward genetic screen for aberrant electroretinograms are partial loss of function mutants of Aats-met. The HV mutant is homozgyous for the Aats-met c.125T>A, p.V42D change, and the FB mutant is homozygous for the c.671C>T, p.S224L change. HV/FB and HV/HV flies appear morphologically normal but have decreased life spans and inability to fly. Analysis of HV/FB flies by transmission electron microscopy revealed progressive loss of photoreceptors, degeneration of glia with lipid droplet accumulation, aberrant mitochondria and fragmented muscle. Enzyme activities of HV/Df and FB/Df flies revealed decreased complex I activity, increased citrate synthase activity, and normal complex IV activity. (Fig. 2, 3, 5).",Score,1 (2),evidence of mito dysfunction (complex I deficiency observed in patients) and developmental delay/regression (early mortality),https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b65af5c2-f03e-4e10-a2c4-e4524b64f1cc-2022-05-04T160000.000Z,1251,PubMed:22448145 +KD in HEK293 cells,Functional Alteration Non-patient cells,"Bayat V, et al., 2012, PMID: 22448145","A severe shRNA-mediated knockdown (SH-452) clearly affects mitochondrial protein translation (Figure S6E), whereas a less severe reduction in MARS2 (SH-152) does not cause an obvious reduction in mitochondrial protein translation when compared to wild-type controls. Overexpression of MARS2 had no effect on mitochondrial protein translation (Figure S6D,F).",Score,0.5 (0.5),gene knockdown disrupts mitochondrial protein translation,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b65af5c2-f03e-4e10-a2c4-e4524b64f1cc-2022-05-04T160000.000Z,1251,PubMed:22448145 +mitochondrial dysfunction in patient cells,Functional Alteration Patient cells,"Bayat V, et al., 2012, PMID: 22448145","MARS2 mRNA levels in lymphoblast cell lines were elevated while protein levels were significantly reduced (EE41-hom dup1, P24-hom dup1, and AA35-dup1, dup2) compared to controls (Fig. 8A, C, D). P24-hom dup1 showed reduced mitochondrial protein translation (Fig. 8B). Cultured patient fibroblasts displayed reduced Complex I activity (patients: D38-dup1, dup2; D9-dup1, dup-del; Y31-dup1, dup-del), increased ROS levels (indicated by reduced native aconitase activity; 6 patients with unspecified genotypes), and concomitantly decreased cell proliferation rates (patients: RR57-hom dup1; D9-dup1, dup-del) (Figure 8E–G). A non-significant reduction in cell proliferation rates was observed for DD38-dup1, dup2; Y31-dup1, dup-del; and EE41-hom dup1.",Score,1 (1),"evidence of mitochondrial dysfunction in patient cells (same genotypes as patients included in case data, but these individuals not scored as cases)",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b65af5c2-f03e-4e10-a2c4-e4524b64f1cc-2022-05-04T160000.000Z,1251,PubMed:22448145 +Review of mitochondrial translation disorders,Biochemical Function A,"Boczonadi V, et al., 2018, PMID: 29980628",See PMID: 16476954 for MT-TA related myopathy,Score,2 (0.5),>10+ genes with mitochondrial disease association implicated in mitochondrial translation,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b65af5c2-f03e-4e10-a2c4-e4524b64f1cc-2022-05-04T160000.000Z,1251,PubMed:29980628 +Kitajiri Protein Interaction,Protein Interaction,"Kitajiri S, et al., 2014, PMID: 25063198",Tricellulin was dislocalized in ILDR-1 deficient mice. Tested with immunofluorescense.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ba6df3f7-a000-401c-94d9-0dc5cb901f32-2018-01-05T170000.000Z,1252,PubMed:25063198 +Kamitani Animal Model,Model Systems Non-human model organism,"Kamitani T, et al., 2015, PMID: 26677943","knockout mouse generated. Mice had rapidly progressive hearing loss associated with hair cell degeneration, similar to knock-in model in Nayak 2013. Tricellulin shown to be required to maintain ion homeostasis around cochlear hair cells.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ba6df3f7-a000-401c-94d9-0dc5cb901f32-2018-01-05T170000.000Z,1252,PubMed:26677943 +Knock-out MBOAT7 mouse,Model Systems Non-human model organism,"Lee HC, et al., 2012, PMID: 23097495",Cortical atrophy is a recurrent phenotype observed in humans,Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ea008bc0-1c4f-459c-adb9-0e646b50c340-2023-11-21T170000.000Z,1254,PubMed:23097495 +Zebrafish models,Model Systems Non-human model organism,"Chen F, et al., 2022, PMID: 35362222","zebrafish with knocked-down mbtps1 gene expression exhibited growth limitations and spinal curvature, along with skin abnormalities. Observation under microscopy revealed encapsulation of mitochondria in lysosomes, increased mitochondrial number, and morphological alterations such as multilamellar globules and onion-like circles in the inner membrane cristae. Quantitative analysis confirmed these changes, showing an increase in mitochondrial number per cell, alterations in mitochondrial length, and changes in the length-to-width ratio of mitochondria.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_8bcb2ba1-90ff-48b3-860b-a658c0e9abed-2024-05-07T160000.000Z,1255,PubMed:35362222 +Morpholino knockdown of MCI (MCIDAS) in Xenopus laevis,Model Systems Non-human model organism,"Stubbs JL, et al., 2012, PMID: 22231168","In humans, multiciliated cells are present in the choroid plexus and the ependyma of the brain to drive the circulation of cerebrospinal spinal fluid, in respiratory epithelial cells to assist in mucociliary clearance, and in the efferent ducts and oviducts for spermatozoa and egg transport, respectively. Patients with defective MCIDAS genes exhibit a reduced generation of multiple motile cilia (RGMC) and present with a PCD phenotype that includes recurrent upper and lower respiratory tract infections as well as in some cases hydrocephalus and sub-fertility. Xenopus embryos which differentiate epidermal multiciliated cells for mucus clearance serve as a model for human multiciliated cells. While the entire human phenotype cannot be replicated in this model, the Xenopus knockdown model does reproduce the absence or severely reduced numbers of cilia seen in human patients.",Score,1.5 (2),Down-scored because these experiments on Xenopus skin provide insight into the general effect of MCIDAS knockout on muliciliated cell differentiation but are unable to recapitulate the full spectrum of phenotypes seen in human patients.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_866c87d2-9c7d-4f5e-bd7f-358d8e44fa54-2022-12-29T200000.000Z,1261,PubMed:22231168 +Multicilin binds E2f4/E2f5,Protein Interaction,"Ma L, et al., 2014, PMID: 24934224","During multiciliate cell differentiation, centriole amplification is initiated by MCIDAS (Multicilin). These centrioles go on to generate the basal bodies required for multiple cilia extension. Multicilin acts by forming a ternary complex with E2f4 (or E2f5) and Dp1 (The EDM complex). This EDM complex acts as a transcriptional activator for most of the genes required for centriole biogenesis. Multicilin on its own, lacks a DNA binding domain. When in complex with E2f4, a transcription factor, and its dimerization partner, Dp1, Multicilin is able to act as a transcriptional regulator. For Multicilin, complex formation is mediated through a 45-amino-acid region at the C terminus, called the TIRT domain. In addition to centriole amplification, the EDM complex has also been associated with the activation of other genes involved in cilia formation (PMID: 29243212).",Score,0.25 (0.5),Down-scored because E2F4 has not been implicated in PCD.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_866c87d2-9c7d-4f5e-bd7f-358d8e44fa54-2022-12-29T200000.000Z,1261,PubMed:24934224 +Cultured nasal epithelial cells of MCIDAS patient,Functional Alteration Patient cells,"Lee DDH, et al., 2021, PMID: 33795320","MCIDAS is a transcriptional co-activator that regulates multiciliogenesis in epithelial cells. Cultured basal epithelial patient cells were grown to confluence in air–liquid interface (ALI) culture to stimulate ciliogenesis. Quantitative PCR analysis comparing MCIDAS mRNA abundance between patient cells versus a healthy control donor after 7 days of ALI culture detected no mRNA expression in patient cells and strong expression in healthy cells. Consistent with the finding of no detectable MCIDAS gene expression, cilia were not detected on cells carrying the MCIDAS variant. Combinations of readthrough agents and inhibitors of nonsense-mediated decay (NMD) were able to restore the formation of basal bodies, but not cilia, in the patient's epithelial cells.",Score,0.5 (1),Down-scored because Western Blot Multicilin (MCIDAS) expression data that might have strengthened gene expression data was confusing and hard to interpret.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_866c87d2-9c7d-4f5e-bd7f-358d8e44fa54-2022-12-29T200000.000Z,1261,PubMed:33795320 +Late passage HCT116 MCM10+/-,Functional Alteration Non-patient cells,"Baxley RM, et al., 2021, PMID: 33712616","Increase in cells with abnormal morphology and multiple enlarged/pyknotic nuclear (reduced viability), late passage increased genomic instabliity, acquired chrommosomal rearrangements overlapping with common fragile sites. Shorter telomere at early passage and eroded overtime.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_4b68b9e6-cc1a-44ee-8860-319bc131e948-2024-06-20T170000.000Z,1262,PubMed:33712616 +HEK transfection,Functional Alteration Non-patient cells,"Gao J, et al., 2015, PMID: 26196677","WT MCM2-transfected cells had significantly fewer apoptotic cells after 48h than mutant MCM2-transfected culture, and both were significantly higher than the culture that lacked exogenous MCM2. These results support that MCM2 has pro-apoptotic activity. The same results were seen with Western blot of whole cell lysates, with the ratio of caspase3 to cleaved caspase3 used as a measure of apoptosis.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_29172723-c896-4cbf-a20b-9921fc72547f-2020-04-21T190000.000Z,1263,PubMed:26196677 +Guinea Pig Cochlea Expression,Expression A,"Gao J, et al., 2015, PMID: 26196677","MCM2 was shown to be expressed in guinea pig cochlea by RT-PCR, Western blot, and immunofluorescence staining. The latter showed expression mainly in the cytoplasm, and especially in the hair skin plate of both IHCs and OHCs.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_29172723-c896-4cbf-a20b-9921fc72547f-2020-04-21T190000.000Z,1263,PubMed:26196677 +FAS II pathway and lipoic acid,Biochemical Function A,"Rahman J, et al., 2017, PMID: 27977873","Human disorders of Lipoic Acid synthesis or attachment defects (i.e., through mutations in LIAS [MIM: 607031] or LIPT1 [MIM: 610284]) have been reported",Score,1 (0.5),MECR shares similar function to 2-5 genes known to cause Leigh syndrome (Score 1 pt per scoring rubric),https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_75fcef99-f3fe-43b3-a544-a91f04ed1285-2021-06-14T142534.349Z,1270,PubMed:27977873 +MED27 Knockout Drosophila Model,Model Systems Non-human model organism,"Li-Kroeger D, et al., 2018, PMID: 30091705",Death before adulthood was seen in 16% of cases,Score,0 (2),"Drosophila model does not recapitulate the disease phenotype. Deletion of Med27 is pupal lethal. However, no human cases that are homozygous or compound heterozygous for loss-of-function variants have been reported, suggesting that complete loss of function may be embryonically lethal.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_58234a0f-9c8b-432f-9397-815ccfae66fc-2023-12-15T170000.000Z,1276,PubMed:30091705 +MED27 Knockout Mouse Model,Model Systems Non-human model organism,"Groza T, et al., 2023, PMID: 36305825",Death before adulthood was seen in 16% of cases,Score,0 (2),"Mouse model does not recapitulate the disease phenotype: pre-weaning lethality. However, no human cases that are homozygous or compound heterozygous for loss-of-function variants have been reported, suggesting that complete loss of function may be embryonically lethal.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_58234a0f-9c8b-432f-9397-815ccfae66fc-2023-12-15T170000.000Z,1276,PubMed:36305825 +MEF2C Neocortical and hippocampal KO mice,Model Systems Non-human model organism,"Harrington AJ, et al., 2016, PMID: 27779093","The homozygous MEF2C floxed, Emx1-Cre mice (Mef2c cKO) were tested for a number of behavioral paradigms associated with learning and memory, and social interaction. Ultrasonic vocalization (USVs) were recorded in Mef2c cKO mice versus control littermates. The Mef2c cKO adult male mice prodiced 70% fewer USV calls in the presence of a sexually-receptive female than control littermates (Figure 5B). furthermore, the type of USC being produced by the Mef2C cKO mice varied significantly compared to wildtype littermates. When infantile mice (postnatal day 4-10) were recorded for USV production, the Mef2c cKO mice produced fewwer USVs than control littermates (figure 5D), supporting reduction in communication which is consistent with the absence of speech and/or language impairment observed in humans with MEF2C variants. +In the three chamber assay to test for sociability, the Mef2c cKO equally preferred the chamber housing another mouse than the empty chamber similar to control mice, however the Mef2c cKO did spend significantly less time interacting with the mouse in the chamber compared to control mice (figure 5E). This deficits was shown to be independent of any deficit in olfaction (Figure 5F). Nest building was also tested, and the Mef2c cKO mice showed significantly less structured nest building than control littermates (figure 5G). The Mef2C cKO also showed deficits in the sucrose preference test, indicating difference in reward-related behavior. +Mef2c cKO mice showed an increase in repetitive jumping behavior, with a 3 fold increase in both novel and home cage setting compared to control littermates (Figure 6A). This was also true of repetitive fine motor movements (Figure 6B). Hyperactivity was noted in the novel open cage paradigm (Figure 6D). +Mef2C cKO mice also showed significant deficits in the fear conditioning assays (figure 7C-E), in which robust freezing behaviors were not observed following tone-shock pairing, unlike that observed in the control littermates. +Lastly, RNA-seq performed on the somatosensory cortex of Mef2c cKO mice showed significantly reduced expression of gene associated with autism including Ntng1, Nlgn1, Nrxn1, Nrxn3, Pcdh19, Shank2, Shank3, Pten, and Htr1b.",Score,3 (2),"This mouse model follows the molecular mechanism described in the humans with MEF2C variation (loss of function) and outlines several behavioral deficits that are consistent with learning and memory and social deficits. Furthermore, RNA-seq performed on specific brain regions in the knockout mice show reduction in the expression of genes associated with Autism and intellectual disability, therefore I am increasing the score.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_34354e8f-4343-4fba-82ba-e49579e504bb-2019-02-06T170000.000Z,1277,PubMed:27779093 +MEGF10 Expression in Muscle/Satellite Cells,Expression A,"Holterman CE, et al., 2007, PMID: 18056409","Quantitative PCR was performed during the differentiation of wild-type and MyoD -/- myoblasts. Myoblasts currently in proliferation demonstrated a 6.4 fold increase in MEGF10 expression than differentiated myotubes. Investigation into the presence of MEGF10 in adult skeletal muscle yielded higher than baseline levels in peripheral muscle fiber cells and 5-7% of resting muscle cells, supporting the involvement of the protein in sattelite cell proliferation and migration. Quantitative PCR on these freshly isolated sattelite cells showed an over 100 fold upregulation.",Score,0.5 (0.5),"Although MEGF10 is most significantly expressed in the brain in non-developing organisms, this expression data clearly shows the upregulation in skeletal muscle sattelite cells and during myoblast differentiation. Since the phenotypes of EMARDD and the multiminicore myopathy are both related to the levels of myoblast and sattelite cell proliferation and enhanced premature differentiation in an organism, this evidence earns default points.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1d00193c-b0fd-40b4-b5d5-51eecece9669-2020-01-27T170000.000Z,1279,PubMed:18056409 +MEFG10 Regulates Proliferation and Differentiation,Biochemical Function B,"Holterman CE, et al., 2007, PMID: 18056409","All of the muscular phenotypes listed can directly stem from the various functions of MEGF10 including proliferation regulation, differentiation, and regulation in myosattelite cells. These cells are integral in both developing the muscle system in organisms and repairing them following injury or disease. Individuals with the EMARDD presentation lack a significant portion, up to any, of MEGF10 expression. This causes premature differentiation in the myoblasts during development, paritcularly in these sattelite cells leaving very low levels in organisms with this genotype. Those that do exist lack significant proliferative capabilities or migration to the sites where they are needed, leading to the lack of necrosis/regeration observed in patients and fatty infiltration of the damaged muscle. This leaves individuals with the EMARDD presentation with significant muscle-related deficencies such as areflexia, hypotonia, and muscle weakness from birth and the multiminicore presentation with similar symptoms when the ""reserves"" of PAX7-positive sattelite cells diminish later in life. Disruption of the notch signalling pathway could also play a part due to its major role in promoting proliferation and the embryonic development regulation of crucial systems.",Score,0.5 (0.5),The role of MEGF10 in myoblast differentiation and sattelite cell proliferation/migration is consistent with the muscle-related phenotypes and gives this evidence default points.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1d00193c-b0fd-40b4-b5d5-51eecece9669-2020-01-27T170000.000Z,1279,PubMed:18056409 +MEGF10 Knockdown in Zebrafish,Model Systems Non-human model organism,"Boyden SE, et al., 2012, PMID: 22371254","The phneotypes observed in the zebrafish knockdown model bear similarities to those demonstrated in both EMARDD and multiminicore patients. MO1-4 treated fish all displayed varying levels of curved tails, defective swimming, disorganized muscle tissue/myofibers, and muscle atrophy detected by reduced birefringence. Further, MO2 displayed small heads and unhatched eggs. All of these phenotypes support the presence of a myopathy in the zebrafish due to disruption of myofiber development and differentiation. Human probands directly display muscle atrophy and myopathic facies/myofiber disorganization, with similar phenotypes like high palate and decreased fetal movement/areflexia compared with the small heads and diminished motility.",Score,1.5 (2),"The MO-treated zebrafish recapitulated several of the phenotypes displayed in EMARDD and multiminicore myopathy such as myopathic signs and features, muscle atrophy, and the disorganized muscle tissue/myofibers that can be similarly be seen in human probands. However, the similarities between zebrafish and humans are limited and thus the model was not able to/did not display many specific phenotypes such as dysphagia, respiratory involvement, scoliosis, or lack of muscle fiber necrosis/regeneration. Because of this lack of information and the simple KO method, this model is downgraded to 1.5 points.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1d00193c-b0fd-40b4-b5d5-51eecece9669-2020-01-27T170000.000Z,1279,PubMed:22371254 +Megf8 p.Leu1775Pro homozygous mouse,Model Systems Non-human model organism,"Engelhard C, et al., 2013, PMID: 24052814","The two lines of mice had a similar phenotype. For nulls, 36% had exencephaly, 100% had polydactyly, and 33% had reversed heart looping, among other features. While the exencephaly phenotype differs from the craniosynostosis feature seen in human patients with Carpenter syndrome, polydactyly, heart defects, and heterotaxy are core features.",Score,1 (2),Downgraded because exencephaly phenotype does not align well with craniosynotosis in humans.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_dd9400f1-2c0b-4ffd-989a-486b81779a53-2021-12-23T193047.075Z,1280,PubMed:24052814 +Expression in mouse embryo,Expression A,"Engelhard C, et al., 2013, PMID: 24052814",In situ hybridization showed that Megf8 was strongly expressed in the pharyngeal arches of WT mouse embryos at embryonic days 8.5-10.5.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_dd9400f1-2c0b-4ffd-989a-486b81779a53-2021-12-23T193047.075Z,1280,PubMed:24052814 +Human iPSC derived disease model of MERTK,Model Systems Cell culture model,"Lukovic D, et al., 2015, PMID: 26263531","They induced patient’s and the healthy individual’s iPSCs to differentiate toward RPE cells in parallel, by removing the pluripotency factor bFGF and culturing the cells in suspension until dark patches appeared in the floating aggregates as previously described. The pigmented areas of the aggregates were mechanically excised, trypsinized and plated as a monolayer cell culture. After 3–4 weeks in culture the iPSC-derived RPE (iPSC-RPE) cells appeared to exhibit polygonal, cobblestone-like morphology, which is characteristic of mature RPE cells. To validate the identity of generated RPE cells, RT-PCR of selected RPE specific genes was performed to compare the expression levels throughout the differentiation process. On checking expression of MERTK by RT-PCR, mRNA is detectable in both healthy and MERTK p.Ser331Cysfs5 iPSCs. The level of expression of MERTK in healthy individual was higher than in MERTK p.Ser331Cysfs5 patient.",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b09e0755-aae3-47ef-b438-802285d5963b-2022-07-07T160000.000Z,1282,PubMed:26263531 +Behavioral assays,Model Systems Non-human model organism,"Thompson BL, et al., 2015, PMID: 26523156","The conditional KO MET mice showed some behaviors which were similar to the human phenotype (hypoactivity, blunted spontaneous alternation) but other behavioral assays were normal for these animals (no anxiety like behavior, repetitive behavior).",Score,0 (2),"In the absence of human genetic evidence, this line of experimental evidence was downgraded to 0 points.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d55c61af-ef8e-475d-9ff7-454496cb6462-2021-01-19T170000.000Z,1285,PubMed:26523156 +Shared biochemical function,Biochemical Function A,"Rahman J, et al., 2017, PMID: 27977873","MFF shares biochemical function with two genes involved in mitochondrial dynamics, SLC25A46 and DNM1L, which are associated with similar phenotype.",Score,1 (0.5),Points increased based on scoring guide,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_4484881f-277f-47a2-b1dd-70072ec941e0-2021-04-09T141836.756Z,1286,PubMed:27977873 +Mitochondrial dynamics and morphology,Functional Alteration Non-patient cells,"Chen H, et al., 2003, PMID: 12527753","Leading to smaller spherical, and fragmented mitochondria where there's a lack of directed +movement in most mitochondria.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a04350b3-5fe9-438a-9e90-db0055ed15e7-2022-10-10T160000.000Z,1287,PubMed:12527753 +Mitochondrial fusion assay,Functional Alteration Non-patient cells,"Chen H, et al., 2003, PMID: 12527753",Two ovoid mitochondria contact each other but do not fuse until much later. Unfused mitochondria,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a04350b3-5fe9-438a-9e90-db0055ed15e7-2022-10-10T160000.000Z,1287,PubMed:12527753 +Matic 2018 KO mouse,Model Systems Non-human model organism,"Matic S, et al., 2018, PMID: 29572490",Multiple mtDNA deletions are observed in tissues of affected individuals,Score,0.5 (2),0.5 pts for biochemical or mitochondrial dysfunction,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_15cc7c6b-dcdc-4289-a1c2-b4fad44c2f82-2023-08-07T040000.000Z,1290,PubMed:29572490 +Milenkovic 2022 KO mouse model,Model Systems Non-human model organism,"Milenkovic D, et al., 2022, PMID: 35533204","Altered lens and retina morphology in eye tissue close to the optic nerve recapitulates the ocular abnormalities seen in patients. Significant weight loss corresponds to the emancipation seen in several affected patients. Phenotypes in mice are observed in aging mice, in patients onset of symptoms is variable but in the few cases reported.",Score,0.5 (2),"Partial recapitulation of patient phenotype. Altered lens and retina morphology in eye tissue close to the optic nerve recapitulates the ocular abnormalities seen in patients. Significant weight loss corresponds to the emancipation seen in several affected patients. Phenotypes in mice are observed in aging mice, in patients onset of symptoms is variable but in the few cases reported.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_15cc7c6b-dcdc-4289-a1c2-b4fad44c2f82-2023-08-07T040000.000Z,1290,PubMed:35533204 +Guarani 2015,Model Systems Non-human model organism,"Guarani V, et al., 2015, PMID: 25997101","Using the UAS/Gal4 system, depleted QIL1 mRNA in Drosophila third larval instar bodywall muscle (Figure 4A). +Muscle tissue from knockdown larvae showed abnormal mitochondrial structure (Fig. 4). +Silencing of QIL1 specifically in neurons using the Elav-Dcr-Gal4 driver also disrupted mitochondrial and cristae structure. +Recapitulation of mitochondrial morphology defects observed in patient tissue",Score,1 (2),Recapitulation of mitochondrial morphology defects observed in patient tissue,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_2b19a224-a6a5-4056-b69d-2d3090b8a9e6-2023-08-07T040000.000Z,1292,PubMed:25997101 +Guarani 2015 knockdown in non-patient cells,Functional Alteration Non-patient cells,"Guarani V, et al., 2015, PMID: 25997101","siRNA-mediated QIL1 depletion in HeLa cells show abnormal cristae structure and impaired mitochondrial respiration (Fig. 3). +Knockdown in HCT116 cells resulted in similar defects in cristae structure. +Quantitative proteomic analysis revealed a marked reduction of MICOS subunits at ∼700 kDa (Figure 5), corresponding to the mature heterooligomeric complex and concomitant accumulation of MIC19, MIC25, and MIC60 upon QIL1 depletion. Total protein abundance for MIC26 and MIC27 was also reduced. Western blotting of lysates from mitochondria isolated from shRNA-treated HCT116 cells confirmed a reduction in the mature complex and accumulation of MIC60 and MIC19.",Score,0.5 (0.5),Evidence of mitochondrial dysfunction and impaired MICOS complex assembly following knockdown in non-patient cells,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_2b19a224-a6a5-4056-b69d-2d3090b8a9e6-2023-08-07T040000.000Z,1292,PubMed:25997101 +Guarani 2016 rescue in patient cells,Rescue Patient cells,"Guarani V, et al., 2016, PMID: 27623147","Patient fibroblasts showed reduced abundance of other MICOS subunits, with MIC10, MIC26 and MIC27 being affected to the largest extent (Figure 3A,B). Blue-native gel electrophoresis showed loss of MICOS assembly in patient fibroblasts, with an overall reduction in mature MICOS and an increase in the abundance of a sub-complex containing MIC19 and MIC60. +Expression of QIL1-HA-FLAG (Figure 5G–I) rescued MICOS complex assembly as assessed using anti-MIC10 on blue-native gels (Figure 5G) and levels of MIC10, MIC60, MIC19, MIC27 (Figures 4, 5, supplement 1), consistent with formation of MICOS.",Score,1 (1),Rescue of MICOS complex assembly via expression of WT in patient cells,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_2b19a224-a6a5-4056-b69d-2d3090b8a9e6-2023-08-07T040000.000Z,1292,PubMed:27623147 +Kishita_rescue,Rescue Patient cells,"Kishita Y, et al., 2020, PMID: 32749073","This increased levels of MICOS10, restored formation of complexes I and V, increased oxygen consumption rate",Score,1 (1),Default for rescue experiment.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_2b19a224-a6a5-4056-b69d-2d3090b8a9e6-2023-08-07T040000.000Z,1292,PubMed:32749073 +Neuron KO of MICU1 in Mice,Model Systems Non-human model organism,"Singh R, et al., 2022, PMID: 35302860",Mice should abnormal calcium flux and diminished function on rotarod test and grip test,Score,1 (2),"Score 0.5 for calcium flux abnormalities, Score 0.5 for phenotype",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_4c9276ee-39e6-408f-9ae0-a4c3000f3089-2023-11-20T050000.000Z,1293,PubMed:35302860 +siRNA knockdown of MICU2 in HeLa cells,Functional Alteration Non-patient cells,"Patron M, et al., 2014, PMID: 24560927",Abnormal calcium flux similar to Matesan-Isabel et al 2016,Score,0.5 (0.5),0.5 for abnormal calcium flux studies,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6c0069ac-5c56-41c3-a008-f494802e7579-2023-10-19T160000.000Z,1294,PubMed:24560927 +Mouse Model with Gene trap vector,Model Systems Non-human model organism,"Bick AG, et al., 2017, PMID: 29073106","confirmed prior studies that demonstrate that Micu2−/− mitochondria take up a high-concentration pulse of calcium more slowly than wild-type mitochondria (likely due to the reduction in Mcu levels) (28) but more rapidly take up lower concentration pulses of calcium +Biochemically similar pattern to Shamseldin patient (0.5) +MICU2-/- Mice developed left atrial enlargement at 16 months – not reported in phenotype so not scored",Score,0.5 (2),Score 0.5 for abnormal calcium flux,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6c0069ac-5c56-41c3-a008-f494802e7579-2023-10-19T160000.000Z,1294,PubMed:29073106 +Chen Animal Model,Model Systems Non-human model organism,"Chen L, et al., 2016, PMID: 27349893",Elimination of MITF-M isoform caused profound hearing loss and depigmentation,Score,2 (2),More evidnece for MITF-M being hearing isoform is in Yajima 1999 10400990,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_bc5d40d2-44b5-49b6-97a9-7bdfc39bee49-2017-11-21T170000.000Z,1297,PubMed:27349893 +Sun Biochemical Function,Biochemical Function B,"Sun J, et al., 2017, PMID: 28356565","Stoploss variant seen in human WS patients was shown to not affect DNA-binding activity, despite reduction in transcriptional activation. Haploinsufficiency is concluded to be mechanism of this variant",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_bc5d40d2-44b5-49b6-97a9-7bdfc39bee49-2017-11-21T170000.000Z,1297,PubMed:28356565 +MMADHC crystal structure,Protein Interaction,"Froese DS, et al., 2015, PMID: 26483544","A series of human MMADHC and MMACHC truncation proteins was expressed and interactions between them was assessed using blue native-PAGE and size-exclusion chromatography. The MMADHC region C-terminal to amino acid 154 and the MMACHC region without the C terminus was found to be sufficient for direct protein-protein interaction. Next, mouse MMADHC was analyzed by X-ray crystallography to further elucidate the MMACHC interaction. Key findings included that MMADHC binds Cbl-bound MMACHC after Cbl has been processed by MMACHC; and the MMACHC interaction region of MMADHC contains a modified nitrogen reductase (NTR) fold that abolishes homodimerization, and favors heterodimerization with another modified NTR fold from MMACHC. Of note, variants in MMACHC result in ""methylmalonic aciduria and homocystinuria type cblC"" (definitive gene-disease relationship based on assessment by the ClinGen Aminoacidopathy gene Curation Expert Panel.",Score,1 (0.5),The score is increased due to the level of evidence available including multiple experimental approaches taken to analyze the interaction between MMADHC and MMACHC.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_40ec59af-a143-4424-9218-7fd75deb6a61-2021-05-12T182739.747Z,1307,PubMed:26483544 +Mouse model expression,Expression A,"Zhou J, et al., 2012, PMID: 22396656",MNS1 is expressed in the germ cells of the testes and localizes to sperm flagella.,Score,0.25 (0.5),Mouse protein expression already scored in Ta-Shma paper,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_255ba802-ece2-43c7-9089-6e54672b4f4a-2022-09-13T170000.000Z,1309,PubMed:22396656 +Knockout mouse,Model Systems Non-human model organism,"Zhou J, et al., 2012, PMID: 22396656","In the mouse model, the sperm are not functioning correctly, similar to a potential phenotype seen in humans. In addition, some mice exhibit laterality defects, again, a phenotype seen in human patients with PCD.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_255ba802-ece2-43c7-9089-6e54672b4f4a-2022-09-13T170000.000Z,1309,PubMed:22396656 +Mouse embryo model,Expression A,"Ta-Shma A, et al., 2018, PMID: 30148830",Author performed in situ hybridization analyses- identified MNS1 in gastrulating mouse embryo. Expression strongly enriched in ventral node.,Score,0.25 (0.5),Default points reduced for identification in mouse model vs. human,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_255ba802-ece2-43c7-9089-6e54672b4f4a-2022-09-13T170000.000Z,1309,PubMed:30148830 +Human Western Blot,Expression A,"Ta-Shma A, et al., 2018, PMID: 30148830","Using rabbit polyclonal antibody specific to MNS1, MNS1 expressed in human nasal respiratory epithelial cells and in whole sperm lysates",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_255ba802-ece2-43c7-9089-6e54672b4f4a-2022-09-13T170000.000Z,1309,PubMed:30148830 +Interactions between MNS1 and ODA/ODADC Proteins,Protein Interaction,"Ta-Shma A, et al., 2018, PMID: 30148830","Evaluated MNS1 ODA function. In MNS1-deficient cilia, CCDC14 normally localizes along the entire axoneme. In combined MNS1 + DNAH5 deficient cilia, localized only to proximal region of axonemes. Suggest combined deficiency results in abnormal ODA-DC assembly. Using myc- and FLAG tagged proteins coexpressed in HEK293 cells (immunoprecipitation), identified that MNS1 interacted with CCDC114 but not ODA proteins DNAI1, DNAI2 and DNAL1. Also verified reciprocal interaction between CCDC114 and MNS1 by yeast 2 hybrid analysis.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_255ba802-ece2-43c7-9089-6e54672b4f4a-2022-09-13T170000.000Z,1309,PubMed:30148830 +Chu 2013 Zebrafish,Model Systems Non-human model organism,"Chu J, et al., 2013, PMID: 22899857","The function of MPI in N-glycosylation is to produce mannose-6-phosphate which is then converted to mannose-1-phosphate by PMM2, and subsequently to GDP-mannose, which is used as the substrate for generating the mature lipid-linked oligosaccharide (LLO). Both mature LLO and mannose-6-phosphate levels were decreased in mpi morphants (47 and 41% respectively). Mpi morphants also had 47% decrease in N-linked glycans, consistent with hypoglycosylated serum glycoproteins in MPI-CDG patients.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a6c880b8-c9fc-453b-8975-236a97047192-2023-12-20T170000.000Z,1316,PubMed:22899857 +Akahoshi et al. MPST- KO mice,Model Systems Non-human model organism,"Akahoshi N, et al., 2020, PMID: 32012740","This animal model recapitulates the only consistent phenotype associated with MPST enzymatic deficiency, elevated urinary mercaptolactate excretion. In addition, MPST KO mice displayed elevated passive systemic anaphylactic responses, a phenotype that has not yet been associated with the deficiency in humans. MPST KO mice were otherwise normal, displaying normal serum biochemistry, suggestive of normal liver and kidney function. Due to the presence of 0 genetic evidence associated with this gene-disease relationship, further work is needed to establish a connection to MPST enzymatic deficiency and elevated urinary 3ML.",Score,0.5 (2),"MPST KO mice recapitulated the only consistently observed phenotype associated with MPST enzymatic deficiency, elevated urinary 3-mercaptolactate excretion. However, due to the existence of 0 genetic evidence, this model was downscored.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_cc10dd44-961d-4925-b387-ed4569242eff-2023-04-28T160000.000Z,1319,PubMed:32012740 +Patient fibroblasts,Functional Alteration Patient cells,"Dalla Rosa I, et al., 2016, PMID: 26760297","MPV17-deficient human fibroblasts, comparison of proliferating cells and quiescent cells. mtDNA levels were depleted and dNTP levels reduced in quiescent patient fibroblasts. +This mtDNA depletion phenotype was rescued with dNTP supplementation. These data provide evidence that limited precursor availability for DNA synthesis is the underlying cause of the mtDNA depletion in MPV17 deficiency.",Score,1 (1),These data provide evidence that limited precursor availability for DNA synthesis is the underlying cause of the mtDNA depletion in MPV17 deficiency.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_fc7c6e4d-1a22-4ab4-b1d5-8de6bcc3b961-2022-07-21T040000.000Z,1320,PubMed:26760297 +"Mpv17 knockout mouse, further characterisation",Model Systems Non-human model organism,"Dalla Rosa I, et al., 2016, PMID: 26760297",Mpv17-/- mice have a shortage of the deoxynucleotides dGTP and dTTP in liver mitochondria that slows mtDNA replication: Liver mitochondria of Mpv17-/- mice displayed reduced levels of dGTP (30% relative to the wild-type) and dTTP (35% of wild-type). 2D PAGE demonstrated an increase in mtDNA replication intermediates in the liver of Mpv17-/- mice.,Score,0.5 (2),"liver specific phenotype, supporting mechanism of disease",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_fc7c6e4d-1a22-4ab4-b1d5-8de6bcc3b961-2022-07-21T040000.000Z,1320,PubMed:26760297 +spontaneous zebrafish mpv17 mutant,Model Systems Non-human model organism,"Martorano L, et al., 2019, PMID: 30833296",Liver specific phenotype and evidence of mitochondrial dysfunction.,Score,1 (2),"0.5 pts mitochondrial dysfunction, 0.5 pts Liver specific phenotype",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_fc7c6e4d-1a22-4ab4-b1d5-8de6bcc3b961-2022-07-21T040000.000Z,1320,PubMed:30833296 +immunohistochemistry,Expression B,"Ye Q, et al., 2014, PMID: 24752797","Low expression of MRE11 and MDC1 was detected in 14.4 % and 3.1 % of the patient samples, and negative expression of ATM, ATR and BRCA1 was found in 11.3 %, 6.3 % and 29.9 % of the patient samples, respectively. ATR deficiency was significantly associated with menopause (P = 0.025), strong expression of ATM (P = 0.017) and MRE11 (P = 0.040) with pre-menopausal SOC, strong expression of MRE11 (P = 0.016) with low tumor grade, and strong expression of BRCA1 (P = 0.015) with early clinical stage. In addition, low expression of MRE11 was strongly associated with negativity of ATR (P < 0.001) and BRCA1 (P = 0.004) Furthermore, ATR deficiency was associated with low expression of ATM (P = 0.028) and loss expression of BRCA1 (P = 0.009). Our results suggest that reduced expression or loss of proteins in HR pathway is associated with SOC development. Abnormality of MRE11 and BRCA1 are strongly associated with late clinical stage in SOC patients.",Review,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_f5b721c7-52ab-4475-a87e-cb0fa3be198f-2023-12-15T180000.000Z,1324,PubMed:24752797 +immunohistochemistry,Expression B,"Brandt S, et al., 2017, PMID: 28073364",Results: Lack of MRN complex protein detection was seen in 41% (55/134) of EOC and was more frequent in low-grade (57.6%; 19/33) than in high-grade EOC (18.8%; 36/101; n = 134; p = 0.04). There was an association with the ovarian carcinoma subtype (60.3%; 35/58 lack of detection in type I versus 26.3%; 20/76 in type II; n = 134; p < 0.001) as well as undetectable DNA mismatch repair proteins MLH1 and MSH2 (89.3%; 25/28; n = 131; p < 0.001). MRE11 knockdown led to moderately increased sensitivity towards the PARP inhibitor BMN673 in one ovarian carcinoma cell line in vitro.,Review,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_f5b721c7-52ab-4475-a87e-cb0fa3be198f-2023-12-15T180000.000Z,1324,PubMed:28073364 +MRPS34 mouse model,Model Systems Non-human model organism,"Richman TR, et al., 2015, PMID: 25816300",Individuals with Leigh syndrome may demonstrate reduced respiratory chain activities in a tissue specific manner which is recapitulated in this MRPS34 mouse model.,Score,0.5 (2),Utilized model scoring system developed for Leigh spectrum syndrome experimental evidence. (0.5/1 pts for biochemical abnormalities),https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_41d20487-f150-41b6-947c-ce77e405e8de-2020-08-27T162259.700Z,1330,PubMed:25816300 +IP and pulldown assay,Protein Interaction,"Wada-Hiraike O, et al., 2005, PMID: 15886699","Immunoprecipitation and glutathione-S-transferase pulldown assay revealed that ER-Alpha (ERa) and hMSH2 interacted in a ligand-dependent manner, whereas ER-Beta (ERb) and hMSH2 interacted in a ligand-independent manner. Estrogen receptor a/b bound to hMSH2 through the hMSH3/hMSH6 interaction domain of hMSH2. In a transient expression assay, hMSH2 potentiated the transactivation function of liganded ER a, but not that of ER b.",Score,0.5 (0.5),"This study showed that endogenous ER a/b associated with wild-type hMSH2 in the cultured human cells. The direct interaction between ER a/b and hMSH2 was confirmed by GST pulldown +assays. This paper further demonstrated hMSH2 potentiated the transactivation function of liganded ERa. These results suggest that hMSH2 may play an important role as a putative coactivator in ER a dependent gene expression, which is involved in breast cancer progression.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9cb3ff3b-3e0e-42f2-85d5-3ffb1506a255-2023-03-14T170000.000Z,1334,PubMed:15886699 +Decreased Moesin Expression,Expression B,"Kovács AL, et al., 2022, PMID: 36119109","Moesin mRNA expression in PBMCs of the patients, the mother, and healthy controls was analyzed by qPCR. Compared to the controls, significantly decreased MSN transcript values were detected in the patients and lower mRNA expression in the mother.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3d65d1f9-be54-4e41-b8d7-c8a48e8c4146-2023-01-19T180000.000Z,1340,PubMed:36119109 +Lymphocyte proliferation,Biochemical Function B,"Kovács AL, et al., 2022, PMID: 36119109",Affected individuals have profound immunophenotype alterations,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3d65d1f9-be54-4e41-b8d7-c8a48e8c4146-2023-01-19T180000.000Z,1340,PubMed:36119109 +Misato Drosophila,Model Systems Non-human model organism,"Min S, et al., 2017, PMID: 29255146","In this study, we have shown that depletion of mst in the whole muscle tissues specifically impaired intestinalfunctions while skeletal muscles remained unaffected. +Having shown that depletion of mst in the Drosophila visceral muscle elicits a series of intestinal phenotypes, we wondered whether genetic restoration of mst expression in mef2 > mst RNAi flies would rescue the phenotypes. By combining UAS-mst transgene with mef2 > mst RNAi flies, we observed that the dilated intestine of mef2 > mst RNAi flies was completely normalized by the restoration of mst expression in the flies",Score,0.5 (2),"Scored 0.5 points because of imperfect phenotype overlap - (visceral myopathy v. skeletal myopathy, some evidence for visceral myopathy as well)",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_10089a58-c9b4-497a-afb0-d249220eb2aa-2023-05-18T160000.000Z,1341,PubMed:29255146 +Rescue of Mitochondrial Fusion in P4's cells with WTMSTO1,Rescue Patient cells,"Donkervoort S, et al., 2019, PMID: 31463572","The similarity and consistency of the cellular phenotypes described across all seven MSTO1 patient fibroblast lines strongly support the notion that loss of MSTO1 function is the underlying cause responsible for these observations. In order to further confirm that the cellular phenotypes were in fact due to the loss of MSTO1, we transiently expressed wild-type MSTO1 in two of the patient cell lines (P4 and P7) (Fig. 7a, b). Similar to previous reports [16, 35], we found that expression of wild-type MSTO1 restored mitochondrial morphology after 48 h (Fig. 7c). Notably, we also observed more fused mitochondrial networks in control cells overexpressing MSTO1, further validating the role of MSTO1 in promoting fusion. In addition, we also see that lysosome abnormalities are restored (Fig. 7d). While we observed a significant rescue in MSTO1 fibroblasts with regard to mtDNA nucleoid size (Fig. 7e), the number of mtDNA nucleoids did not change in MSTO1 fibroblasts (Fig. 7f). A potential confounding factor is that the transfection protocol itself causes a decrease in mtDNA nucleoid counts, which could be masking a rescue. However, mtDNA copy number was also not rescued after only 48 h (Fig. 7g). This incomplete rescue of mtDNA nucleoid abundance and copy number likely reflects the fact that it may take longer than 48 h for the mtDNA copy number to be re-established.",Score,1.5 (1),"0.5 rescuing mitochondrial fusion, 0.5 for rescuing mitochondrial morphology, 0.5 rescuing mtDNA nucleiod size",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_10089a58-c9b4-497a-afb0-d249220eb2aa-2023-05-18T160000.000Z,1341,PubMed:31463572 +Western Blot MSTO1 in P6 FCL,Expression B,"Donkervoort S, et al., 2019, PMID: 31463572",Absence of MSTO1 on Western blot in patients but not control with normal expression of other mitochondrial fusion genes,Score,1 (1),0.5 per variant for absence MSTO1 on Western Blot,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_10089a58-c9b4-497a-afb0-d249220eb2aa-2023-05-18T160000.000Z,1341,PubMed:31463572 +Western Blot MSTO1 in P7 FCL,Expression B,"Donkervoort S, et al., 2019, PMID: 31463572",Absence of MSTO1 on Western blot in patients but not control with normal expression of other mitochondrial fusion genes,Score,1 (0.5),"arr[GRCh37] 1q22(155582110_155708204)x1) + p.L450F (in trans) +0.5 for absence per variant",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_10089a58-c9b4-497a-afb0-d249220eb2aa-2023-05-18T160000.000Z,1341,PubMed:31463572 +Complex V,Biochemical Function A,"Rahman J, et al., 2017, PMID: 27977873",Complex V subunits/assembly factors.,Score,1 (0.5),2-5 gene products needed for Complex V function.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_8d7b0569-8dfe-40cf-a83b-44071430206f-2023-05-18T160000.000Z,1345,PubMed:27977873 +Complex V subunit,Protein Interaction,"Rahman J, et al., 2017, PMID: 27977873",Complex V subunits,Score,0.5 (0.5),Shares a function/interacts with one other gene product (ATP5MD aka USMG5),https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e492464b-cb98-4bf4-a12e-169b59576b04-2021-06-28T145350.161Z,1346,PubMed:27977873 +Complex IV subunits,Protein Interaction,"Rahman J, et al., 2017, PMID: 27977873",,Score,1.5 (0.5),several COX subunits associated with LSS,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_996428ee-5af2-458b-afb7-6e29348c585a-2021-06-28T144716.059Z,1352,PubMed:27977873 +Respiratory Chain Studies in Xu et al patient,Functional Alteration Patient cells,"Xu M, et al., 2021, PMID: 34054915","The activities of CIV in the patient’s muscles were reduced to 16.5 ± 6.5% and 20.3 ± 8.1% compared with those of CS and complex II, respectively +CI, CII, CII+III, and CIII were 65-100% of control by CS or CI - ie normal",Score,0.5 (1),0.5 for isolated complex IV deficiency,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d58759e1-bf55-44f2-9a97-839a9360d156-2023-03-20T160000.000Z,1353,PubMed:34054915 +Complex I genes,Protein Interaction,"Zhu J, et al., 2016, PMID: 27509854",Structural modelling of Complex I,Score,2 (0.5),>10 genes associated with LSS,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1d55015a-dd90-479e-8e5b-4693e321c705-2023-04-03T160000.000Z,1355,PubMed:27509854 +Complex I structural model,Protein Interaction,"Zhu J, et al., 2016, PMID: 27509854",Structural modelling of Complex I,Score,2 (0.5),At least 18 complex I subunits are associated with Leigh syndrome spectrum.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_8bb99c59-15c9-4e19-ba8b-df6cb800c32d-2021-04-14T040000.000Z,1356,PubMed:27509854 +Drosophila model,Model Systems Non-human model organism,"Burman JL, et al., 2014, PMID: 25085991","Evaluated w1118 (control) and ND2del1 Drosophila mutants. ND2del1 (ND2del1) bears a nine-nucleotide deletion in the ND2 coding sequence (Xu et al., 2008) that removes three amino acids at positions 186-188 of the ND2 protein. ND2 mutants exhibit phenotypes that resemble symptoms of mitochondrial disease, including shortened lifespan, heat-induced paralysis, impaired flight in an established assay, and increased sensitivity to carbon dioxide, nitrogen, and oxygen (Fig. 1). Analysis of muscle and brain integrity by hematoxylin and eosin staining of tissue from middle-aged and old ND2 mutants and controls revealed no abnormalities in the flight muscles of middle-aged or old ND2 mutants or in the brains of middle-aged ND2 mutants (Fig. 2A,B). However, neurodegenerative vacuoles observed in the brains of old ND2 mutants were both significantly larger and more numerous than those seen in age-matched controls (Fig. 2B-D). In muscle, no significant differences in actin organization, mitochondrial size or cleaved caspase-3 staining were observed between ND2 mutants and aged-matched controls. Mitochondria isolated from either middle-aged or old ND2 mutants showed unimpaired state 3 respiration, but maximal state 3 values were significantly decreased in ND2 mutants relative to age-matched controls (Fig. 3A and Table 1), indicating a complex-I-dependent respiratory defect specifically under maximally demanding conditions. No significant differences in respiration, complex-II-dependent ADP/O ratios or complex-IV-dependent respiration were observed between ND2 mutant and control mitochondria (Table 1). A significant decrease in complex-I-dependent ADP/O ratios were observed in both middle-aged and old ND2 mutants (Fig. 3B and Table 1). This decrease is likely not explained by a change in the efficiency of ATP production by complex V, nor a proton leak in the mitochondrial membrane, because ND2 mutant ADP/O ratios were normal when respiration was dependent on complex II (Table 1). Moreover, the mitochondrial respiratory rate following depletion of ADP (state 4), an indicator of proton leak across the mitochondrial inner membrane, was unaffected by the ND2del1 mutation (Fig. 3A and Table 1). Blue native gel analysis revealed that the abundance of fully assembled complex I was decreased in ND2 mutants relative to controls, without an accompanying decrease in complex V abundance (Fig. 3C). Western blot analysis also revealed a decrease in the abundance of the complex I subunit NDUFS3 in ND2 mutants, but little to no change in the abundance of the β-subunit of complex V relative to age-matched controls (Fig. 3D,E and supplementary material Fig. S5). Measured mitochondrial membrane potential in dissociated neurons from old ND2 mutants and controls and compared ATP levels in the thoraces and heads of old ND2 mutants and controls. A decrease in the fraction of cells with polarized mitochondria was detected in the brains of old ND2 mutants relative to controls, and reduced ATP abundance in ND2 mutants that was specific to heads (Fig. 4A-C). +Female ND2 mutants exhibited stronger phenotypes than males and were exclusively used for most experiments. +Another strain, ND2ins1 (ND2ins1) bears a three-nucleotide insertion in the ND2 coding sequence and adds a serine at position 189; these mutants did not show a phenotype in initial screening.",Score,1 (2),"ND2 mutants exhibit phenotypes that resemble symptoms of mitochondrial disease, including shortened lifespan, progressive neurodegeneration, diminished neural mitochondrial membrane potential and lower levels of neural ATP. Biochemical studies suggest that complex I is unable to efficiently couple electron transfer to proton pumping. +0.5 for behavioral/developmental differences, 0.5 for impaired mito function",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_80f1dcc9-aaf3-45f7-987a-4e0d83140913-2021-04-14T040000.000Z,1357,PubMed:25085991 +Leigh map,Biochemical Function A,"Rahman J, et al., 2017, PMID: 27977873","18 other complex I genes in Leigh map: NDUFA1, NDUFA2, NDUFA9, NDUFA10, NDUFA12, NDUFS1, NDUFS2, NDUFS3, NDUFS4, NDUFS7, NDUFS8, NDUFV1, NDUFV2, MT-ND1, MT-ND2, MT-ND3, MT-ND4, MT-ND5, MT-MD6, NDUFAF2, NDUFAF4, NDUFAF5, NDUFAF6, C17ORF89, FOXRED1, NUBPL",Score,2 (0.5),scored according to rubric,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_80f1dcc9-aaf3-45f7-987a-4e0d83140913-2021-04-14T040000.000Z,1357,PubMed:27977873 +Drosophila,Model Systems Non-human model organism,"Burman JL, et al., 2014, PMID: 25085991","ND2 mutants exhibit phenotypes that resemble symptoms of mitochondrial disease, including shortened lifespan, progressive neurodegeneration, diminished neural mitochondrial membrane potential and lower levels of neural ATP. ​ +Biochemical studies suggest that complex I is unable to efficiently couple electron transfer to proton pumping.",Score,2.5 (2),"ND2 mutants exhibit phenotypes that resemble symptoms of mitochondrial disease, including shortened lifespan, progressive neurodegeneration, diminished neural mitochondrial membrane potential and lower levels of neural ATP. ​ +Biochemical studies suggest that complex I is unable to efficiently couple electron transfer to proton pumping.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ce38deed-d954-4e68-aed1-ede90e274a2c-2023-05-18T160000.000Z,1358,PubMed:25085991 +Complex I Structural Model,Protein Interaction,"Zhu J, et al., 2016, PMID: 27509854",,Score,2 (0.5),MT-ND3 is one of at least 19 complex I subunits associated with Leigh syndrome spectrum (Rahman et al. 2017),https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_06aaf3f7-69d3-415d-be22-257ed21abbc1-2023-03-06T170000.000Z,1359,PubMed:27509854 +Complex I structural model,Protein Interaction,"Zhu J, et al., 2016, PMID: 27509854",A 4.2-Å resolution single-particle electron cryomicroscopy structure of complex I from Bos taurus.,Score,2 (0.5),MT-ND3 is one of at least 19 complex I subunits associated with Leigh syndrome spectrum (Rahman et al. 2017),https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_8af71e8b-b1f8-45d6-9dd7-e403a6f6080e-2021-03-24T040000.000Z,1360,PubMed:27509854 +Complex I genes,Protein Interaction,"Zhu J, et al., 2016, PMID: 27509854",Structural modelling of complex I,Score,2 (0.5),>10 genes associated with PMD.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_14ad3d43-a07b-4420-bc18-f10e71b5f974-2023-03-06T170000.000Z,1361,PubMed:27509854 +Complex I structural model,Protein Interaction,"Zhu J, et al., 2016, PMID: 27509854",Structural modelling of complex I,Score,2 (0.5),At least 18 complex I subunits are associated with Leigh syndrome spectrum.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_f05be3e5-352f-49a5-84af-8846d6839373-2021-05-17T040000.000Z,1362,PubMed:27509854 +Cryo EM Mammalian Complex I,Biochemical Function A,"Zhu J, et al., 2016, PMID: 27509854",">45 complex I genes, including catalytic subunits, assembly factor, iron/sulfur proteins and >10+ involved in disease",Score,2 (0.5),">45 complex I genes, including catalytic subunits, assembly factor, iron/sulfur proteins and >10+ involved in disease",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_315cca07-6aef-4749-abf2-c0eba7d6c1c5-2022-10-20T160000.000Z,1363,PubMed:27509854 +Zhu_Structural modelling of Complex I,Protein Interaction,"Zhu J, et al., 2016, PMID: 27509854",At least 18 complex I subunits are associated with mitochondrial disease.,Score,2 (0.5),>10 genes associated with PMD.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_af2efc84-7d75-49a9-ae61-2ea59bf3ce5f-2023-05-03T160000.000Z,1364,PubMed:27509854 +Galera-Monge_iPSC MT-ND5 m.13513G>A,Functional Alteration Patient cells,"Galera-Monge T, et al., 2020, PMID: 32366037","1) Patient derived fibroblasts with 55% heteroplasmy were shown by high-resolution respirometry to be deficient in the maximal respiratory capacity and in complexes I (Fig1. ). Decreased mitochondrial mass was reported in the fibroblasts: A defect in complexes I, III+V and IV was detected when normalizing with GAPDH but not when normalizing with both CS and GAPDH (Figure 1B). Analysis of enzymatic activities of respiratory complexes highlighted a normal function of complexes II, III and IV (CS normalized) but a decreased activity of CS in LS fibroblasts (Figure 1C), supporting a decrease in mitochondrial mass as the main contribution to the lower levels of respiration. Extracellular lactate measurements demonstrated that LS fibroblasts produced more than twice the lactate generated by control fibroblasts. 2. iPSC line, LND554SV.4,m.13513G>A at 45% heteroplasmy, derived from the patient fibroblasts. A control line was also generated from normal human dermal fibroblasts (NHDFs); iPSC line (N44SV.1). The LND554SV.4 line showed a defect in the activity of complexes I and III of LS iPSC (Figure 2C). Similar to fibroblasts, lactate levels were increased in LS iPSCs as compared to control iPSCs (Figure 2D). 3) Neural stem cells (NSCs) were derived from both patient and control iPSCs and stained positive for the NSC marker nestin (Figure 3A). The m.13513G>A mutation was retained in patient NSCs at a percentage of 19.26%. The NSCs were differentiated into neurons over 6 weeks (iPSC-iNs). LS neural stem cells (NSCs) manifested similar proliferative and differentiation capacity (Fig3.) Fig 4. iNs co-cultured with mouse astrocytes showing a marked neurodegeneration in the patient in comparison with the control both at days 21 and 42. Seahorse XFe96 Analyzer was used to quantify oxygen consumption whilst the neurons were in culture, showing a reduced basal and maximal respiration in patient cells as well as reduced complex I contribution. Patch clamp studies were used to demonstrate no abnormalities in intrinsic properties or AP characteristics of patient neurons as compared to control. Intracellular calcium concentrations were analyzed by live cell calcium imaging in NSC-derived neurons, after 6 weeks of differentiation and used to demonstrate a Ca2+ buffering defect.",Score,2 (1),"Differentiated iNeurons (19% heteroplasmy) showed an increased rate of cell death compared to a control line, reduced respiration , including reduced complex I contribution to respiration and dysregulation of calcium homeostasis.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_af2efc84-7d75-49a9-ae61-2ea59bf3ce5f-2023-05-03T160000.000Z,1364,PubMed:32366037 +Structural modelling of Complex I,Protein Interaction,"Zhu J, et al., 2016, PMID: 27509854",At least 18 complex I subunits are associated with Leigh syndrome spectrum,Score,2 (0.5),Scored based on LS scoring rubric - encoded protein interacts with 10+gene products whose dysfunction is known to cause Leigh syndrome.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e941d385-716f-4264-8f24-ffe3022579e2-2021-06-14T155537.548Z,1365,PubMed:27509854 +iPSC MT-ND5 m.13513G>A,Functional Alteration Patient cells,"Galera-Monge T, et al., 2020, PMID: 32366037","Patient derived fibroblasts with 55% heteroplasmy were shown by high-resolution respirometry to be deficient in the maximal respiratory capacity and in complexes I (Fig1. ). +Decreased mitochondrial mass was reported in the fibroblasts: A defect in complexes I, III+V and IV was detected when normalizing with GAPDH but not when normalizing with both CS and GAPDH (Figure 1B). Analysis of enzymatic activities of respiratory complexes highlighted a normal function of complexes II, III and IV (CS normalized) but a decreased activity of CS in LS fibroblasts (Figure 1C), supporting a decrease in mitochondrial mass as the main contribution to the lower levels of respiration. Extracellular lactate measurements demonstrated that LS fibroblasts produced more than twice the lactate generated by control fibroblasts. + + +iPSC line, LND554SV.4,m.13513G>A at 45% heteroplasmy, derived from the patient fibroblasts. A control line was also generated from normal human dermal fibroblasts (NHDFs); iPSC line (N44SV.1). The LND554SV.4 line showed a defect in the activity of complexes I and III of LS iPSC (Figure 2C). Similar to fibroblasts, lactate levels were increased in LS iPSCs as compared to control iPSCs (Figure 2D). + + +Neural stem cells (NSCs) were derived from both patient and control iPSCs and stained positive for the NSC marker nestin (Figure 3A). The m.13513G>A mutation was retained in patient NSCs at a percentage of 19.26%. The NSCs were differentiated into neurons over 6 weeks (iPSC-iNs). LS neural stem cells (NSCs) manifested similar proliferative and differentiation capacity (Fig3.) +Fig 4. iNs co-cultured with mouse astrocytes showing a marked neurodegeneration in the patient in comparison with the control both at days 21 and 42. Seahorse XFe96 Analyzer was used to quantify oxygen consumption whilst the neurons were in culture, showing a reduced basal and maximal respiration in patient cells as well as reduced complex I contribution. +Patch clamp studies were used to demonstrate no abnormalities in intrinsic properties or AP characteristics of patient neurons as compared to control. +Intracellular calcium concentrations were analyzed by live cell calcium imaging in NSC-derived neurons, after 6 weeks of differentiation and used to demonstrate a Ca2+ buffering defect.",Score,2 (1),"Differentiated iNeurons (19% heteroplasmy) showed an increased rate of cell death compared to a control line, reduced respiration , including reduced complex I contribution to respiration and dysregulation of calcium homeostasis.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e941d385-716f-4264-8f24-ffe3022579e2-2021-06-14T155537.548Z,1365,PubMed:32366037 +Zhu_Complex I subunit,Protein Interaction,"Zhu J, et al., 2016, PMID: 27509854",Complex I,Score,2 (0.5),>10 genes associated with PMD,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7f581c96-e3cc-49bb-aa2b-98650efa4157-2023-05-03T160000.000Z,1366,PubMed:27509854 +Yardeni_mouse,Model Systems Non-human model organism,"Yardeni T, et al., 2021, PMID: 33536343","Further characterization of the mouse described in 23129651: Lin et al. 2012. A variety of behavioral tests (Fig 2) revealed that these mice exhibit impaired social interaction (three-chamber social interaction assay), increased anxiety (open field tests), increased response in a fear conditioning test compared to wildtype mice. The mice showed an altered EEG background power compared to wildtype mice which corresponds to similar observations in ASD patients. Significantly, the ND6P25L mice were more prone to induced seizures than the WT controls (flurothyl ether exposure, Fig 4). Analysis of mitochondrial respiration and ROS production of the cortex, hippocampus, and ND6P25L olfactory bulb of the and WT mice using the Oroboros O2k Respirometer showed differential defects across the brain regions. The most significant decrease in global mitochondrial respiration and complex I-linked respiration was within the cortex (Fig 6), mitochondrial ROS production was increased in the cortex in association with complex I and complex II respiration with ADP as well as for FCCP-stimulated maximum respiration (Fig 7).",Score,1 (2),"Neuronal phenotype including predisposition to epilepsy: 1 pt +Mutant mice are more prone to induced seizures than controls (Fig 4.) +Battery of behavioural tests showed mice exhibit impaired social interaction, increased anxiety, EEG background similar to ASD patients (Fig 4). +Differential defects in mitochondrial respiration across brain regions (Fig 5 and 6): The most significant decrease in global mitochondrial respiration and complex I-linked respiration was within the cortex, mitochondrial ROS production was increased in the cortex in association with complex I and complex II respiration with ADP as well as for FCCP-stimulated maximum respiration.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7f581c96-e3cc-49bb-aa2b-98650efa4157-2023-05-03T160000.000Z,1366,PubMed:33536343 +Complex I structural model,Protein Interaction,"Zhu J, et al., 2016, PMID: 27509854",Structural modelling of Complex I,Score,2 (0.5),"At least 18 complex I subunits are associted with Leigh syndrome spectrum: NDUFA1, NDUFA2, NDUFA9, NDUFA10, NDUFA12, NDUFS1, NDUFS2, NDUFS3, NDUFS4, NDUFS7, NDUFS8, NDUFV1, +NDUFV2, MT-ND1, MT-ND2, MT-ND3, MT-ND4, MT-ND5. Per rubric score 2 pts.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_836f975f-27f5-47c9-a58e-35089b6b39e6-2021-05-17T040000.000Z,1367,PubMed:27509854 +MT-ND6 P25L mouse model,Model Systems Non-human model organism,"Yardeni T, et al., 2021, PMID: 33536343","Further characterization of the mouse described in 23129651: Lin et al. 2012. A variety of behavioral tests (Fig 2) revealed that these mice exhibit impaired social interaction (three-chamber social interaction assay), increased anxiety (open field tests), increased response in a fear conditioning test compared to wildtype mice. The mice showed an altered EEG background power compared to wildtype mice which corresponds to similar observations in ASD patients. Significantly, the ND6P25L mice were more prone to induced seizures than the WT controls (flurothyl ether exposure, Fig 4). Analysis of mitochondrial respiration and ROS production of the cortex, hippocampus, and ND6P25L olfactory bulb of the and WT mice using the Oroboros O2k Respirometer showed differential defects across the brain regions. The most significant decrease in global mitochondrial respiration and complex I-linked respiration was within the cortex (Fig 6), mitochondrial ROS production was increased in the cortex in association with complex I and complex II respiration with ADP as well as for FCCP-stimulated maximum respiration (Fig 7).",Score,0.5 (2),Neuronal phenotype including predisposition to epilepsy: 0.5,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_836f975f-27f5-47c9-a58e-35089b6b39e6-2021-05-17T040000.000Z,1367,PubMed:33536343 +MT-RNR2 iPSC patient cells,Functional Alteration Patient cells,"Li S, et al., 2018, PMID: 29456182","Induced pluripotent stem cell-derived cardiomyocytes from human patients who harbor homoplasmic m.2336T>C variant showed cellular and electrophysiological abnormalities, including reduced mitochondrial membrane potential (Fig. 5A) and elevated intracellular Ca2+ concentration (Fig. 6), delayed afterdepolarization (DAD)-like arrhythmia, and prolonged action potential duration (Fig. 7). These abnormalities have been observed in iPSCs derived from HCM patients with MYH7 variants in other studies.",Score,0.5 (1),Note: decision at GCEP meeting to reduce points because unaffected family members not tested and genetic heterogeneity not accounted for.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_f5cd88bf-4d80-4d6f-b479-cd4a3725b039-2022-12-05T170000.000Z,1369,PubMed:29456182 +Kauppila_mouse,Model Systems Non-human model organism,"Kauppila JHK, et al., 2016, PMID: 27626666",Multisystem disease,Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_222b73fe-4a05-457f-bc36-f32dc4877056-2024-03-04T170000.000Z,1370,PubMed:27626666 +Gammage_rescue,Rescue Non-human model organism,"Gammage PA, et al., 2018, PMID: 30250142","There was an altered metabolic signature in treated mice, demonstrating significantly increased pyruvate levels and significantly decreased lactate levels, suggestive of a diminished reliance on glycolysis, coupled to elevated aspartate levels in treated mice, suggestive of improved mitochondrial respiration.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_222b73fe-4a05-457f-bc36-f32dc4877056-2024-03-04T170000.000Z,1370,PubMed:30250142 +Overview of Mitochondrial Transcription and Translation,Biochemical Function A,"D'Souza AR, et al., 2018, PMID: 30030363",MT-tRNA involved in mitochondrial translation,Score,2 (0.5),13 OXPHOS polypeptides in mtDNA which is >10 genes,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c3d92b0e-6753-4355-a982-2f9cf7cad8be-2023-03-20T160000.000Z,1371,PubMed:30030363 +Northern Blot Studies of MT-TC mRNA in patient muscle,Functional Alteration Patient cells,"Hippen M, et al., 2022, PMID: 35252560","Therefore, we performed Northern blotting experiments and found that the amount of the mitochondrial tRNACys in the patient’s skeletal muscle was 56% of the mean value of 3 control samples when normalized to the mitochondrial tRNASerUCN (p < 0.01). +ETC: CS upregulated ~2x control; Complex I was <33% of control after CS corrected, CIV mildly reduced (~60-70%) +No alteration of amino acid charging of tRNACys was observed (Figure 2E).",Score,1 (1),0.5 for Northern Blot and 0.5 for ETC,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c3d92b0e-6753-4355-a982-2f9cf7cad8be-2023-03-20T160000.000Z,1371,PubMed:35252560 +Overview of mitochondrial transcription and translation,Biochemical Function A,"D'Souza AR, et al., 2018, PMID: 30030363",MT-tRNA involved in mitochondrial translation,Score,2 (0.5),13 OXPHOS polypeptides in mtDNA which is >10 genes,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_620f9725-7a33-4b55-99bc-3d32d9e8ff63-2023-01-19T170000.000Z,1372,PubMed:30030363 +Patient lymphoblast cells,Functional Alteration Patient cells,"Xu C, et al., 2022, PMID: 35472031","Pathogenic m.616T>C abolished a highly conserved base pair (A31-U39) in the anticodon stem-loop which altered the structure of mt-tRNAPhe, as confirmed by a decreased melting temperature and slower electrophoretic mobility of the mutant tRNA. Furthermore, the unstable structure of mt-tRNAPhe contributed to a shortage of steady-state mt-tRNAPhe and enhanced aminoacylation efficiency, which resulted in impaired mitochondrial RNA translation and a significant decrease in mtDNA–encoded polypeptides",Score,0.5 (1),These are patient cell studies but only mtDNA sequencing was performed; did score 0.5 for tRNA-specific studies.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a4b94030-f2dd-431d-9114-a7fd8b1e32a5-2023-02-16T170000.000Z,1374,PubMed:35472031 +MT-TH FA - Gong,Functional Alteration Non-patient cells,"Gong S, et al., 2014, PMID: 24920829","The goal of this paper was to determine the cellular consequences of the m.12201T>C variant, which was uncovered in a large Han Chinese pedigree segregating maternally-inherited, non-syndromic deafness. The authors generated a set of three cybrid lines using cells from an affected individual from this family, and a second set from an unaffected control. +Using a Northern blot, the authors determined the expression levels of five mt tRNAs, and used nuclear 5S rRNA as a loading control. tRNA(His) was specifically reduced in the patient lines vs control (Fig. 2). This experiment was repeated under conditions to detect charged vs uncharged tRNAs, and found a slight but significant increase in the proportion of charged tRNA(His) (Fig. 3). They next performed a Western blot of mitochondrially-encoded proteins, finding significant reductions in steady-state levels of all targets assessed (Fig. 4). +These experiments were followed by assays of metabolic activity. Oxygen consumption rates were 58% lower in patient cybrids vs controls under basal conditions. Treatment with various specific inhibitors to determine which step of electron transport was deficient revealed a general reduction at every step (Fig. 5). Measures of mitochondrial ATP production using a luciferase assay revealed a reduction of ~35% in the patient cybrids (Fig. 6). This was correlated with reduced mitochondrial membrane potential in these cells, as assayed by fluorescence microscopy after treatment with a redox-sensitive dye (Fig. 7). Finally, the production of reactive oxygen species was assessed using flow cytometry, demonstrating an ~40% increase in ROS levels in the patient cells compared to controls (Fig. 8).",Score,1 (0.5),Score upgraded due to the thoroughness of the investigation,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_debb8afe-e379-465f-8b74-0241e1b14f8a-2022-11-07T170000.000Z,1376,PubMed:24920829 +Northern blot analysis of 22 mt-tRNAsteady-statelevels among,Expression A,"He Q, et al., 2021, PMID: 34265302","Northern blot analysis of 22 mt-tRNAsteady-statelevels among 5 mouse tissues +found MT-TI expressed in mouse hearts",Score,1 (0.5),"supported by 2 other papers with patient heart tissue +Merante et al., 1996 PMID: 8889580 PCR amplification from heart tissue of all tRNA genes and directly sequenced – variant in siblings and mother +Giordano et al., 2013 PMID: 21945886 Northern blot analysis of patient and control cardiac muscle RNA",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3ac07ab9-8580-4fbf-b599-35dd25f3025d-2023-12-18T010000.000Z,1377,PubMed:34265302 +Review: LeighMap,Biochemical Function A,"Rahman J, et al., 2017, PMID: 27977873",Rahman et al. reviews all genes associated with Leigh syndrome in Leigh Map 2017 (PMID: 27977873). These genes included at least thirteen nuclear genes directly involved in mitochondrial translation as well as five additional mt-tRNA genes.,Score,2 (0.5),per rubric: More than 10 gene with a related function,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_69991755-b62f-42aa-bbe3-30ac10e4311d-2021-02-03T050000.000Z,1378,PubMed:27977873 +Mitochondrial translation defects,Biochemical Function A,"Rahman J, et al., 2017, PMID: 27977873",Rahman et al. reviews all genes associated with Leigh syndrome in Leigh Map 2017 (PMID: 27977873). These genes included at least thirteen nuclear genes directly involved in mitochondrial translation as well as five additional mt-tRNA genes.,Score,2 (0.5),>10 genes associated with mitochondrial translation,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_bbdedc92-8d9d-4912-a4d1-69a91ea65ef0-2023-06-05T040000.000Z,1379,PubMed:27977873 +Single Fiber Studies in Patient Muscle Tissue,Functional Alteration Patient cells,"Gill JS, et al., 2017, PMID: 28729369","39-year-old male patient with sensorineural deafness who presented to the eye clinic with nyctalopia, retinal pigmentary changes and bilateral cortical cataracts NO PEO +At 5 years of age he was diagnosed and treated for myoclonic epilepsy. He stopped treatment at the age of 15 years and has remained seizure free since. +Muscle biopsy analysis showed remarkable mitochondrial histochemical abnormalities characterised by a mosaic pattern of cytochrome c oxidase (COX) deficiency affecting ~40% of all fibres on both the individual enzyme reaction and the sequential cytochrome c oxidase-succinate dehydrogenase (COX-SDH) reaction (figure 3A) and subsarcolemmal mitochondrial accumulation (ragged-blue fibres affecting ~5% of the total biopsy) on the individual SDH reaction",Score,1 (1),Score 1 point for single fiber study,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3d7a973c-7786-48a1-bf82-3764761739ba-2023-04-17T160000.000Z,1380,PubMed:28729369 +Overview of mitochondrial transcription and translation,Biochemical Function A,"D'Souza AR, et al., 2018, PMID: 30030363",>10 genes involved in mitochondrial translation,Score,2 (0.5),13 OXPHOS polypeptides in mtDNA which is >10 genes,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3d7a973c-7786-48a1-bf82-3764761739ba-2023-04-17T160000.000Z,1380,PubMed:30030363 +Review: LeighMap,Biochemical Function A,"Rahman J, et al., 2017, PMID: 27977873",Rahman et al. reviews all genes associated with Leigh syndrome in Leigh Map 2017 (PMID: 27977873). These genes included at least thirteen nuclear genes directly involved in mitochondrial translation as well as five additional mt-tRNA genes.,Score,2 (0.5),per rubric: More than 10 gene with a related function,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3f237644-83f5-412e-9bfa-01fbd280c15a-2021-06-28T155537.306Z,1381,PubMed:27977873 +Overview of mitochondrial transcription and translation,Biochemical Function A,"D'Souza AR, et al., 2018, PMID: 30030363",MT-TL1 is a tRNA for leucine in mitochondrial and is involved in mitochondrial translation,Score,2 (0.5),13 OXPHOS polypeptides in mtDNA which is >10 genes,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_555b9573-762e-4c6a-904e-f2227c916bc4-2023-04-17T160000.000Z,1382,PubMed:30030363 +MT-TL1 Mouse Model A2748G (3302A>G),Model Systems Non-human model organism,"Tani H, et al., 2022, PMID: 35998911","Patients with 3302A>G and other MT-TL1 variants notably have elevated lactate and diabetes +inability to create mouse line at higher levels of heteroplasmy (3 embryonic stem cell clones implanted about 94% did not produce any F1 mice with the variant) compatible with severe disease",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_555b9573-762e-4c6a-904e-f2227c916bc4-2023-04-17T160000.000Z,1382,PubMed:35998911 +Review: LeighMap,Biochemical Function A,"Rahman J, et al., 2017, PMID: 27977873",Rahman et al. reviews all genes associated with Leigh syndrome in Leigh Map 2017 (PMID: 27977873). These genes included at least thirteen nuclear genes directly involved in mitochondrial translation as well as five additional mt-tRNA genes.,Score,2 (0.5),per rubric: More than 10 genes with a related function,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_efef782a-88db-470d-9687-23629c75e05a-2021-06-28T154710.419Z,1383,PubMed:27977873 +Mitochondrial translation defects,Biochemical Function A,"Rahman J, et al., 2017, PMID: 27977873",Rahman et al. reviews all genes associated with Leigh syndrome in Leigh Map 2017 (PMID: 27977873). These genes included at least thirteen nuclear genes directly involved in mitochondrial translation as well as five additional mt-tRNA genes.,Score,2 (0.5),>10 genes associated with mitochondrial translation,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6cd5832f-dd32-4217-bec4-93bd4b7b6618-2023-06-05T040000.000Z,1384,PubMed:27977873 +Mouse model to study mtDNA variants prenatally,Model Systems Non-human model organism,"Freyer C, et al., 2012, PMID: 23042113","M.3875delC affected tRNAMet anticodon loop +tRNA Met transcripts are stable (from mice carrying variant) but aberrantly migrated on gel suggesting conformation change +M.3875delC led to severe aminoacylation defect in heart and muscle, and less so liver (Mice carrying variant at 80% heteroplasmy) +Increasing levels of the m.3875delC mutation were accompanied by a progressive increase in steady-state levels of all other mitochondrial mRNAs and tRNAs apart from ND6 (Fig.4e) +No respiratory chain deficiency was detected",Score,0 (2),"GCEP opted to exclude out of abundance of caution given two variants seen in mice (MT-TC and MT-TM) +Mouse also contains the m.5245T>C variant, no impact on fecundity, no clinical data about the mice +biochemical defect including aminoacylation defect and structural change to tRNA",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_56195896-f357-403b-b7db-118314bcec94-2022-12-19T170000.000Z,1386,PubMed:23042113 +Overview of mitochondrial transcription and translation,Biochemical Function A,"D'Souza AR, et al., 2018, PMID: 30030363",MT-tRNA involved in mitochondrial translation,Score,2 (0.5),13 OXPHOS polypeptides in mtDNA which is >10 genes + NSUN3 which formylates and methylates wobble cytosine in MT-TM,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_56195896-f357-403b-b7db-118314bcec94-2022-12-19T170000.000Z,1386,PubMed:30030363 +Overview of mitochondrial transcription and translation,Biochemical Function A,"D'Souza AR, et al., 2018, PMID: 30030363",MT-tRNA involved in mitochondrial translation,Score,2 (0.5),13 OXPHOS polypeptides in mtDNA which is >10 genes,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_4659b074-c4eb-4290-9716-f39a213e37cc-2022-10-20T160000.000Z,1387,PubMed:30030363 +Hardy et al 2016 Patient 4 Single Fiber Studies,Functional Alteration Patient cells,"Hardy SA, et al., 2016, PMID: 27536729","COX- fibers (25%), RRFs 5% +SFS show +46.8 ± 9.1 (n=14) COX+ +94.7 ± 0.5 (n=9) COX- +p=0.0004",Score,1 (1),Default compelling SFS,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_60c99f15-3a4b-4d7f-be1c-5edde18a4396-2022-12-19T170000.000Z,1388,PubMed:27536729 +Hardy et al 2016 Patient 2 Single Fiber Studies,Functional Alteration Patient cells,"Hardy SA, et al., 2016, PMID: 27536729","Combined OXPHOS defect I, III, IV (>80 COX - fibers) + 1 SFS (38.33 ± 6.09 (n=12) COX + +92.47 ± 0.62 (n=15) COX - p<0.0001",Score,1 (1),Default for SFS,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_60c99f15-3a4b-4d7f-be1c-5edde18a4396-2022-12-19T170000.000Z,1388,PubMed:27536729 +Overview of mitochondrial transcription and translation,Biochemical Function A,"D'Souza AR, et al., 2018, PMID: 30030363",MT-tRNA involved in mitochondrial translation,Score,2 (0.5),13 OXPHOS polypeptides in mtDNA which is >10 genes,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_60c99f15-3a4b-4d7f-be1c-5edde18a4396-2022-12-19T170000.000Z,1388,PubMed:30030363 +Cybrid notes,Functional Alteration Patient cells,"Möllers M, et al., 2005, PMID: 16199753","Mitochondrial Cybrids created from patient E in Jaksch (homoplasmic 6 year old boy) +n=22 clones for m.7512T>C +created from osteosarcoma cell cybrids (143B is used at control) +Restriction fragment length analysis showed that all clones, but also the patients fibroblasts were homoplasmic +The complete absence of patient-derived nuclear DNA was confirmed in all clones used for further studies. +In all 143B control cells, 143B rho0 acceptor cells and all tested clones amplification yielded only +one fragment of a given size while amplification in the two patient fibroblast cell lines yielded one or two fragments, in both cases of a different size. This confirmed successful cybrid generation and homogeneity of 143B-derived nuclear DNA in all clones ++0.5 - identified COX deficiency in all tested clones by spectrophotometry, complex I deficiency by OCR (greater deficiency in presence of malate and glutamate than succinate and glycerol 3 phosphate) ++0.5 reduction in steady state leave of tRNA Ser(UCN) to 6% of control with normal MT-TV, MT-TL1, MT-TQ +-Aminoacylation was not affected +But protein synthesis was 58% of control for the m.7512T>C cybrids by pulse labelling +Hypothesis is that mutations lead to defect in maturation from unmodified to mature tRNAs leading to degradation (maybe a processing defect at play too) +m.7497G>A studies: +n=15 clones for m.7497G>A clones, all homplasmic, complete absence of patient derived nuclear DNA confirmed in all clones +-On non-denaturating northern blots we detected an altered electrophoretic mobility +for G7497A containing tRNA molecules suggesting a structural impact of this mutation, which was confirmed by structural probing. +-Complex IV deficiency seen in 7497G>A cybrid cell lines (+0.5) + +Steady state levels of MT-TS1 2% of control when normalized to nuclear 5S rRNA (0.5+)",Score,0 (1),Will be scored as a definite recurrent pathogenic variant due to compelling cybrid data in cases,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d6647b8f-3d8a-4a6f-b54d-383a33fc9828-2023-01-19T170000.000Z,1391,PubMed:16199753 +Overview of mitochondrial transcription and translation,Biochemical Function A,"D'Souza AR, et al., 2018, PMID: 30030363",MT-tRNA involved in mitochondrial translation,Score,2 (0.5),13 OXPHOS polypeptides in mtDNA which is >10 genes and ELAC2 (16361254),https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d6647b8f-3d8a-4a6f-b54d-383a33fc9828-2023-01-19T170000.000Z,1391,PubMed:30030363 +Mitochondrial translation defects,Biochemical Function A,"D'Souza AR, et al., 2018, PMID: 30030363",Mitochondrial tRNA,Score,2 (0.5),Mitochondrial translation defects are a known cause of primary mitochondrial disease.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_99e85f3e-3c1f-4265-8b70-0870e95d4c30-2023-04-17T160000.000Z,1393,PubMed:30030363 +Review: LeighMap,Biochemical Function A,"Rahman J, et al., 2017, PMID: 27977873",Rahman et al. reviews all genes associated with Leigh syndrome in Leigh Map 2017 (PMID: 27977873). These genes included at least thirteen nuclear genes directly involved in mitochondrial translation as well as five additional mt-tRNA genes.,Score,2 (0.5),per rubric: More than 10 gene with a related function,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_42f2fc91-c26d-416c-8d93-448e4a52983b-2021-04-14T040000.000Z,1394,PubMed:27977873 +Review: LeighMap,Biochemical Function A,"Rahman J, et al., 2017, PMID: 27977873",Rahman et al. reviews all genes associated with Leigh syndrome in Leigh Map 2017 (PMID: 27977873). These genes included at least thirteen nuclear genes directly involved in mitochondrial translation as well as five additional mt-tRNA genes.,Score,2 (0.5),per rubric: More than 10 genes with a related function,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3dc54202-27f3-4bf4-883f-5273a49dcb70-2021-06-28T150550.120Z,1397,PubMed:27977873 +Golden Retrievers with single nt deletion on MT-TY and SAN,Model Systems Non-human model organism,"Baranowska I, et al., 2009, PMID: 19492087","One affected dog with paracrystalline inclusions +Reductions in respiratory chain studies - not sufficient to meet ""Walker Criteria"", but statistically significant +We also analyzed the degree of heteroplasmy in different tissues from three affected dogs. The frontal lobe, spinal cord with dorsal root ganglia (7th thoracal and 5th lumbar), optic nerve, recurrent laryngeal nerve, pancreas, thyroid gland, and skeletal muscle of both pelvic and thoracic limb were analyzed by qOLA. The results revealed that all analyzed tissues had a higher mutation load, closeto 0% wt, compared with that found in blood cells from the same affected individuals. Unfortunately, we do not have access to tissues from clinically healthy relatives with a similarly high mutation load as that found in the affected dogs. +Northern Blot Analysis +Steady-state levels of three mtDNA tRNA species were assessed by northern blot analysis. Analysis of tRNAs extracted from muscle tissue of three SAN-affected dogs and two controls, a dachshund +and a healthy golden retriever, showed that all three SAN-affected dogs had significantly reduced levels of tRNATyr compared to the two controls (Figure 2C); the hybridization intensity was on average about 10-fold lower than for controls (P,0.001 in a student’s t-test). In contrast, all affected dogs showed normal expression of tRNACys and tRNAGln compared with the controls (Figure 2C).",Score,1 (2),"0.5 for phenotype, 0.5 for reduction in MT-TY",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d035d0c2-f0c9-4767-b833-99be610d3e46-2023-02-16T170000.000Z,1398,PubMed:19492087 +Overview of mitochondrial transcription and translation,Biochemical Function A,"D'Souza AR, et al., 2018, PMID: 30030363",MT-tRNA involved in mitochondrial translation,Score,2 (0.5),13 OXPHOS polypeptides in mtDNA which is >10 genes,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d035d0c2-f0c9-4767-b833-99be610d3e46-2023-02-16T170000.000Z,1398,PubMed:30030363 +BN PAGE study not scored in Lim et al 2020 Case data,Functional Alteration Patient cells,"Lim AZ, et al., 2020, PMID: 32684384","BN PAGE in muscle : decreased assembly of fully assembled complex I, normal assembly complex II, III, IV, V +(score 0.5 in Experimental (patient cells0 data)",Score,0.5 (1),Score 0.5 for BN PAGE data (separate from immunofluorescence and steady state data),https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d035d0c2-f0c9-4767-b833-99be610d3e46-2023-02-16T170000.000Z,1398,PubMed:32684384 +Translation of mtDNA,Biochemical Function A,"Boczonadi V, et al., 2018, PMID: 29980628","Review: MTFMT encodes mitochondrial methionyl-tRNA formyltransferase which catalyses the formylation of the mitochondrial methionine tRNA (Met-tRNAMet). This formylation is +required for the initiation of translation and elongation of mitochondrial protein synthesis.",Score,2 (0.5),At least 10 genes with a role in the translation of mtDNA encoded proteins are associated with Leigh syndrome (reviewed Rahman et al. (2017); PMID: 27977873.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0e7a00ee-ef09-443f-9d66-03128e1fb225-2020-03-19T194517.723Z,1400,PubMed:29980628 +Zebra Fish Model,Model Systems Non-human model organism,"Dowling JJ, et al., 2009, PMID: 19197364","Both humans and zebra fish exhibit skeletal muscle abnormalities and specific nucelar structures and T-tubule disorganization is seen in both models. Additionally, both exhibit impaired movement.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_2b60f008-871f-4c5f-aa46-099d09fb66df-2019-11-22T170000.000Z,1402,PubMed:19197364 +MTMR2 and SBF2 (MTMR13) are PTPases,Biochemical Function A,"Raghu P, et al., 2019, PMID: 31507376","Both genes belong to the MTM family of protein tyrosine phosphatases, which are known regulators of cellular remodeling and morphological changes. PTPs have a known role in myelination, and perturbation of a PTP is likely to result in abnormal cellular morphologies and dynamics.",Score,1 (0.5),"Given that MTMR2 is in the same protein family as SBF2 (aka. MTMR13) and both genes cause a near identical form of demyelinating neuropathy, I have increased the score form default.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_44a837e2-ae06-4e4d-b7cf-ae2a3009b47d-2020-02-11T170000.000Z,1403,PubMed:31507376 +Mto1 mouse model (hypomorph),Model Systems Non-human model organism,"Becker L, et al., 2014, PMID: 25506927","Mouse ortholog: strong similarity (87%) +mouse model generated by gene trap mutagenesis (Mutant mice were generated by insertion of the gene trap vector U3CEO into intron 6 of the Mto1 gene by the German Gene Trap Consortium +(Mto1Gt(G019A03)Wrst). The analysis of full-length transcripts revealed 17% residual transcripts compared to wild-type (Fig. 1B). Hence, the gene trap created a hypomorphic Mto1 allele. +Het mice normal, Fertility, breeding as well as offspring ratios were unaffected in homozygous and heterozygous mutants. Lifespan was not affected under normal conditions and mutants also reached high ages. +-No obvious changes between mutant and wild-type mice were found in basic observation tested according to a modified SHIRPA protocol. +-Body weight at the age of 10 weeks was significantly reduced +-Heart rate was consistently reduced in mutants as compared to controls at different ages and conditions: +-Qualitative analysis of the ECG in mice under anesthesia demonstrated an extremely high incidence of arrhythmic events in mutant animals, 16 of 19 mutant animals had marked arrhythmias (p,0.001), mainly atrioventricular blocks, but also premature ventricular beats or a higher degree of sinoatrial node blocks seen as an intermittent complete loss of the P wave. +-At echocardiography, we detected slightly dilated hearts in the knockout mice with significantly increased diastolic and systolic internal LV diameters +-Heart weight at the age of 22 weeks was significantly increased related to body weight in mutants compared to controls +-histopathological examination of hearts from the 10 months old mice revealed focal signs of myofiber degeneration (e.g. atrophy and vacuolization) and fibrosis in the mutant animals. +-Transmission Electron Microscopy revealed focal necrosis in cardiac muscle cells with intracristal swelling in mitochondria and dilated sarcoplasmic reticulum in young adult mutant mice +-mtDNA ND1 copy number of heart mtDNA reduced to 60% (Fig6A) +-heart tissue: lower amounts of complex I protein were detected in samples from mutant mice whereas there was no difference between mutants and control mice in the other complexes (Fig 6B) +-Maximal respiration rate normalized to total protein was significantly reduced in mutant mitochondria isolated from heart tissue (p=0.008, Fig. 6D). (seahorse method) +BNE in gel activity assay confirmed reduced abundance and activity of complex I only, +Changes in the abundance of any complex in skeletal muscle, liver and brain were not detected.",Score,2 (2),"Hypomorphic mouse. Milder phenotype than observed in clinical phenotype: +0.5 pts abnormal heart conduction and reduced heart rate (bradycardia); +0.5 pts cardiomyopathy, observed as heavier hearts, dilated hearts in the knockout mice with significantly increased diastolic and systolic internal LV diameters. +0.5pts abnormal heart muscle histology, indicating myofiber degeneration, EM showed abnormal mitochondrial morphology, specifically cristae +0.5 pts biochemistry reduced mtDNA in heart, reduced MRR and complex I activity.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_08fff88b-cbbd-46f3-bf35-f7b7a348ab54-2024-03-04T170000.000Z,1404,PubMed:25506927 +zebrafish KO mto1 model,Model Systems Non-human model organism,"Zhang Q, et al., 2021, PMID: 33836087","Zebrafish Mto1 is 52.7% identical to human MTO1 aminoacid sequence +Using CRISPR/Cas9 technology an allele, mto1del7bp was generated by introducing a 7 bp deletion in the exon 3 of mto1. +Both mto1+/− and mto1−/− zebrafish were adult-viable +-Deletion of mto1 resulted in defects in embryonic heart development, fig 1. +-Histology 6 month fish: cardiomyocytes mto1−/− zebrafish showed hypertrophy of cardiac myocytes and myocardial fiber disarray. The abnormal myocytes included the enlarged size, bizarre-shaped nuclei and disorganized patterns. EM showed defects in cardiac myofibrils and widened I-bands (Fig 2). Figure 2G, cardiomyocytes of mto1−/− mutant zebrafish +displayed abnormal mitochondrial morphology including fragmented mitochondria and partial loss of cristae. +-Biochemistry: Figure 6A,B, the levels of complex I, complex IV and complex V in the mto1−/− zebrafish were 24%, 31% and 75%, relative to the mean values measured in the WT zebrafish. levels of complex III were comparable with those in WT zebrafish. Figure 6C, the activities of complex I, III and IV in mto1−/− zebrafish were 57%, 80% and 43%, relative to the mean values measured in the WT zebrafish. activities of complex II and complex V in mto1−/− and mto1+/− zebrafish were comparable with those in WT zebrafish. +In addition: Deficient aminoacylation of mitochondrial tRNAs, Fig 3, Altered conformation of mitochondrial tRNAs Fig 4.",Score,1.5 (2),0.5 heart malformation during embryogenesis; 0.5 pts abnormal heart histopathology; 0.5pt reduced complex I and IV.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_08fff88b-cbbd-46f3-bf35-f7b7a348ab54-2024-03-04T170000.000Z,1404,PubMed:33836087 +Pyle et al_functional alteration in patient cells,Functional Alteration Patient cells,"Pyle A, et al., 2014, PMID: 26380172","Measured oxygen consumption as a marker of the electron transport chain (ETC) capacity. As shown in Fig. 3, the patient cell lines showed a decrease in OCR when compared to controls. This difference is notably bigger after treating the cells with FCCP, an ETC accelerator which acts as an uncoupling agent transporting hydrogen ions the inner mitochondrial membrane, showing a clear ETC defect in the patient cell lines.",Score,0.5 (1),Evidence of electron transport chain defect in patient cells.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_78f97463-d8b2-411a-9292-1908646dac77-2021-04-01T174500.572Z,1408,PubMed:26380172 +Wesolowska et al_functional alteration in patient cells,Functional Alteration Patient cells,"Wesolowska M, et al., 2015, PMID: 27858754","Cell morphology (Fig. 2D) and growth rate of fibroblasts derived from the patient were comparable to control cells on glucose. However, these failed to proliferate on galactose (Fig. 2E, F), a substrate that forces cells to utilise oxidative phosphorylation rather than glycolysis for ATP production. This observation confirmed that the cells express a mitochondrial respiratory chain defect, consistent with the decrease in complex IV activity determined spectrophotometrically. +De novo mitochondrial translation was assessed in patient fibroblasts and indicated a global decrease in protein synthesis (Fig. 4A), as seen in previously reported patients. This reduction in mt-protein synthesis is not a consequence of a reduction in mt-RNA levels, which are modestly elevated (Fig. 4B), again as seen in other C12orf65 patients. When cells are artificially depleted of C12orf65 protein using siRNA, the elevation in mt-RNA levels is more striking (Fig. 4C). A mitoribosome defect is unlikely to be responsible in +this patient, as no global differences were observed in the steady state levels of mitoribosomal protein levels (Fig. 4D). To identify if the synthesised polypeptides are stable, steady state levels of RC proteins were assessed by western blotting following SDS-PAGE. This confirmed decreased levels of complex IV (COX2 expression), consistent with our biochemical assays but also revealed reduced levels of CI and modest changes in CIII subunits (Fig. 4E). To determine if synthesised polypeptides were incorporated into fully assembled oxidative phosphorylation complexes, western blots of mitochondrial fractions separated by 1D BN-PAGE were performed. A reduction in the amount of fully assembled complexes I, IV and V was observed in the patient compared to controls, together with a minor complex III defect, visible in the I+III supercomplex (Fig. 4F). These data are consistent with C12orf65 playing a ubiquitous role in mt-translation but with a more severe effect on CIV activity. This translation defect caused by loss of C12orf65 does not appear to trigger an unfolded protein response as no increase was seen in relevant proteases (Fig. 4G, LONP and CLPX).",Score,0.5 (1),Evidence of respiratory chain defect and reduction in intra-mitochondrial protein synthesis in patient fibroblasts.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_78f97463-d8b2-411a-9292-1908646dac77-2021-04-01T174500.572Z,1408,PubMed:27858754 +Leigh map,Biochemical Function A,"Rahman J, et al., 2017, PMID: 27977873","According to Leigh Map, C12ORF65 is one of 13 nuclear genes involved in mitochondrial translation (Table 2).",Score,1.5 (0.5),Genes associated with translation,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_78f97463-d8b2-411a-9292-1908646dac77-2021-04-01T174500.572Z,1408,PubMed:27977873 +MTRR SSO pseudoexon rescue,Rescue Patient cells,"Palhais B, et al., 2015, PMID: 25878036","c.903+469T>C, the most frequent variant in MTRR reported in patients with cblE, has been shown to create an Exonic Splice Enhancer (ESE), which facilitates the recognition of a weak 5´splice site, leading to pseudoexon inclusion and a subsequent frameshift. +Detailed experiments with splicing reporter minigenes expressed in HEK293 cells, showed that splice-shifting oligonucleotides (SSOs), designed to be complementary to critical regions of the pseudoexon, including the exonic splice enhancer (ESE), were effective in restoring normal splicing (note: this was counted as variant-level evidence). Subsequently, the authors found that ESE-SSO treatment could also restore correct splicing in MTRR patient cells (homozygous for c.903+469T>C) to levels almost those of control fibroblasts (Figure 4). The effect persisted until at least 96 h after treatment and could be achieved with different SSO-doses and transfection procedures. In addition, MTRR activity was shown to be rescued to about 50% of that in control cells when the ESE-SSO was used to correct MTRR splicing.",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_905575cf-cb80-4038-b82b-1de3ae1c469d-2021-07-02T160000.000Z,1409,PubMed:25878036 +MTX2 and MTX1 deficiency hampers TNF-α-induced apoptosis,Functional Alteration Patient cells,"Elouej S, et al., 2020, PMID: 32917887","The number of dead cells upon apoptosis was significantly reduced in patients compared to control fibroblasts, confirmed by the reduction of Caspase 3 cleavage in MTX2-mutant fibroblasts. +Observed Increased macro-autophagy in MTX2 deficient patient fibroblast cells. +The mitochondrial dysfunction and hampered apoptosis may account for the lipodystrophy and progeroid like features, hepatomegaly",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_95b2738d-c934-401b-8665-dd6a19ec6a05-2024-06-05T160000.000Z,1410,PubMed:32917887 +Immunoblot analysis of MTX2,Functional Alteration Patient cells,"Elouej S, et al., 2020, PMID: 32917887","Immunoblot analysis of MTX2 and other outer mitochondrial membrane proteins of whole-cell extracts from healthy control (WT) and patients’ (MADM2, MADM3) fibroblasts shows that MTX2 deficiency leads to loss of Metaxin-1 (MTX1) and mitochondrial dysfunction, including network fragmentation and oxidative phosphorylation impairment. May account for Poor growth, hypotonia, muscle weakness, skeletal abnormalities, nephrotic proteinuria and glomerulopathy",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_95b2738d-c934-401b-8665-dd6a19ec6a05-2024-06-05T160000.000Z,1410,PubMed:32917887 +Wild-type MTX2-cDNA transfection restores disease phenotypes,Rescue Patient cells,"Elouej S, et al., 2020, PMID: 32917887","Mitochondrial network analysis using the MINA toolset on healthy and MADM2 and MADM3 patients’ fibroblasts before and after MTX2-cDNA transfection showing improved mitochondrial footprint, individuals, networks, and branches per network for all parameters in PT conditions, when compared either to the patient’s nontransfected cells or to control cells.",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_95b2738d-c934-401b-8665-dd6a19ec6a05-2024-06-05T160000.000Z,1410,PubMed:32917887 +MTX2 Knock-out,Model Systems Non-human model organism,"Elouej S, et al., 2020, PMID: 32917887","mtx-2 knock-out in C. elegans showed nuclear and mitochondrial morphological abnormalities. +mtx-2 downregulation was obtained in C. elegans using both mtx-2 RNAi in a strain-expressing lmn-1:gfp(Ce-lamin-GFP) and mtx-2 KO in a strain expressing a mitochondrial matrix-targeted GFP in body-wall muscle cells (mitogfp). +from the text: ""mtx-2 downregulation by siRNA led to nuclear morphological abnormalities together with Ce-lamin-GFP nuclear aggregates that increased with the worm’s age (Fig. 5g–h), similar to previous +results on patients’ cells""",Score,1.5 (2),model organism,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_95b2738d-c934-401b-8665-dd6a19ec6a05-2024-06-05T160000.000Z,1410,PubMed:32917887 +IHC and IF of mutated MUC1 in kidney biopsy from patient,Expression B,"Kirby A, et al., 2013, PMID: 23396133","In patients with the disease is present mutated MUC1 (frame shifted MUC1 = MUC1-fs) which is not present in healthy controls. +MUC1-fs can be also detected in other tissues in patients with shifted mutation in VNTR of MUC1 gene (e.g. skin, breast).",Score,1 (0.5),Presence of MUC1-fs (mutated MUC1) in kidney tissue is one of the diagnostic marker of ADTKD due to mutations in MUC1.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_effa2b38-35c6-4071-b0d1-ce6970bb6ec1-2021-01-13T170000.000Z,1411,PubMed:23396133 +Venesio_2012_Expression,Expression A,"Venesio T, et al., 2012, PMID: 22876359",Diffuse localization of wild-type MUTYH protein in colonic epithelial cells.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_4330fde4-0116-4781-a5ac-40c387a0b41f-2022-06-20T170000.000Z,1414,PubMed:22876359 +MYBPC3-/- iPS cells,Model Systems Cell culture model,"Ma Z, et al., 2018, PMID: 31015724","Demonstrated pronounced DCM-like contractile phenotypes (impaired systolic contraction force, faster decay of calcium dynamics and calcium desensitization) in MYBPC3–/– cardiac microtissues contracting against stiffer fibres.",Score,0 (1),Homozygous models best represent AR disease but human variants indicate AD disease.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_652d0370-9574-450c-b7c4-eec86ade9046-2020-09-04T160000.000Z,1420,PubMed:31015724 +Xenopus tropicalis model,Model Systems Non-human model organism,"Abu-Daya A, et al., 2009, PMID: 19769958",Abnormal development of the cardiac chambers,Score,1 (2),"Model demonstrates abnormal heart development, not exact CHD phenotype seen in humans.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_44f4a5ee-8b1d-44b7-87ca-967968d8c0c4-2023-05-09T040000.000Z,1426,PubMed:19769958 +Human cardiac tissue and patient-specific iPSC-CMs with MYH6,Rescue Cell culture model,"Kim MS, et al., 2020, PMID: 32656206",Cells become organized,Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_44f4a5ee-8b1d-44b7-87ca-967968d8c0c4-2023-05-09T040000.000Z,1426,PubMed:32656206 +Patient cells functional alteration,Functional Alteration Patient cells,"Kim MS, et al., 2020, PMID: 32656206","iPSC-CMs with the MYH6-R443P variant were substantially disorganized in both the inserted C/VAR and inserted VAR/VAR compared to WTcc-CMs. Tissue became organized in correct WT iPSC-CMs +Dysmorphic sarcomeres were observed in atrial tissues from HLHS patients with MYH6 variants, but not in ventricles.",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_44f4a5ee-8b1d-44b7-87ca-967968d8c0c4-2023-05-09T040000.000Z,1426,PubMed:32656206 +human cardiac myofibrils with MYH7 E1426K variant,Functional Alteration Patient cells,"Vikhorev PG, et al., 2017, PMID: 29093449","while faster relaxation kinetics observed, passive stiffness was significantly reduced",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_4ec27d4f-70ea-4c6a-ad67-d6260ecadcde-2020-11-13T170000.000Z,1430,PubMed:29093449 +troponin destabilization impairs sarc-cyto interaction,Protein Interaction,"Dai Y, et al., 2020, PMID: 31937807",sarcomere well established ontology for DCM and other CMs,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_4ec27d4f-70ea-4c6a-ad67-d6260ecadcde-2020-11-13T170000.000Z,1430,PubMed:31937807 +Cultured HM myoblast,Model Systems Cell culture model,"Dahl-Halvarsson M, et al., 2017, PMID: 28125727",Myosin storage myopathy is a protein aggregate myopathy associated with the characteristic subsarcolemmal accumulation of myosin heavy chain in muscle fibers. R1845W and H1901L mutants were prone to formation of myosin aggregates without assembly into striated sarcomeric thick filaments in cultured muscle cells.,Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_8974721a-f333-4fb7-b8b7-043233d3d100-2021-05-13T160000.000Z,1431,PubMed:28125727 +A1603P and K1617del in Vitro and in Vivo,Functional Alteration Non-patient cells,"Parker F, et al., 2018, PMID: 29660325",Both A1603P and K1617del mutations affected filament formation in vitro and also affect the localization of myosin into the muscle sarcomere in cultured skeletal muscle myotubes.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_8974721a-f333-4fb7-b8b7-043233d3d100-2021-05-13T160000.000Z,1431,PubMed:29660325 +Drosophila model - R1845W rescue,Rescue Non-human model organism,"Dahl-Halvarsson M, et al., 2020, PMID: 33234710","Overexpression of Abba can restore muscle morphology in flies with overexpressing eMhc R1844W mutation. Although some muscle dysfunction was enhanced, lack of flight ability was, however, not rescued by overexpression of Abba possibly due to a dominant antimorphic feature of embryonic Mhc.",Score,0 (2),"The model system doesn't involve in gene disruption in MYH7 homolog, instead an overexpression of mutation R1844W. The rescue doesn't directly target MYH7 gene",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_8974721a-f333-4fb7-b8b7-043233d3d100-2021-05-13T160000.000Z,1431,PubMed:33234710 +Knock-in mouse generated with p.R702C,Model Systems Non-human model organism,"Suzuki N, et al., 2013, PMID: 23976996","Knock-in mouse generated with p.R702C mutation which is common in humans with disease. Mice recapitulated platelet, granulocyte, renal, and hearing loss phenotypes. Low birthrate of hets (12%) and no homs were born suggesting lethality of homozygosity. Mice had significantly elevated ABR thresholds. Did not have cataracts which is consistent with human phenotype for this variant.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d6801442-c490-44a0-9a60-84ab5b20f7ac-2018-02-20T050000.000Z,1433,PubMed:23976996 +Zhou Cell Culture Model,Model Systems Cell culture model,"Zhou Z, et al., 2016, PMID: 27378946","In skinned porcine cardiac muscles, RLC-depleted and IVS6-1 reconstituted muscle strips displayed a significant decrease in maximal contractile force and a significantly increased Ca(2+) sensitivity, both hallmarks of hypertrophic cardiomyopathy-associated mutations in MYL2. The amino-acid changes in IVS6-1 were sufficient to impose significant conformational alterations in the RLC protein and trigger a series of abnormal protein-protein interactions in the cardiac muscle sarcomere. Notably, the mutation disrupted the RLC-MHC interaction and the steady-state and kinetics of the actomyosin interaction. Specifically, slower myosin cross-bridge turnover rates and slower second-order MgATP binding rates of actomyosin interactions were observed in IVS6-1 vs. WT reconstituted cardiac preparations.",Score,0.5 (1),"Infants who were IVS6-1(+∕+)-positive died between 4 and 6 months of age due to cardiomyopathy and heart failure. In vitro results suggest that when placed in vivo, IVS6-1 may lead to cardiomyopathy and early death of homozygous infants by severely compromising the ability of myosin to develop contractile force and maintain normal systolic and diastolic cardiac function.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7b25ff6c-3ede-46a3-a637-3eab7aa18569-2021-07-13T154913.625Z,1434,PubMed:27378946 +D94A Variant in Mouse Models,Model Systems Non-human model organism,"Yuan CC, et al., 2018, PMID: 29463717","Transgenic mice with D94A heterozygous genetic variant have normal phosphorylation properties, but abnormal response to Ca2+ and drop in ATPase activity. Leads to hypocontractility. Mice develop DCM phenotype by 12 months including by echocardiogram and invasive hemodynamics.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_8405609b-1664-4849-848e-bec138350c92-2020-10-09T160000.000Z,1435,PubMed:29463717 +Mouse KO,Model Systems Non-human model organism,"Millay DP, et al., 2013, PMID: 23868259","Early embryos had signs of skeletal muscle deficiency such as paralysis, kyphosis and flaccid limbs. Longitudinal sections through hindlimb muscles of mymk−/− embryos at E14 revealed an absence of multi-nucleated myofibers",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_570cb879-d299-41b0-87ba-406bf9567266-2022-04-08T040057.342Z,1440,PubMed:23868259 +Multiple in vitro differentiation assays using primary myobl,Functional Alteration Non-patient cells,"Millay DP, et al., 2013, PMID: 23868259","Myoblasts from WT and mymk -/- mouse embryos were studied to evaluate effect on myoblast fusion. In the WT myoblasts extensive myotubes with many nuclei were formed, but the mymk -/- embryos had mostly mono-nucleated myotubes. A differentiation index was calculated as the percentage of nuclei in myosin-positive cells. The fusion index was calculated as the percentage of nuclei contained in myosin-positive myotubes. While the differentiation index did not differ between WT and mymk-/- myoblasts, the fusion index was significantly reduced compared to WT myoblasts indicating that the lack of muscle formation is due to the absence of myoblast fusion.Myomaker overexpression in C2C12 cells resulted in an increase in myotubes with multiple nuclei, despite no differences in expression of several muscle differentiation factors. +Cell-mixing experiments (differential labelling) using primary myoblasts from WT, mymk+/− and mymk−/− embryos demonstrated that mymk+/− myoblasts formed multi-nucleated myotubes without WT myoblasts, while mymk−/− myoblasts failed to fuse. myomk−/− myoblasts could only form multi-nucleated myotubes in the presence of WT myoblasts",Score,1 (0.5),Four independent in vitro differentiation assays were used to investigate myoblast fusion in myoblasts from WT and mymk -/- mouse embryos.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_570cb879-d299-41b0-87ba-406bf9567266-2022-04-08T040057.342Z,1440,PubMed:23868259 +Expression of Myomaker protein during embryogenesis,Expression A,"Millay DP, et al., 2013, PMID: 23868259","This study describes the expression of Myomaker during mouse embryogenesis. Myomaker is expressed in myotomes of the somites and later in limb buds and axial skeletal muscles. Transcriptional expression of Myomaker matches that of other muscle transcripts such as for Myogenin and M-cadherin. Myomaker expression is limited to skeletal muscle in E19 embryos. Expression of a FLAG-tagged Myomaker protein in C2C12 cells demonstrated localization to the surface of myoblasts. In myoblast cultures undergoing myoblast fusion, Myomaker was detected at sites of cell-cell interaction. Permeabilized C2C12 cells demonstrate intracellular vesicle localization, as expected for a membrane protein",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_570cb879-d299-41b0-87ba-406bf9567266-2022-04-08T040057.342Z,1440,PubMed:23868259 +Zebrafish KO,Model Systems Non-human model organism,"Di Gioia SA, et al., 2017, PMID: 28681861","Loss of myoblast fusion. Zebrafish show reduced growth, craniofacial deformities and fatty infiltration in muscles.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_570cb879-d299-41b0-87ba-406bf9567266-2022-04-08T040057.342Z,1440,PubMed:28681861 +Myosin Va function in Purkinje Neurons,Biochemical Function B,"Wagner W, et al., 2011, PMID: 21151132","Functional null allele of Myo5a in dilute lethal mice display severe ataxia. +Metabotropic glutamate receptor (mGluR)-dependent Ca2+ transient is observed to be missing in dl20J/dl20J PNs (Purkinje neurons of mice homozygous for functional null allele of Myo5a) via two-photon laser glutamate uncaging (Fig. 1c). Spine Endoplasmic reticulum (ER) which releases Ca2+ is present within the dendrites of dl20J/dl20J PNs, but it is almost completely missing from their spines (Fig. 2e). +Cerebellar cultures from dl20J/dl20J mice transfected with PN-specific plasmids expressing a GFP-tagged version of the brain-spliced isoform of myosin-Va and mRFP-ER restores the characteristic tubular ER that protrudes from the dendritic shaft into spines in the dl20J/dl20J PNs (Fig. 3a, b, and top panels in d). Volume marker (GFP) analysis of these PNs showed that ER targeting is rescued to the level of WT PNs (Fig. 5a). +Myosin-Va-dependent ER motility was analyzed in WT PNs and dl20J/dl20J PNs expressing WT myosin-Va or mutant versions of the myosin that display both reduced velocities and run lengths in vitro, and myosin-Va drives the movement of the ER towards the spine tip was concluded (Figure 5a, 5b).",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_792cf7b2-5ca7-4d85-95a5-a43eaa52b180-2021-07-27T144901.941Z,1444,PubMed:21151132 +Myosin Va expression in human cerebellum,Expression A,"Souza CC, et al., 2013, PMID: 23558932","Western blotting of a homogenate of human cerebral cortex shows intense staining of a 200-kDa region, corresponding to myosin Va heavy chain (Fig 1). Myosin Va was expressed at all ages from the 10th postnatal day to the 98th year of life, in molecular, Purkinje and granular cerebellar layers (Fig 2).",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_792cf7b2-5ca7-4d85-95a5-a43eaa52b180-2021-07-27T144901.941Z,1444,PubMed:23558932 +Colocalization of myosin Va tail domains and melanosome,Biochemical Function B,"Wu X, et al., 1998, PMID: 9864363","Myosin Va was characterized as a molecular motor that binds to pigment granules and captures them in the filamentous actin (F-actin)-rich tips of the melanocytes from where they are transferred to keratinocytes. +Myosin Va tail domain fusion proteins (without ‘head’ motor domains containing ATP-binding sites as well as having the capability to bind to actin fibers) was expressed in wild-type melanocytes. Cooperative/capture mechanism operating in reverse was demonstrated, i.e. melanosomes, displaced from actin in the periphery by myosin Va tail domains, redistribute on microtubules to the cell center, creating a dilute-like phenotype (acting as dominant negative effect) (Figs. 6–8).",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_792cf7b2-5ca7-4d85-95a5-a43eaa52b180-2021-07-27T144901.941Z,1444,PubMed:9864363 +Wong Mouse Model,Model Systems Non-human model organism,"Wong EY, et al., 2016, PMID: 27171474",Linkage and WES performed on mouse. Heterozygotes displayed intermediate phenotype between wildtype and homozygotes.,Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_50d408fe-e298-4683-985c-57a37b30e273-2018-02-20T170000.000Z,1445,PubMed:27171474 +Kim Expression,Expression A,"Kim YY, et al., 2017, PMID: 28400833",Myo7a was over-expressed significantly in Tmie mutant circling mouse,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1e897a2f-d4cf-4e13-85d8-f37405a09b18-2018-06-28T160000.000Z,1446,PubMed:28400833 +Yu Protein Interaction,Protein Interaction,"Yu IM, et al., 2017, PMID: 28660889",Myo7a binds to harmonin (USH1C) PDZ domain. Also binds to SANS (USH1G). Myo7/harmonin/SANS form a tripartite complex linking cadherins to the actin-rich core of stereocilia and microvili,Score,1 (0.5),Upgraded because this paper cites other studies that provide evidence for Myo7a and Ush1g interaction.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1e897a2f-d4cf-4e13-85d8-f37405a09b18-2018-06-28T160000.000Z,1446,PubMed:28660889 +MYOC Model Flies,Model Systems Non-human model organism,"Carbone MA, et al., 2009, PMID: 19148291","Like the JOAG linked with MYOC in humans, the flies suffer fluid discharge from overexpressed mutant or wildtype MYOC. This mirrors the increased pressure that humans suffer, and also causes rapid deterioration in visual function similar to the glaucoma phenotype. The UPR in response to the accumulation of MYOC is predicted to be the human disease mechanism, and the ER stress in the flies activated the response and induced apoptosis similar to that in humans. Note that the Q368X protein yielded less aggregation than the other mutants, likely because of the smaller size and weaker aggregates it forms. This agrees with both mouse and human predicted models of glaucoma.",Score,1.5 (2),"This model demonstrates mirroring of some important phenotypes of glaucoma in humans, however the difference between the Drosophilia physiology and our own makes direct comparison more difficult. It does yield more support for the MYOC accumulation disease mechanism theory, which is considered the likely mechanism of the disease. Therefore, despite its limitations, this model is only downgraded to a 1.5.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_fe5896cf-ec59-431e-bf95-02de61729269-2022-02-17T170000.000Z,1448,PubMed:19148291 +MYOC Mutations Activate Stress Pathway,Functional Alteration Non-patient cells,"Itakura T, et al., 2015, PMID: 26396484","The wild-type MYOC protein was found entirely in the cell culture medium, while the mutant proteins were retained entirely in the cell according to western blot analysis. The activity of stress-response genes associated with glaucoma, such as IL1A, ACTA2, and FOXO1 were increased in these cells similarly to those found in glaucoma patients. This signals an increased stress on the cells, part of the mechanism of MYOC-related glaucoma. The expression of the variants also caused cellular toxicity, with cell death after long exposure. This is also observed in glaucoma patients, with premature apoptosis being a mechanism for the increased pressure. These results were further confirmed with the addition of a mild POAG variant; both the wild-type and A427T were found in the medium, with the mutants collecting in the cell lysates.",Score,0.5 (0.5),"This evidence shows that mutant MYOC accumulating influences the stress pathway, causing cell toxicity and apoptosis. It also upregulates stress genes seen in glaucoma patients. This evidence is enough to earn default points.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_fe5896cf-ec59-431e-bf95-02de61729269-2022-02-17T170000.000Z,1448,PubMed:26396484 +Knockout Mouse,Model Systems Non-human model organism,"Filomena MC, et al., 2020, PMID: 31647200",Similar histopathological features were seen.,Score,1 (2),Downgraded because KO mice phenotype does not display muscle weakness and specifics of phenotypes were not seen in both.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6aeb67cc-c960-4511-a708-b0acadb34588-2020-06-17T194636.472Z,1449,PubMed:31647200 +Bang 2001 Expression 1,Expression A,"Bang ML, et al., 2001, PMID: 11309420","Human RNA master blots (Northern analysis) showed that MYPN gene expression was restricted to adult striated muscles, with the highest expression in cardiac muslces.",Score,0.5 (0.5),"Restricted expression in human heart and skeletal muscle in adults, and heart only in fetal tissue (Northern blot). Western blot showed localization to Z-band in rat myocytes.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d992d892-856b-4f25-bab1-997f6493018c-2023-06-14T160000.000Z,1450,PubMed:11309420 +Bang 2001 Protein Interaction 1,Protein Interaction,"Bang ML, et al., 2001, PMID: 11309420",Y2H screen of human skeletal muscle cDNA using myopalladin as bait revealed ACTN2 as an interacting partner and also ANKRD1.,Score,0 (0.5),"Limited to moderate involvement and limited involvement in HCM, respectively. This was shown in Purejvav too.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d992d892-856b-4f25-bab1-997f6493018c-2023-06-14T160000.000Z,1450,PubMed:11309420 +Bang 2001 Funct. Alt. 1,Functional Alteration Non-patient cells,"Bang ML, et al., 2001, PMID: 11309420",Overexpression of NH-2 domain of MYPN in chick cardiac myocytes resulted in disruption of the Z line architecture and sarcomere filaments.,Score,0 (0.5),"Since this was an overexpression model, and overexpression of an entire domain, the experts decided that it would be difficult to draw conclusions on a specific mutation. Therefore, no points were awarded.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d992d892-856b-4f25-bab1-997f6493018c-2023-06-14T160000.000Z,1450,PubMed:11309420 +MYPN over-expression,Functional Alteration Non-patient cells,"Bang ML, et al., 2001, PMID: 11309420","Marked disruption of the Z-line architecture and disruption of thin, titin, and thick filaments resulting in the disruption of the cardiac sarcomere structure. Similar results were seen in PMID 18006477 with over-expression of patient variants (P1112L and V1195M).",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ffd924ad-55ce-4b05-8a91-584ef49b4e80-2020-10-09T160000.000Z,1451,PubMed:11309420 +MYPN Expression,Expression A,"Bang ML, et al., 2001, PMID: 11309420",Northern blots showing MYPN RNA in fetal and adult human hearts. Western blots and immunofluorescence showing MYPN protein expression in rat and chicken cardiomyocytes.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ffd924ad-55ce-4b05-8a91-584ef49b4e80-2020-10-09T160000.000Z,1451,PubMed:11309420 +MYPN and ACTN2,Protein Interaction,"Bang ML, et al., 2001, PMID: 11309420",GST pull-down showed the interaction of MYPN with ACTN2. PMID 18006477 also showed similar interaction using immunofluorescence.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ffd924ad-55ce-4b05-8a91-584ef49b4e80-2020-10-09T160000.000Z,1451,PubMed:11309420 +MYPN and CARP (ANKRD1),Protein Interaction,"Bang ML, et al., 2001, PMID: 11309420","GST pull-down identified and interaction between MYPN and CARP (ANKRD1). This was also shown using co-localization in mouse myofibrils using electron microscopy. PMID 19608031, 25541130, and 14583192 also identified MYPN-CARP interactions.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ffd924ad-55ce-4b05-8a91-584ef49b4e80-2020-10-09T160000.000Z,1451,PubMed:11309420 +Mouse MYPN mRNA,Expression A,"Gu Q, et al., 2017, PMID: 28515850",Showed RNA levels of MYPN present in mouse heart.,Score,0 (0.5),Previously scored mRNA information for the human heart in PMID 11309420.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ffd924ad-55ce-4b05-8a91-584ef49b4e80-2020-10-09T160000.000Z,1451,PubMed:28515850 +Phenotype characterization,Model Systems Non-human model organism,"Ree R, et al., 2015, PMID: 26251455",Knockdown of Naa10 in zebrafish recapitulates growth retardation and developmental abnormalities in human patients with Naa10 variants.,Score,1 (2),A non-mammalian model and because they used a morpholino approach.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_fcdd3d02-82f3-4ea3-a2b0-8ac2d4c40b1b-2020-09-02T040000.000Z,1454,PubMed:26251455 +Functional Alteration/Non-Patient Cells (iPSCs),Functional Alteration Non-patient cells,"Ward T, et al., 2021, PMID: 33557580","Ward et al. (2021) introduced NAA15 variants into human induced pluripotent stem cells (iPSCs) using CRISPR/Cas9 and assessed the consequences on RNA and protein expression. N-terminal acetylation levels of 32 and 9 NatA-specific targeted proteins were reduced in null and haploinsufficient NAA15 cells, respectively. In addition, steady-state protein levels of 562 proteins were altered in both null and haploinsufficient NAA15 cells.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_f9732e0c-1306-4fb5-b1b3-873258903e75-2022-01-05T170000.000Z,1455,PubMed:33557580 +murine Nacc1-R284W impairs glutamatergic neurotransmission,Model Systems Cell culture model,"Daniel JA, et al., 2023, PMID: 37533751","Nacc1-R284W mutation impairs glutamatergic neurotransmission. Neurons expressing Nacc1-R284W exhibited significantly reduced glutamate-induced currents compared to neurons expressing Nacc1-WT. +Glutamate receptors of the kainic acid (KA) type have long been implicated in epilepsy. KA elicited significantly smaller currents in Nacc1-R284W neurons than neurons expressing Nacc1-WT. +Altered glutamatergic transmission is frequently observed in experimental models of epilepsy, intellectual disability and autism.",Score,0 (1),This experimental evidence is not scored because it has been awarded points for genetic evidence serving as functional support for the R298W variant in patients.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_bd05706d-fd13-4f5e-9063-f49d7bbefd97-2023-10-04T160000.000Z,1456,PubMed:37533751 +R284W causes loss of binding to key synpatic proteins,Functional Alteration Non-patient cells,"Daniel JA, et al., 2023, PMID: 37533751","In mouse neurons, Nacc1 R248W (murine homology of human R298W) exhibits increased SUMO conjugation, resulting in impaired protein interaction with SynGAP1, a post-synaptic ptrotein +Inhibition of Nacc1 R248W SUMOylation partially restores protein interaction with SynGAP1. Nacc1-R284W also exhibits reduced binding to GluK2A, encoding a glutamate receptor subunit of the kainate subtype. This effect is independent of SUMOylation.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_bd05706d-fd13-4f5e-9063-f49d7bbefd97-2023-10-04T160000.000Z,1456,PubMed:37533751 +NACC1 interacts with SynGAP1 and GluK2A,Protein Interaction,"Daniel JA, et al., 2023, PMID: 37533751","NACC1 interacts with SynGAP1 and GluK2A proteins, encoded by SYNGAP1 and GRIK2 genes, respectively. Both genes have a definitive relationship with complex neurodevelopmental disorder. +NACC1 also interacts with cullin 3 (CUL3) (PMID: 17699672), implicated in a neurodevelopmental disorder (definitive relationship with complex neurodevelopmental disorder).",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_bd05706d-fd13-4f5e-9063-f49d7bbefd97-2023-10-04T160000.000Z,1456,PubMed:37533751 +NARS1 Biochemical Function,Biochemical Function B,"Rubio Gomez MA, et al., 2020, PMID: 32303649","Elements related to aminoacyl-tRNA synthatases such as tRNA biogenesis, modification, elongation factors and ribosome biosynthesis are also implicated in several diseases, including neurodegenerative diseases like Charcot-Marie Tooth.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_42f31685-bea9-4543-9aef-ed80859be363-2024-03-06T170000.000Z,1458,PubMed:32303649 +NARS1 Biochemical Function,Biochemical Function B,"Rubio Gomez MA, et al., 2020, PMID: 32303649","Elements related to aminoacyl-tRNA synthatases such as tRNA biogenesis, modification, elongation factors and ribosome biosynthesis are also implicated in several diseases, including neurodegenerative diseases like Charcot-Marie Tooth.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c46ba676-3297-4e2c-a88f-bc479c32de60-2024-03-06T170000.000Z,1459,PubMed:32303649 +Wang_expression,Expression B,"Wang L, et al., 2020, PMID: 32788587","Western-blot analysis was performed on control, unaffecteds (U1 and U2), and affected patient fibroblasts (A1 and A2) to determine NARS1 protein expression. Patients were A1 (homozygous p.Thr17Met) and A2 (compound het p.Met69Aspfs*4; p.Asp356Ala). Patient cells with NARS1 variants show reduced NARS1 protein levels by about half.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c46ba676-3297-4e2c-a88f-bc479c32de60-2024-03-06T170000.000Z,1459,PubMed:32788587 +Wang_Functional Alteration,Functional Alteration Patient cells,"Wang L, et al., 2020, PMID: 32788587","By day in vitro 52, affected organoids were noticeably smaller than unaffected organoids. By day in vitro 90, the majority of unaffected COs were >5 mm, while none of the affected COs were >5 mm, and most were <1 mm diameter.",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c46ba676-3297-4e2c-a88f-bc479c32de60-2024-03-06T170000.000Z,1459,PubMed:32788587 +Patient fibroblast NARS2 rescue,Rescue Patient cells,"Simon M, et al., 2015, PMID: 25807530","Lentiviral transfection of NARS2 fibroblasts resulted in a significantly increased oxygen consumption rate (OCR) (Fig 5B). In the patient fibroblast cells overexpression of wild type NARS2 significantly rescued the activity of complexes I, III and IV.",Score,1 (1),"The activity of complexes I, III and IV is directly affected by the level of NARS2",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_8874861d-9d28-440d-a751-54c22df0d4ad-2019-12-19T190722.572Z,1460,PubMed:25807530 +Biochemical function:Review,Biochemical Function A,"Boczonadi V, et al., 2018, PMID: 29980628",Review: The primary function of mitochondrial-aminoacyl-tRNA synthetases is to charge mitochondrial tRNA (mt-tRNA) molecules with their cognate amino acids.,Score,2 (0.5),At least 11 genes involved in mitochondrial translation have been associated with Leigh syndrome (PMID 27977873),https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_8874861d-9d28-440d-a751-54c22df0d4ad-2019-12-19T190722.572Z,1460,PubMed:29980628 +Van Bergen 2023_Functional alteration patient cells,Functional Alteration Patient cells,"Van Bergen NJ, et al., 2023, PMID: 36834994","Performed whole-cell proteomic profiles in adult patient and previously reported patients and showed ‘mitochondrial distress signature’​ +A significant number of dysregulated proteins were identified, including the elevation of four proteins related to mitochondrial apoptotic processes (SOD2, BAX, CYCS and AIMF2), reduction in complex-I, complex-IV and small and large mitoribosome ​ +Muscle biopsies demonstrated the deficiency of AMP deaminase, which is part of the purine nucleotide cycle",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_eb15469f-f6a5-4f4e-b434-267c88c04fe3-2024-02-22T170000.000Z,1461,PubMed:36834994 +Zebrafish null,Model Systems Non-human model organism,"Albers CA, et al., 2011, PMID: 21765411","The model system recapitulates human phenotypes of thrombocytopenia and abnormal bleeding, manifested as spontaneous bleeding the the tail of the MO-zebrafish.",Score,1 (2),"The zebrafish recapitulated human phenotypes but was more severe, which may be expected due to the difference between a null-phenotype in zebrafish and a loss of function one in the GPS cases. Also the typical GPS platelet morphology (i.e.absent alpha-granules) was not observed due to the complete abrogation of thrombocytes in the zebrafish.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ae8bd4d6-8810-423b-83e0-98667f06426d-2019-06-26T160000.000Z,1464,PubMed:21765411 +GNF Expression Atlas,Expression A,"Albers CA, et al., 2011, PMID: 21765411","NBEAL2 is expressed in megakaryocytes and upregulated during megakaryopoiesis. GNF expression Atlas 2 data from U133A and GNF1H indicating high expression of NBEAL2 in whole blood, BM - CD34+, and BM-CD33+ myeloid cells compared to expression in brain tissue.",Score,0.5 (0.5),"NBEAL2 is expression in megakaryocytes and upregulation during megakaryopoiesis is consistent with its role in gray platelet syndrome. In contrast with Nbea, which in mouse is required for the formation and functioning of central neuronal synapses, NBEAL2 is not expressed in brain, consistent with the lack of neurological phenotypes in cases with GPS.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ae8bd4d6-8810-423b-83e0-98667f06426d-2019-06-26T160000.000Z,1464,PubMed:21765411 +Cultured Megakaryocytes,Functional Alteration Patient cells,"Di Buduo CA, et al., 2016, PMID: 26987485","Despite normal differentiation,α-granules, von Willebrand factor, thrombospondin and P-selectin, were markedly reduced in GPS patients compared to controls. Additionally, several GPS megakaryocytes displayed emperipolesis, while this abnormality was not observed in any of the mature megakaryocytes from control subjects. GPS megakaryocyte interaction with type I collagen revealed abnormal actin stress fibers formation, microtubule assembly, and megakaryocyte spreading. Further, proplatelet formation on fibronectin revealed that megakaryocytes derived from GPS patients displayed shorter proplatelet branches compared to control megakaryocytes. The percentage of proplatelet forming megakaryocytes was markedly reduced in GPS megakaryocytes compared to controls.",Score,1 (1),"Proplatelets from GPS megakaryocytes displayed abnormal architecture with significant reduction in the absolute number of bifurcations compared to healthy controls. These results were consistent with median platelet number of GPS patients, which was significantly lower (56 × 103 platelets/μl, range: 30–65) than in healthy controls (294 × 103 platelets/μl, range: 200–380). Moreover, the presence of giant proplatelet tips and released platelets in cell cultures from GPS patients was consistent with the findings that these patients displayed a significant macrothrombocytopenia (mean platelet volume: 3.9 μm, range: 3.5–4.3) with respect to healthy controls (mean platelet volume: 2.4 μm, range: 2–2.7). All together these data suggest that altered megakaryocyte interaction with extracellular environment, together with a severe defect in proplatelet formation and branching, may be the major causes of reduced platelet count and increased platelet size that characterize GPS.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ae8bd4d6-8810-423b-83e0-98667f06426d-2019-06-26T160000.000Z,1464,PubMed:26987485 +NBN 657del5 XRay,Functional Alteration Patient cells,"Nowak J, et al., 2017, PMID: 28261280",Heterozygous b-lymphocytes displayed significantly increased double strand breaks compared to wild type with 5Gy of X-ray radiation.,Score,0 (1),Removing points because this data duplicates other data showing the role of NBN in DNA repair.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_fc101ed8-f6ae-49b8-8850-384da62eb9b9-2023-03-14T170000.000Z,1465,PubMed:28261280 +rescued by WT cDNA (Cybrid),Rescue Patient cells,"Uehara N, et al., 2014, PMID: 25356405",CO-I deficiency (~30% fibroblasts); rescued by WT cDNA (Cybrid),Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_497170a6-a042-46cb-9809-3c3094fcd05e-2019-05-20T184847.372Z,1469,PubMed:25356405 +C.elegans RNAi knockdown,Model Systems Non-human model organism,"Falk MJ, et al., 2009, PMID: 19672299","RNAi-generated hypomorphic C. elegans strains were generated for 28 nDNA-encoded complex I subunits and complex I assembly factors, strains were exposed for 3 generations to RNAi. +Data summarised in Table 3, the 58% RNAi knockdown lead to a 41% reduction in complex I activity of isolated mitochondria, the mean respiratory control ratio (RCR) was significantly decreased for the NDUFA10 knockdown compared to wildtype.",Score,0.5 (2),Biochemical recapitulation of disease (reduced complex I activity and reduced respiratory capacity),https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1abd1440-686c-4bc9-91fb-59f7191891dd-2023-11-06T050000.000Z,1470,PubMed:19672299 +Molecular model,Biochemical Function A,"Zhu J, et al., 2016, PMID: 27509854","The study built on previous structural models of the complex I core and used further cryo EM mapping to model the location and interactions of all 31 supernumerary subunits present in complex I from Bos Taurus. Fig 1-4. NDUFA10 contains a central α/β nucleoside kinase fold with a parallel 5-strand β-sheet, plus three extensions that dock it to the matrix face of ND2.",Score,2 (0.5),"NDFA10 is present in complex I. According to Leigh map (Rahman et al. 2016) a number of other non-catalytic subunits of complex I have been associated with Leigh syndrome: NDUFA1 (XL); NDUFA2, NDUFA9, +NDUFA12, NDUFS1, NDUFS2, NDUFS3, NDUFS4, NDUFS7, NDUFS8, NDUFV1, NDUFV2. (The encoded protein interacts with 10+ gene products whose dysfunction is known to cause Leigh syndrome, max score of 2 assigned, note not all the genes here have been curated at time of this work).",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1abd1440-686c-4bc9-91fb-59f7191891dd-2023-11-06T050000.000Z,1470,PubMed:27509854 +Molecular model,Protein Interaction,"Zhu J, et al., 2016, PMID: 27509854","The study built on previous structural models of the complex I core and used further cryo EM mapping to model the location and interactions of all 31 supernumerary subunits present in complex I from Bos Taurus. Fig 1-4. NDUFA10 contains a central α/β nucleoside kinase fold with a parallel 5-strand β-sheet, plus three extensions that dock it to the matrix face of ND2.",Score,2 (0.5),"NDFA10 is present in complex I. According to Leigh map (Rahman et al. 2016) a number of other non-catalytic subunits of complex I have been associated with Leigh syndrome: NDUFA1 (XL); NDUFA2, NDUFA9, +NDUFA12, NDUFS1, NDUFS2, NDUFS3, NDUFS4, NDUFS7, NDUFS8, NDUFV1, NDUFV2. (The encoded protein interacts with 10+ gene products whose dysfunction is known to cause Leigh syndrome, max score of 2 assigned, note not all the genes here have been curated at time of this work).",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e40eec3c-0ce0-442e-9058-6bf4d90d6dc3-2019-11-25T162049.949Z,1471,PubMed:27509854 +Functional alteration 2,Functional Alteration Non-patient cells,"Jang S, et al., 2018, PMID: 30531981","Used siRNA knockdown in H9c2 cells (cardioblast cell line) of the complex I subunit NDUFA11. Knockdown stimulated dissociation of a supercomplex (respirasome composed of complexes I, III, and IV) and reduced the activity of complexes I, III, and IV (Fig. 2). The activity of complex I was almost completely blocked in cells treated with NDUFA11 siRNA, complex III and IV activity was also reduced (Fig. 2). Knockdown of NDUFA11 significantly reduced ATP levels in the cells (Fig. 4).",Score,0.5 (0.5),"Knockdown of NDUFA11 suggests NDUFA11 is important for assembly/structural integrity of complex I, and is important for the respirasome formation with complexes III and IV.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_210108ec-da38-4a32-80b6-8d88f4d22677-2022-02-17T050000.000Z,1472,PubMed:30531981 +C.elegans model,Model Systems Non-human model organism,"Knapp-Wilson A, et al., 2021, PMID: 34106255","Identified nduf-11 (B0491.5) as encoding the C.elegans homologue of NDUFA11 (sequence analysis and homology modeling). Animals homozygous for a CRISPR-Cas9-generated knockout allele of nduf-11 arrested at the second larval (L2) development stage. Reducing (but not eliminating) expression using RNAi allowed development to adulthood. nduf-11 knockdown reduced NDUF-11 was downregulated to ~20% of wild-type levels and complex I levels were reduced to ~50% (Fig. S2). They confirmed nduf-11 is associated with complex I in C.elegans with BN-PAGE, and knockdown of nduf-11 results in destabilization of complex I and its supercomplexes (Fig. 4C) and a dysregulation of respiratory function, including downregulation of fatty acid biosynthesis and upregulation of fatty acid catabolic pathways (Fig. 3). A targeted GFP reporter was used to observe changes in mitochondrial morphology; nduf-11 knockdown mitochondria appeared fragmented and less reticulated (Fig. 5) and cryoelectron +tomography highlighted aberrant morphology of cristae and widening of both cristae junctions and the intermembrane space (Fig. 6). The respiratory performance of isolated mitochondria was assessed based on their oxygen consumption and membrane potential. When stimulated by the addition of ADP, the rate of respiration increased to drive OXPHOS. This activation dropped from 6.9-fold to a modest 2.3-fold in mitochondria with reduced levels of NDUF-11 (Fig. 7). They next measured the individual enzymatic activities of complex I and II in isolated mitochondrial fractions from N2 control and nduf-11(RNAi)-treated animals (Fig. 8). In line with the proteomic data, we observed a marginal increase in complex II and a significant decrease in complex I activities (Fig. 8A).",Score,0.5 (2),"Depletion of the C. elegans NDUFA11 homologue led to destabilization of complex I and its supercomplexes, a dysregulation of respiratory function, and altered mitochondrial morphology.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_210108ec-da38-4a32-80b6-8d88f4d22677-2022-02-17T050000.000Z,1472,PubMed:34106255 +Zhu et al. (2016) Function 1,Protein Interaction,"Zhu J, et al., 2016, PMID: 27509854",All genes are components of mitochondrial complex I. The study built on previous structural models of the complex I core and used further cryo EM mapping to model the location and interactions of all 31 supernumerary subunits present in complex I from Bos Taurus. Fig 1-4. NDUFA12 (B17.2) is one of five subunits which contain long loops running over the surface of the NADH dehydrogenase domain.,Score,2 (0.5),"NDUFA12 is present in complex I. According to Leigh map (Rahman et al. 2016) a number of other non-catalytic subunits of complex I have been associated with Leigh syndrome: NDUFA1; NDUFA2, NDUFA9, NDUFA10, NDUFS1, NDUFS2, NDUFS3, NDUFS4, NDUFS7, NDUFS8, NDUFV1, NDUFV2.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_81f38f43-5e0c-4cb8-9be8-091f2c8a2c71-2019-11-25T160815.348Z,1473,PubMed:27509854 +Structural model of Complex I,Protein Interaction,"Zhu J, et al., 2016, PMID: 27509854",The study built on previous structural models of the complex I core and used further cryo EM mapping to model the location and interactions of all subunits present in complex I from Bos Taurus. NDUFA13 is one of three supernumery subunits with transmembrane helices which form a cage around the core membrane domain (Fig 1b).,Score,2 (0.5),At least 13 nuclear encoded complex I genes associated with LSS (27977873: Rahman et al. 2017),https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0bc56951-c454-4e79-95f3-7ffda20482b7-2021-01-21T005411.435Z,1474,PubMed:27509854 +Patient fibroblasts,Functional Alteration Patient cells,"González-Quintana A, et al., 2020, PMID: 32722639","Patient fibroblasts CH:NDUFaA13 c.107T>C; p.(Leu36Pro); c.194delT(p.(Phe65SerfsTer34) Cultured skin fibroblasts from the proband showed 65% reduction in complex I activity, +Respirometry results showed lower levels of basal Oxygen Consumption rate (by 24%) and MRR (by 47%) than the control fibroblasts, indicating decay in the electron flux through the MRC. +Patient cells showed a lower level (by 33%) of ATP synthesis rate than control fibroblasts (Figure 2a, b) +From day four of culture the growth rate of patient cells was lower than controls and by day 7 of culture the number of viable cells was reduced.",Score,1 (1),Patient cells demonstrate a reduction in complex I activity and CI-related respiration which is consistent with LSS and observed in other LSS disorders associated with complex I genes.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0bc56951-c454-4e79-95f3-7ffda20482b7-2021-01-21T005411.435Z,1474,PubMed:32722639 +Mouse brain expression,Expression A,"Wirtz S, et al., 2011, PMID: 21556144","https://www.genecards.org/cgi-bin/carddisp.pl?gene=NDUFA2 +NDUFA2 is overexpressed in heart (6.7) abd brain (6.4) vs other tissues +Using in situ hybridization we investigated the relative expression of 33 nuclear encoded complex I subunits in different brain regions of the mouse at E11.5, E17.5, P1, P11, P28 and adult (12 weeks).",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3f40eb04-1cc3-477c-ab0a-c8162958fd4f-2019-05-20T190623.871Z,1475,PubMed:21556144 +Rahman 1,Biochemical Function A,"Rahman J, et al., 2017, PMID: 27977873",NDUFA4 interacts with two other gene products whose dysfunction is known to cause Leigh syndrome as part of the Compex IV subunit: COX8A and MT-CO3,Score,1 (0.5),Used internal guidance for scoring encoded protein shares a biochemical relationship or function with 2 -5 gene products whose dysfunction is known to cause Leigh syndrome,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_2854d105-0d20-4a19-9dee-d7aa6a60ed99-2021-01-14T214439.481Z,1477,PubMed:27977873 +Mouse,Model Systems Non-human model organism,"Dickinson ME, et al., 2016, PMID: 27626380","International Mouse Phenotyping Consortium (IMPC) showed this is embryonic lethal (pre-weaning lethality = death anytime between fertilization and weaning age, approximately 3-4 weeks of age).",Score,0.5 (2),"International Mouse Phenotyping Consortium (IMPC) showed this is embryonic lethal (pre-weaning lethality = death anytime between fertilization and weaning age, approximately 3-4 weeks of age).",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_34368748-ec12-4b2a-8bfc-3d81b7583033-2024-01-18T050000.000Z,1478,PubMed:27626380 +Molecular model,Protein Interaction,"Zhu J, et al., 2016, PMID: 27509854","The study built on previous structural models of the complex I core and used further cryo EM mapping to model the location and interactions of all 31 supernumerary subunits present in complex I from Bos Taurus. Fig 1-4. The 39 kDa subunit NDUFA9, is attached to core subunits NDUFS7 and 30 kDa NDUFS3 in the hydrophilic arm.",Score,2 (0.5),"NDFA9 is present in complex I. According to Leigh map (Rahman et al. 2016) a number of other non-catalytic subunits of complex I have been associated with Leigh syndrome: The NDUFA9 protein interacts with 10+ gene products whose dysfunction is known to cause Leigh syndrome, max score of 2 assigned.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_87c6c5c5-7bf7-4bd2-94f0-2d529a512e74-2019-11-25T162851.567Z,1479,PubMed:27509854 +NDUFAF1 Drosophila model,Model Systems Non-human model organism,"Cho J, et al., 2012, PMID: 23226344","Figure 2. dCIA30 mutation results in developmental arrest and defects in mitochondrial function and ultrastructure. +Figure 3. RNAi knock down of dCIA30 confers loss of complex I holoenzyme. +Figure 4. dCIA30 knockdown flies display developmental and physiological phenotypes that are rescued by NDI1 (Yeast NDUFAF1 ortholog) +Figure 5. Loss of dCIA30 results in multiple stress sensitivity phenotypes that are ameliorated by NDI1.",Score,1 (2),Complex I deficiency 90.5 pts) Developmental phenotype (0.5pts),https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_20bd44f6-360d-42ef-ba08-549773282d2e-2022-02-17T170000.000Z,1480,PubMed:23226344 +Electron cryomicroscopy structure of complex I,Biochemical Function A,"Zhu J, et al., 2016, PMID: 27509854","Mammalian complex I contains 45 subunits, comprising 14 core subunits that house the catalytic machinery and are conserved from bacteria to humans, and a mammalian-specific cohort of 31 supernumerary subunits. Zhu et al. present a structural model of complex I.",Score,2 (0.5),10+ gene products and components of complex I are associated with primary mitochondrial disease,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_20bd44f6-360d-42ef-ba08-549773282d2e-2022-02-17T170000.000Z,1480,PubMed:27509854 +Electron cryomicroscopy structure of complex I,Biochemical Function A,"Zhu J, et al., 2016, PMID: 27509854","Mammalian complex I contains 45 subunits, comprising 14 core subunits that house the catalytic machinery and are conserved from bacteria to humans, and a mammalian-specific cohort of 31 supernumerary subunits. Zhu et al. present a structural model of complex I.",Score,2 (0.5),Scored 2 pts per scoring rubric (> 10 proteins associated with PMD),https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_fbdf3ba5-37d8-447d-888b-2762701bab49-2022-03-07T050000.000Z,1483,PubMed:27509854 +NDUFAF3 Drosophila model,Model Systems Non-human model organism,"Murari A, et al., 2021, PMID: 34386730",Complex I assembly defect and reduced complex I activity,Score,0.5 (2),Complex I assembly defect,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_fbdf3ba5-37d8-447d-888b-2762701bab49-2022-03-07T050000.000Z,1483,PubMed:34386730 +IV11 PBMC BN-PAGE,Functional Alteration Patient cells,"Gerards M, et al., 2010, PMID: 19542079","Scoring for IV11: BN-PAGE showed a decrease of mature complex I in patient samples IV7 and IV11 to 30e40% of the control values. In carriers (III1, III2 and IV6) this was 70e90% of the normal amount of complex I (figure 4A, B).",Score,1 (1),RC dysfunction in patient cells = 1 point,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_55a2c102-f05d-4ff1-9527-3a55fb3f00c3-2021-04-09T135236.631Z,1486,PubMed:19542079 +Dictyostelium model,Model Systems Non-human model organism,"Carilla-Latorre S, et al., 2013, PMID: 23536703","The null strain showed a significant defect in growth, delay in development, a significant CI-specific defect was observed (40% activity of that of the wild type).",Score,1 (2),Poor growth = 0.5; C1 deficiency = 0.5,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_55a2c102-f05d-4ff1-9527-3a55fb3f00c3-2021-04-09T135236.631Z,1486,PubMed:23536703 +Complex I deficiency in slime mold,Model Systems Non-human model organism,"Carilla-Latorre S, et al., 2013, PMID: 23536703","Complex I deficiency + increased Citrate Synthase +Note: total cellular ATP was surprisingly increased in NDUFAF5-, but complex I was 40% of control and Citrate synthase was significantly elevated",Score,0.5 (2),Score 0.5 for complex I deficiency by spectrophotometry in slime mold,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_90482ccc-5a6c-40d1-a7ea-d8a78971ac44-2024-01-18T170000.000Z,1487,PubMed:23536703 +Rescue of growth deficit in slime mold,Rescue Non-human model organism,"Carilla-Latorre S, et al., 2013, PMID: 23536703","The strain transformed with the wild-type protein (ndufaf5− rescue strain) complemented the growth phenotype completely, in contrast to the mutated forms (orthologues to L159F and G250V), which showed similar defects as the parental ndufaf5−. Bar, 1 cm.",Score,1 (2),"Score one point (0.5 for growth defect + 0.5 for rescue with WT, but not with mutant variants)",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_90482ccc-5a6c-40d1-a7ea-d8a78971ac44-2024-01-18T170000.000Z,1487,PubMed:23536703 +Patient Cell Line Lentiviral rescue,Rescue Patient cells,"Kohda M, et al., 2016, PMID: 26741492","The mitochondria were isolated from control fibroblasts or Pt330 and Pt512 fibroblasts following the lentiviral-mediated expression of mito-TurboRFP-V5, NDUFAF6, or NDUFAF6-V5 cDNA and were analyzed by BN-PAGE and Western blotting. Complementation with NDUFAF6 or NDUFAF6-V5 restored the assembly levels of complex I in patient fibroblasts",Score,1.5 (1),Restoration of Complex I activity from two different patient cell lines (1.5 pts),https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_f7b6ace1-5b89-41c7-83a6-d6f37826d8c5-2020-11-23T194212.660Z,1488,PubMed:26741492 +Alston et al_functional alteration_patient cells,Functional Alteration Patient cells,"Alston CL, et al., 2020, PMID: 31866046","Complexome profiling (a quantitative mass-spectroscopy assay that has previously been informative in the initial characterization of other complex I genes) - These data show a generalized reduction in complex I subunits in subject 1 fibroblasts relative to healthy control fibroblasts; this result is consistent with the results of initial BN-PAGE analyses. A clear reduction in the assembled respirasome (CI-III2-IV) is apparent in subject 1 fibroblasts, with a concomitant increase in ‘‘free’’ complex III. Given that NDUFAF8 is required for NDUFAF5’s stability, we expect subject 1 to experience the same complex I assembly defects found in subjects with NDUFAF5 mutations, namely defects in Q module assembly. Indeed, absence of NDUFAF8 results in a stalled Q module assembly involving at least three of the Q module subunits (NDUFS2, NDUFS3, and NDUFA5). Stalling at this early assembly stage results in increased turnover of the later modules, as reflected in decreased levels of CI subunits.",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3459bec0-88a8-463b-a135-54670357137a-2021-04-01T195856.777Z,1489,PubMed:31866046 +C1 assembly factor,Biochemical Function A,"Alston CL, et al., 2020, PMID: 31866046",Leigh map,Score,1.5 (0.5),"Per LeighMap (Rahman et al., 2016), there are 6 other complex I assembly factors (NDUFAF2, NDUFAF4, NDUFAF5, NDUFAF6, FOXRED1, NUBPL).",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3459bec0-88a8-463b-a135-54670357137a-2021-04-01T195856.777Z,1489,PubMed:31866046 +Alston et al_rescue_patient cells,Rescue Patient cells,"Alston CL, et al., 2020, PMID: 31866046","Cultured fibroblasts from subject 1 were infected with either a FLAG-tagged NDUFAF8-encoding lentivirus or an empty vector in order to generate two polyclonal cell lines: one line expressing NDUFAF8-FLAG (+AF8), and its empty vector counterpart (–AF8) that served as a negative control for off-target effects. NDUFAF8-FLAG production in the +AF8 cell line was confirmed by immunoblot. To determine whether a rescue was obtained following transduction with wild-type NDUFAF8-FLAG cDNA, BN-PAGE was performed on mitochondria-enriched fractions using the –AF8 and +AF8 lines. The results confirmed a substantial increase in fully assembled Complex I in the subject fibroblasts expressing NDUFAF8-FLAG, supporting the likelihood of a rescue of the complex I assembly defect for subject 1, with little effect on the assembly of the other complexes. Finally, spectrophotometric analysis of the +AF8 and -AF8 lines was undertaken, demonstrating a marked increase in complex I activity in subject 1’s NDUFAF8+ transduced line (+AF8); the empty vector (-AF8) cell line showed no measurable rescue when a colorimetric complex I activity assay was used.",Score,2 (1),Max scoring (showed overexpression of NDUFAF8 is sufficient to rescue complex I assembly and complex I activity; as well as NDUFAF5 levels),https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3459bec0-88a8-463b-a135-54670357137a-2021-04-01T195856.777Z,1489,PubMed:31866046 +C elegans,Model Systems Non-human model organism,"Falk MJ, et al., 2009, PMID: 19672299",Mean respiratory control ratio (RCR) is significantly decreased compared to wildtype,Score,0.5 (2),Scored for mitochondrial/respiration abnormality comparable to human phenotype,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_2bff63e5-63a2-44fe-9a3e-561442d9c931-2022-02-07T170000.000Z,1490,PubMed:19672299 +Complex I subunit,Biochemical Function A,"Zhu J, et al., 2016, PMID: 27509854",well-known composition of complex I,Score,2 (0.5),>10 genes known to interact with this complex I subunit,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_2bff63e5-63a2-44fe-9a3e-561442d9c931-2022-02-07T170000.000Z,1490,PubMed:27509854 +Chlamydomonas model,Model Systems Non-human model organism,", , PMID: 32025618","Complex I activity: +The amc5 mutant displayed decreased rotenone-sensitive NADH: duroquinone oxidoreductase activity (Figure 5a) and exhibited the characteristic sid phenotype of complex I-deficient mutants in both liquid and solid medium (Figures 5b and S8D,E) with an average generation time of 69 hr in the dark, compared to 27 hr for the wildtype strain. Real-time RT-qPCR confirmed the loss of the wild-type NUOB10 mRNA in the amc5 mutant (Figure S8C). The amc5 mutant displayed an accumulation of a subcomplex, migrating at a size similar to the ~700 kDa subcomplex previously observed in Chlamydomonas mitochondrial mutants defective for the distal membrane arm assembly of complex I (Cardol et al., 2008; Remacle et al., 2008; Figure 5c,d). To test whether the mutation in NUOB10 is indeed responsible for the complex I defect, the amc5 mutant was transformed with a cosmid containing the NUOB10 gene (Figures 5 and S8). Molecular analyses of +the [amc5; NUOB10] transformant revealed the presence of the wildtype NUOB10 gene and restoration of relative NUOB10 transcript levels. The [amc5; NUOB10] strain also exhibited restoration of growth in the dark, complex I activity, and assembly. From these results, we conclude that the AMC5 locus corresponds to the NUOB10 gene and the NUOB10 subunit is necessary for complex I membrane arm assembly. +While the amc5 recipient strain displayed a SID phenotype, transformants expressing the wild-type +NUOB10-FLAG had restored growth in the dark similar to those with the NUOB10-containing cosmid.",Score,0.5 (2),"0.5 point for biochemical/mitochondrial dysfunction as seen in humans, per mito GCEP guidance",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_2bff63e5-63a2-44fe-9a3e-561442d9c931-2022-02-07T170000.000Z,1490,PubMed:32025618 +dndufb11-knockdown Drosophila model,Model Systems Non-human model organism,"Kohda M, et al., 2016, PMID: 26741492","Longevity, climbing activity were both reduced in dndufb11 knockdown flies compared to gfp control +Lactate and pyruvate significantly higher in dndufb11 knockdown compared to gfp control +BN PAGE shows reduced CI in knockdown compared to control",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b349c412-dba4-4b4d-91ba-47d72f8f910f-2022-01-20T170000.000Z,1491,PubMed:26741492 +Complex I deficiency in Muscle,Biochemical Function B,"Kohda M, et al., 2016, PMID: 26741492","Major criteria for complex I deficiency noted +Major Bernier criteria (<20% Tissue, <30% FCL) (muscle)",Score,0 (1),not scored because included in variant evidence,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b349c412-dba4-4b4d-91ba-47d72f8f910f-2022-01-20T170000.000Z,1491,PubMed:26741492 +CryoEM Mammalian Complex I,Biochemical Function A,"Zhu J, et al., 2016, PMID: 27509854",">45 complex I genes, including catalytic subunits, assembly factor, iron/sulfur proteins and >10+ involved in disease",Score,2 (0.5),see Leigh Syndrome GCEP criteria,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b349c412-dba4-4b4d-91ba-47d72f8f910f-2022-01-20T170000.000Z,1491,PubMed:27509854 +Complex I subunit,Biochemical Function A,"Zhu J, et al., 2016, PMID: 27509854",Well-described Complex I subunits/assembly factors,Score,2 (0.5),>10 gene products - 2 points per Mito GCEP guidance,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5d93728e-eda7-4f4a-bd64-a1f545476ee8-2022-02-07T170000.000Z,1492,PubMed:27509854 +Structural model of Complex I,Biochemical Function A,"Zhu J, et al., 2016, PMID: 27509854",The study built on previous structural models of the complex I core and used further cryo EM mapping to model the location and interactions of all subunits present in complex I from Bos Taurus. NDUF8 is an accessory subunit.,Score,2 (0.5),"At least 10 further complex I genes have been associated with Leigh syndrome spectrum, scored increased to 2pts as per rubric.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_bef2c930-4b79-4938-8325-94a0f58cdfd9-2021-01-21T004458.566Z,1493,PubMed:27509854 +International Mouse Phenotyping consortium,Model Systems Non-human model organism,"Cacheiro P, et al., 2019, PMID: 31127358","Homozygous knockout noted as having preweaning lethality, https://www.mousephenotype.org/data/genes/MGI:1914514",Score,0.5 (2),"Scored for embryonic lethality, according to agreed rubric.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_bef2c930-4b79-4938-8325-94a0f58cdfd9-2021-01-21T004458.566Z,1493,PubMed:31127358 +Structural model of Complex I,Protein Interaction,"Zhu J, et al., 2016, PMID: 27509854",The study built on previous structural models of the complex I core and used further cryo EM mapping to model the location and interactions of all subunits present in complex I from Bos Taurus.,Score,2 (0.5),"NDUFC2 is an accessory subunit in complex I. According to Leigh map (Rahman et al. 2016) a number of other non-catalytic subunits of complex I have been associated with Leigh syndrome: NDUFA1 (XL); NDUFA2, NDUFA9, NDUFA10, NDUFS1, NDUFA12, NDUFS3, NDUFS4, NDUFS7, NDUFS8, NDUFV1, NDUFV2. (The encoded protein interacts with 10+ gene products whose dysfunction is known to cause Leigh syndrome spectrum, max score of 2 assigned,",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3d819bce-43ed-45a3-a16b-74033d432272-2021-01-21T004055.963Z,1494,PubMed:27509854 +Patient fibroblasts: accumulation of complex I intermediates,Functional Alteration Patient cells,"Alahmad A, et al., 2020, PMID: 32969598",Complexome profiling using mass spectrometry showed an accumualtion of an assembly intermediate comprising of the Q module plus assembly factor TIMMDC1 amd NDUFA13 subunits in patient fibroblasts from subjects 1 and 3. The ND4 module also accumulated (TEME70 and FOXRED). Authors suggets that Complex I assembly is stalled at the Q module formation stage in the absence of the NDUFC2 subunit.,Score,1 (1),NDUFC2 is required for assembly of the complex I holoenzyme.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3d819bce-43ed-45a3-a16b-74033d432272-2021-01-21T004055.963Z,1494,PubMed:32969598 +Numerous Complex I subunits and Assembly Factors,Biochemical Function A,"Zhu J, et al., 2016, PMID: 27509854","Binds to MT-ND2 +Alahmad et al 2020 supports this with complexome analysis showing Intermediates of the N, ND2 and ND5 module were not detected in fibroblasts from Subjects 1 and 3 (Fig 4A). These findings suggest the stalling of complex I assembly at the Q module formation stage in the absence of the NDUFC2 subunit.",Score,2 (0.5),>10 genes involved as complex I subunits and assembly factors,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ba9a01a8-3b86-420f-a7e8-a43898cab9fa-2023-12-18T050000.000Z,1495,PubMed:27509854 +Complexome Studies in Subject 1,Functional Alteration Patient cells,"Alahmad A, et al., 2020, PMID: 32969598",Absence of NDUFC2 protein (mRNA 43% of control),Score,0.5 (1),Score 0.5 for absence of NDUFC2 protein on Complexome analysis,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ba9a01a8-3b86-420f-a7e8-a43898cab9fa-2023-12-18T050000.000Z,1495,PubMed:32969598 +Complexome Studies in Subject 3,Functional Alteration Patient cells,"Alahmad A, et al., 2020, PMID: 32969598",Absence of NDUFC2 on complexome profiling,Score,0.5 (1),Score 0.5 for little detectable NDUFC2 protein on complexome,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ba9a01a8-3b86-420f-a7e8-a43898cab9fa-2023-12-18T050000.000Z,1495,PubMed:32969598 +NDUFS1 (KO mouse),Model Systems Non-human model organism,"Dickinson ME, et al., 2016, PMID: 27626380",No human reported with 2 two null alleles. We expect it would also be embryonic lethal in human with KO alleles,Score,0 (2),No detailed phenotype,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b6995e66-f840-485a-a635-b64cb9f45cd9-2019-06-20T161718.750Z,1497,PubMed:27626380 +Numerous Complex I subunits and Assembly Factors,Biochemical Function A,"Zhu J, et al., 2016, PMID: 27509854",All complex I subunits and assembly factors,Score,2 (0.5),>10 complex I subunits and assembly factors,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3546f79c-056b-4087-88f0-99e97ad1bd4b-2024-01-18T170000.000Z,1498,PubMed:27509854 +Conditional knockout of NDUFS2 in mice,Model Systems Non-human model organism,"Cabello-Rivera D, et al., 2019, PMID: 31297047","Mutant mice were born at the expected Mendelian ratio +At around Postnatal day (P)5, hGFAP-NDUFS2 mice experimented a rapid worsening, showing decreased body size (Supplementary Figure S1C) and onset of ataxia, and died between P7 and P9. At this stage, we observed a marked reduction in the brain size of hGFAP-NDUFS2 mice, in which recombination efficiency was assessed (Figure 2). hGFAPNDUFS2brains showed profound anatomical abnormalities that were more evident in dorsal cortical areas, the hippocampus and +cerebellum (Figures 2B–F). Ndufs2 knockout mice frequently displayed ventricle dilatation and corpus callosum atrophy +Ndufs2 mRNA levels in dorsal telencephalon decreased in heterozygous (Ndufs2flox=-) and in hGFAP-NDUFS2 mice to 55% and 35% respecting the values seen in the homozygous +(Ndufs2flox=C) controls +Complex I activity measured by dipstick assay in brain was significantly lower in hGFAP-NDUFS2 mice (30-40% of control)",Score,1 (2),"Score 0.5 for Flox/Cre NDUFS2 Conditional Knockout Mouse phenotype +Score 0.5 for reduction in complex I activity (significantly lower than control (estimated 30-40%) ) in brain",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3546f79c-056b-4087-88f0-99e97ad1bd4b-2024-01-18T170000.000Z,1498,PubMed:31297047 +Complex I structural model,Protein Interaction,"Zhu J, et al., 2016, PMID: 27509854","The study built on previous structural models of the complex I core and used further cryo EM mapping to model the location and interactions of all subunits present in complex I from Bos Taurus. Fig 1, 3. NDUFS2 (49kDa) is one of the structural core subunits which form the ubiquinone binding channel.",Score,2 (0.5),"NDUFS2 is a core subunit for complex I. According to Leigh map (Rahman et al. 2016) a number of other non-catalytic subunits of complex I have been associated with Leigh syndrome: NDUFA1 (XL); NDUFA2, NDUFA9, NDUFA10, NDUFS1, NDUFA12, NDUFS3, NDUFS4, NDUFS7, NDUFS8, NDUFV1, NDUFV2. (The encoded protein interacts with 10+ gene products whose dysfunction is known to cause Leigh syndrome, max score of 2 assigned",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6df726c1-2897-46f8-aed1-f9939b9acf0c-2021-04-09T143144.546Z,1499,PubMed:27509854 +Conditional mouse knockdown,Model Systems Non-human model organism,"Cabello-Rivera D, et al., 2019, PMID: 31297047","Ndufs2 flox/– alleles and the hGFAP-Cre transgene (hGFAP-NDUFS2 mice) +postnatal day (P) 0 hGFAP-NDUFS2 mice were apparently indistinguishable from littermates and their brains were macroscopically similar to controls (Figure 1A), the histological analyses revealed a decrease in cortical thickness (Figure 1B) and subtle hippocampal abnormalities (Figure 1C). +At P5, hGFAP-NDUFS2 mice showed a rapid decline, showing decreased body size and onset of ataxia, and died between P7 and P9. +Brain abnormalities included abnormal dorsal cortical areas, the hippocampus and cerebellum (Figures 2B–F). Ndufs2 knockout mice displayed ventricle dilatation and corpus callosum atrophy +(Figure 2B). MCI activity was markedly reduced in cells of the dorsal telencephalon from hGFAP-NDUFS2 mice (Figure 2H)",Score,2 (2),"Reduction MCI, reduction in ATP synthesis, Phenotype: regression and ataxia",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6df726c1-2897-46f8-aed1-f9939b9acf0c-2021-04-09T143144.546Z,1499,PubMed:31297047 +NDUFS3-silencing induced mitochondrial dysfunction,Functional Alteration Non-patient cells,"Suhane S, et al., 2013, PMID: 23519235","Real-time PCR measurements revealed that all clones except one showed +significant suppression of NDUFS3.NDUSF3 silencing induces mitochondrial dysfunction +NDUFS3-silencing induced mitochondrial dysfunction exacerbates aerobic glycolysis phenotype (Figure 3-5)",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_4ae2af25-4fc1-48c3-a289-fae04977b192-2019-06-20T162502.779Z,1500,PubMed:23519235 +Complex 1 structure,Protein Interaction,"Zhu J, et al., 2016, PMID: 27509854","NDUFS4 encodes an 18-kd subunit of complex 1 of the mitochondrial respiratory chain (Papa 1996) According to Leigh map, at least 19 other complex 1 subunits (Zhu 2016; PMID: 27509854)) have been implicated in causing Leigh syndrome (Rahman 2017 PMID: 27977873).",Score,2 (0.5),The encoded protein interacts with 10+ gene products whose dysfunction is known to cause Leigh syndrome.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1ed6ae7f-8c64-4ca3-a71b-6e97ae21d71d-2019-04-08T162953.550Z,1501,PubMed:27509854 +NDUFS4 Fly knockdown,Model Systems Non-human model organism,"Foriel S, et al., 2018, PMID: 29590638","Model system demonstrated biochemical abnormalities consisted with Leigh syndrome reduced Complex I activity),neuropathological evidence in histology, along with neurocognitive and developmental symptoms (decreased lifespan, locomotor defects, and feeding difficulties).",Score,2 (2),Utilized model scoring system developed for Leigh syndrome experimental evidence,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1ed6ae7f-8c64-4ca3-a71b-6e97ae21d71d-2019-04-08T162953.550Z,1501,PubMed:29590638 +Foriel_drosophila,Model Systems Non-human model organism,"Foriel S, et al., 2018, PMID: 29590638","Model system demonstrated biochemical abnormalities consisted with Leigh syndrome reduced Complex I activity),neuropathological evidence in histology, along with neurocognitive and developmental symptoms (decreased lifespan, locomotor defects, and feeding difficulties).​",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_cc39144a-f17d-45b9-b9a9-91cf52e01f08-2023-12-04T050000.000Z,1502,PubMed:29590638 +RNAi generated gene knockdown of complex I subunits,Model Systems Non-human model organism,"Falk MJ, et al., 2009, PMID: 19672299","All 7 mtDNA subunits, at least 31 nDNA subunits, and 4 known complex I assembly factors demonstrate extensive evolutionary conservation between humans and C. elegans. RNAi was used to effectively produce animals with targeted loss-of-function in each of 28 individual, nuclear-encoded, structural subunits, and 2 assembly factors for mitochondrial complex I. Quantitative real +time PCR (qPCR) was applied to categorically confirm whether knockdown was achieved. Both patients and the model show reduced complex I activity.",Score,0.5 (2),Reduced points as it is a C. elegans model.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_04cdc50a-1ce4-410e-88bb-9d75ed33bb46-2022-01-31T050000.000Z,1503,PubMed:19672299 +Complex I crystal structure,Biochemical Function A,"Zhu J, et al., 2016, PMID: 27509854","Complex 1 has 45 subunits. Variants in most subunits encoded by different genes, are associated with Leigh syndrome or primary mitochondrial disease.",Score,2 (0.5),The encoded protein interacts with 10+ gene products associated with LS.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_04cdc50a-1ce4-410e-88bb-9d75ed33bb46-2022-01-31T050000.000Z,1503,PubMed:27509854 +Molecular model,Protein Interaction,"Zhu J, et al., 2016, PMID: 27509854",The study builds on previous structural models of the complex I core and used further cryo EM mapping to model the location and interactions of all subunits present in complex I from Bos Taurus.,Score,2 (0.5),"NDUFS7 is a core subunit of complex 1, variants in other complex1 subunits have been associated with Leigh syndrome spectrum disorder (Rahman et al. 2016).",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b702a150-de60-429e-bb12-ba8cde1483e7-2019-11-25T160008.570Z,1504,PubMed:27509854 +Patient fibroblast cell line 2,Functional Alteration Patient cells,"Iannetti EF, et al., 2018, PMID: 30429455","Investigation of cell line in a pyruvate-free medium, cell lines with homozygous variants in NDUFS8 and NDUFV1 also compared. Fig 1. Galatose reduces the viability of the NDUFS7 cell line in culture, measure by cell confluence, cell size and cell number (nuclei count). A series of experiments (Fig2 and Fig 3) showed that metabolites that increased extracellular NAD+ and therefore intracellular NAD+ were able to rescue of the galactose induced cell death of the LS cells. Fig 4. further experiments showed that pyruvate may also rescue galactose induced cell death, and it enhances the effect of eNAD. Fig.6 showed ROS levels are increaased in the galactose induced cell death model. Fig 7. cellular ATP levels are reduced in the galactose model but rescued by addition of extracellular NAD.",Score,1 (1),"The NDUFS7 Patient cell lines are unable to survive in galactose media, unmasking the dysfunction of the oxphos pathway, due to the homozygous NDUFS7 variant and complex I deficiency. Similar alteration is observed in a homozygous NDUFS8 and NDUV1 cell lines, carry homozygous variants.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b702a150-de60-429e-bb12-ba8cde1483e7-2019-11-25T160008.570Z,1504,PubMed:30429455 +Drosophila RNAi model,Model Systems Non-human model organism,"Foriel S, et al., 2019, PMID: 30972103","Drosophila model generated using RNAi induced ubiquitously through driver lines actin Gal4 and daughterless (da)-Gal4 and temperature 925 and 28 degrees C). Suppl data 1 shows % RNA knockdown evaluated using qRTPCR, larval extract: actinGal 4 line: ~75% KD at 25, 50% KD at 28, Da Gal line: 50% KD at 25 and 80% KD at 28. Fig 1. shows reduced complex 1 activity in adult flies at 25 degrees C but increased Comple II, complex III and Complex IV with both lines. Fig. 2 Eclosion rates were significantly reduced (eclosion is an energy intensive process). Fig 3. shows a reduced life expectancy for the knockdown flies in both lines. +Biochemical recapitulation of disease aspects and premature death.",Score,1 (2),"Partial Ndufs7 knockdown model using RNAi casued reduced complex I activity compared to WT lines, reduced eclosion and reduced survival. Biochemical recapitulation of disease aspects and premature death. Note reduction in expression is likely comparable to clinical situation, complete knockout of expression likely lethal.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b702a150-de60-429e-bb12-ba8cde1483e7-2019-11-25T160008.570Z,1504,PubMed:30972103 +C.elegans model,Model Systems Non-human model organism,"Falk MJ, et al., 2009, PMID: 19672299","RNAi-generated hypomorphic C. elegans strains were generated for 28 nDNA-encoded complex I subunits and complex I assembly factors, strains were exposed for 3 generations to RNAi. Data summarised in Table 3, the RNAi knockdown lead to a 43% reduction in complexI activity, the mean respiratory control ratio (RCR) is significantly decreased for the NDUFS8 knockdown compared to wildtype (same phenotype observed with NDUFS2, NDUFS3, NDUFS6, NDUFS8, NDUFV1, NDUFA6, NDUFA10, NDUFAB1, NDUFB4, NDUFB9, NDUFB10 c-elegans equivalent genes). Fig 4 Complex I holoenzyme or associated complexes were not detected in the NDUFS8 knockdown line (T20H4.5).",Score,0.5 (2),Biochemical recapitulation of disease (reduced complex I activity and reduced respiratory capacity).,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_01a27520-f92a-4b81-b63b-c15132c873be-2019-11-25T152406.734Z,1505,PubMed:19672299 +Molecular model,Protein Interaction,"Zhu J, et al., 2016, PMID: 27509854",The study built on previous structural models of the complex I core and used further cryo EM mapping to model the location and interactions of all subunits present in complex I from Bos Taurus.,Score,2 (0.5),"NDUFS8 is a core subunit of complex 1, interacting with other core subunits and accessory proteins, many of which have been associated with Leigh syndrome",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_01a27520-f92a-4b81-b63b-c15132c873be-2019-11-25T152406.734Z,1505,PubMed:27509854 +Falk_C. elegans,Model Systems Non-human model organism,"Falk MJ, et al., 2009, PMID: 19672299",This shows biochemical recapitulation of disease (reduced complex I activity and reduced respiratory capacity).,Score,0.5 (2),This shows biochemical recapitulation of disease (reduced complex I activity and reduced respiratory capacity).,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_f6764a20-2ddc-4ede-9173-409b0ae18c18-2023-11-06T050000.000Z,1506,PubMed:19672299 +Falk 2009,Model Systems Non-human model organism,"Falk MJ, et al., 2009, PMID: 19672299","RNAi-generated hypomorphic C. elegans strains were generated for 28 nDNA-encoded complex I subunits and complex I assembly factors. Strains were exposed for three generations to RNAi. Data summarised in Table 3, the RNAi knockdown lead to a 43% reduction in complex I activity, with the mean respiratory control ratio (RCR) is significantly decreased for the NDUFV1 knockdown compared to wildtype (same phenotype observed with NDUFS2, NDUFS3, NDUFS6, NDUFS8, NDUFV1, NDUFA6, NDUFA10, NDUFAB1, NDUFB4, NDUFB9, NDUFB10 c-elegans equivalent genes).",Score,0.5 (2),Biochemical recapitulation of disease (reduced complex I and respiratory capacity).,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1b96e332-59c4-4636-8bdf-bf893ea059f1-2019-11-26T163430.120Z,1507,PubMed:19672299 +Zhu 1,Protein Interaction,"Zhu J, et al., 2016, PMID: 27509854","NDUFV1 is a core subunit of complex 1. According to Leigh map (Rahman et al. 2016) a number of other non-catalytic subunits of complex I have been associated with Leigh syndrome: NDUFA1 (XL); NDUFA2, NDUFA9, NDUFA10, NDUFS1, NDUFA12, NDUFS3, NDUFS4, NDUFS7, NDUFS8, NDUFV1, NDUFV2. (The encoded protein interacts with 10+ gene products whose dysfunction is known to cause Leigh syndrome, max score of 2 assigned, note not all the genes here have been curated at time of this work).",Score,2 (0.5),"The study built on previous structural models of the complex I core and used further cryo EM mapping to model the location and interactions of all subunits present in complex I from Bos taurus (ED Figure 3). NDUFV1 is a core subunit of complex 1. According to Leigh map (Rahman et al. 2016) a number of other non-catalytic subunits of complex I have been associated with Leigh syndrome: NDUFA1 (XL); NDUFA2, NDUFA9, NDUFA10, NDUFS1, NDUFA12, NDUFS3, NDUFS4, NDUFS7, NDUFS8, NDUFV1, NDUFV2. (The encoded protein interacts with 10+ gene products whose dysfunction is known to cause Leigh syndrome, max score of 2 assigned, note not all the genes here have been curated at time of this work).",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1b96e332-59c4-4636-8bdf-bf893ea059f1-2019-11-26T163430.120Z,1507,PubMed:27509854 +Foriel 2019,Model Systems Non-human model organism,"Foriel S, et al., 2019, PMID: 30972103","Partial Ndufv1 knockdown model using RNAi, showed reduced complex I activity compared to WT lines and reduced survival. Biochemical recapitulation of disease aspects, 1pt assigned. Note reduction in expression is likely comparable to clinical situtaion, complete knockout of expression is lethal.",Score,1 (2),"Partial Ndufv1 knockdown model using RNAi, showed reduced complex I activity compared to WT lines and reduced survival. Biochemical recapitulation of disease aspects, 1pt assigned. Note reduction in expression is likely comparable to clinical situtaion, complete knockout of expression is lethal.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1b96e332-59c4-4636-8bdf-bf893ea059f1-2019-11-26T163430.120Z,1507,PubMed:30972103 +C.elegans RNAi knockdown,Model Systems Non-human model organism,"Falk MJ, et al., 2009, PMID: 19672299","C.elegans: RNAi knockdown (hypomorph) +RNAi-generated hypomorphic C. elegans strains were generated for 28 nDNA-encoded complex I subunits and complex I assembly factors, strains were exposed for 3 generations to RNAi. +Data summarised in Table 3, the 51% RNAi knockdown lead to a 24% reduction in complex I activity in isolated mitochondria.",Score,0.5 (2),Biochemical recapitulation of disease (reduced complex I activity),https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0a5b5d66-4640-48a8-ac99-842593bac366-2023-12-04T050000.000Z,1508,PubMed:19672299 +Zhu 2016: 1,Protein Interaction,"Zhu J, et al., 2016, PMID: 27509854","NDUFV2 is a core subunit of complex 1. According to Leigh map (Rahman et al. 2016) a number of other non-catalytic subunits of complex I have been associated with Leigh syndrome: NDUFA1 (XL); NDUFA2, NDUFA9, NDUFA10, NDUFS1, NDUFA12, NDUFS3, NDUFS4, NDUFS7, NDUFS8, NDUFV1, NDUFV1.",Score,2 (0.5),"The encoded protein interacts with 10+ gene products whose dysfunction is known to cause Leigh syndrome, max score of 2 assigned based on scoring guidelines, note not all the genes here have been curated at time of this work",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1266aed1-8c25-4b28-bf8a-a0e16d9b3da9-2019-11-25T145748.766Z,1509,PubMed:27509854 +NM Muscle Fibers Have Decreased Contractile Strength,Functional Alteration Patient cells,"de Winter JM, et al., 2015, PMID: 25949787","The force-generating capacity of the NEB and control muscle fibers was tested using a length motor and a force transducer element in a single fiber apparatus and exposing them to calcium. Sarcomere length was kept static to minimize the effect of the shortened sarcomeres that appear in typical NM cases. NM fibers showed markedly decreased force-generating capacity from controls at both maximal (NM - 19 ± 3 mN/mm2; CTRLslow - 133 ± 11 mN/mm2; CTRLfast - 172 ± 8 mN/mm2) and submaximal (NM - 7 ± 2 mN/mm2; CTRLslow - 58 ± 6 mN/mm2; CTRLfast - 49 ± 4 mN/mm2) calcium levels. NM fibers also display a lower relative contractile performance at submaximal calcium levels than their control counterparts, demonstrating that these muscle fibers have a lower calcium sensitivity.",Score,0.5 (1),"Although these cultured muscle fiber bundles do demonstrate the reduced contractile strength which causes many of the phenotypes in NEB-related NM, the lack of additional evidence and significant validating testing reduces this score to a 0.5.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_796dd762-f35c-425a-be3f-05424324ade0-2019-10-21T160000.000Z,1510,PubMed:25949787 +Signaling pathway derangement,Functional Alteration Non-patient cells,"Broix L, et al., 2016, PMID: 27694961",PVNH related point mutations result in increased pS6 and pAKT in cell culture,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b131d46a-069b-4c2e-a290-e7df2519a2df-2021-11-30T170000.000Z,1513,PubMed:27694961 +Mouse embryo expression,Expression A,"Broix L, et al., 2016, PMID: 27694961",Mouse immunohistochemistry,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b131d46a-069b-4c2e-a290-e7df2519a2df-2021-11-30T170000.000Z,1513,PubMed:27694961 +In utero electroporation,Model Systems Non-human model organism,"Broix L, et al., 2016, PMID: 27694961","PVNH associated mutations did not migrate to cortical plate properly, analogous to gray matter heterotopia. Process could be partly reversed by application of rapamycin to reduce S6 activity.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b131d46a-069b-4c2e-a290-e7df2519a2df-2021-11-30T170000.000Z,1513,PubMed:27694961 +SALS Spinal Cord Expression,Expression B,"Campos-Melo D, et al., 2018, PMID: 30029677",An increase in NEFH transcript and protein levels in ALS ventral lumbar spinal cords were identified when comparing the relative neurofilament levels in cases compared to controls.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6c71deac-6b11-4947-8834-8391d516a9c9-2023-03-23T160000.000Z,1514,PubMed:30029677 +Embryonic chick spinal cord electroporation,Model Systems Non-human model organism,"Jacquier A, et al., 2017, PMID: 28709447",NEFH mutants form toxic aggregates in the soma of the neurons causing cell death. Progressive apoptosis activation is consistent with the neurodegenerative features observed in the patients.,Score,1 (2),neuronal authophagy is not the typical pathological mechanism in CMT.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_8e1390ea-fd6c-4fa4-9b43-0eccff9e2829-2020-10-05T161645.817Z,1515,PubMed:28709447 +NEFH mutation destabilised NEFL filamentous network in vitro,Functional Alteration Non-patient cells,"Jacquier A, et al., 2017, PMID: 28709447",Overexpression of the mutant NEFH in cells results in NEFL destabilization and aggregation,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_8e1390ea-fd6c-4fa4-9b43-0eccff9e2829-2020-10-05T161645.817Z,1515,PubMed:28709447 +Loss of large calibers axon in NEFH knockout mouse,Biochemical Function A,"Elder GA, et al., 1998, PMID: 9763431",NEFL null mice have diminished axonal caliber.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_8e1390ea-fd6c-4fa4-9b43-0eccff9e2829-2020-10-05T161645.817Z,1515,PubMed:9763431 +Rat sciatic nerve ICC,Expression A,"Poitelon Y, et al., 2015, PMID: 26383514",Rat sciatic nerve immunocytochemistry shows abundant expression of NEFL throughout the nerve tissue.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_49d4cf82-b365-456e-9e35-2b28a66b71ec-2023-01-10T170000.000Z,1516,PubMed:26383514 +Western Blot of murine nervous system tissue,Expression A,"Zhao J, et al., 2017, PMID: 28654681","Murine model western blot showing stable expression of NEFL in cerebellum, DRG, and spinal cord.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_49d4cf82-b365-456e-9e35-2b28a66b71ec-2023-01-10T170000.000Z,1516,PubMed:28654681 +Decreased axonal caliber in KO-NFL iPSC-MN,Functional Alteration Patient cells,"Sainio MT, et al., 2022, PMID: 35237613","iPSC-motor neurons lacking NFL form filamentous structures and have reduced axonal caliber.There are still neurofilament-like structures in the motor neurons, but filamentous unorganized structures in the soma and neurites. Decreased axonal area noted in patient p.Arg367X and in KO isogenic controls when compared to wildtype.",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_49d4cf82-b365-456e-9e35-2b28a66b71ec-2023-01-10T170000.000Z,1516,PubMed:35237613 +Western Blot,Expression A,"Zhao J, et al., 2017, PMID: 28654681",Western blot shows high level of expression in a murine model.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_57ec533a-b1cb-4d1d-b12a-61ee6ac6ab07-2023-01-10T170000.000Z,1517,PubMed:28654681 +Allele-specific gene editing rescue,Rescue Patient cells,"Feliciano CM, et al., 2021, PMID: 34485306","Supernatant NFL, biomarker for axonal degeneration, is decreased",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_57ec533a-b1cb-4d1d-b12a-61ee6ac6ab07-2023-01-10T170000.000Z,1517,PubMed:34485306 +SOD1 inclusions in NEK1+ tissue samples,Biochemical Function A,"Forsberg K, et al., 2019, PMID: 30992335","Evidence of the misSOD1(wt) inclusions in the above genes can be found in this study as well, in the figures described above. +Note: Also gene C9orf72, but the form will not accept it as a HGNC symbol above.",Score,0 (0.5),The ALS GCEP chose not to score this experiment as the results did not specifically demonstrate how NEK1 contributed to the misfolding of SOD1 and because other sporadic ALS cells demonstrated similar findings,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_bb4f311c-df33-4d9e-8ac6-731b43b93615-2022-04-29T192526.542Z,1518,PubMed:30992335 +Co-immunoprecipitation,Protein Interaction,"Hoff S, et al., 2013, PMID: 23793029","Found in a complex with these three proteins, and mutant forms of all three are associated with nephronophthisis +Co-immunoprecipitated with ANKS6 and NPHP3, and by lack of staining in INVS-depleted cells",Score,1 (0.5),NEK8 interacts with three different proteins that when mutated all result in nephronophthisis,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6888a91a-6589-42a9-9622-553b4918bed6-2021-09-08T160000.000Z,1519,PubMed:23793029 +Functional alteration in mouse knockdown cells,Functional Alteration Non-patient cells,"Grampa V, et al., 2016, PMID: 26967905","Reduced NEK8 +Abnormal localisation of NEK8 +Also abnormal localisation of ANKS6",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6888a91a-6589-42a9-9622-553b4918bed6-2021-09-08T160000.000Z,1519,PubMed:26967905 +Altered function in patient cells,Functional Alteration Patient cells,"Grampa V, et al., 2016, PMID: 26967905","Skin fibroblasts from families with compound heterozygous mutations +NEK8 was absent from cilia in fibroblasts with missense mutations and detected in cytoplasmic juxtanuclear vesicular compartment – Golgi apparatus. Normally in proximal ciliary axoneme in control fibroblasts. +No staining in second family with null mutation",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6888a91a-6589-42a9-9622-553b4918bed6-2021-09-08T160000.000Z,1519,PubMed:26967905 +Non-human model (Zebra fish),Model Systems Non-human model organism,"Grampa V, et al., 2016, PMID: 26967905",Laterality defects and kidney cysts,Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6888a91a-6589-42a9-9622-553b4918bed6-2021-09-08T160000.000Z,1519,PubMed:26967905 +Rescue in a non-human model,Rescue Non-human model organism,"Grampa V, et al., 2016, PMID: 26967905",Rescue of curved body,Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6888a91a-6589-42a9-9622-553b4918bed6-2021-09-08T160000.000Z,1519,PubMed:26967905 +Rescue of knockdown murine inner medullary collecting duct,Rescue Cell culture model,"Grampa V, et al., 2016, PMID: 26967905",Normal localisation of nek8 after replacement with WT but not with missense variants from patients,Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6888a91a-6589-42a9-9622-553b4918bed6-2021-09-08T160000.000Z,1519,PubMed:26967905 +Altered expression in patients,Expression B,"Grampa V, et al., 2016, PMID: 26967905","Skin fibroblasts from families with compound heterozygous mutations +NEK8 was absent from cilia in fibroblasts with missense mutations and detected in cytoplasmic juxtanuclear vesicular compartment – Golgi apparatus. Normally in proximal ciliary axoneme in control fibroblasts. +No staining in second family with null mutation",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6888a91a-6589-42a9-9622-553b4918bed6-2021-09-08T160000.000Z,1519,PubMed:26967905 +NEMF C57BL/6J-Nemf R86S/R86S and C57BL/6J-Nemf R487G/R487G,Model Systems Non-human model organism,"Martin PB, et al., 2020, PMID: 32934225","Nemf: C57BL/6J-Nemf R86S/R86S (nucleotide: A258T; protein: R86S) R86S mice appear normal at birth but by 2 weeks of age exhibit an overt motor phenotype that manifests as an abnormal waddle-like gait, smaller body size, and decreased growth rate. Disease is progressive. The median lifespan of 20 days, with 20% of the animals living past 40 days. By 8 weeks surviving R86S mice were completely unable to perform the latency to fall test (motor function). Note: Histopathology: hindlimb muscle show decreased muscle fiber size in the medial gastrocnemius (MG) muscle of 16- to 18-day-old. Neuromuscular junctions (NMJ) showed denervation and fragmentation of postsynaptic terminals in 8 weeks. R86S mice show progressive axonal degeneration with loss of femoral motor myelinated and proximal motor axons at 16-18 days. Het mice are similar to WT. +R487G homozygous mice present with a similar phenotype to the R86S homozygous mice but present with later onset of disease.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_67f2bf82-cc3e-4006-a8e6-3f6f1dcb2513-2023-10-04T160000.000Z,1520,PubMed:32934225 +"NEMF-null allele: c. 296_297insT, p.D100GfsX6 (D106*)",Model Systems Non-human model organism,"Martin PB, et al., 2020, PMID: 32934225","This mice presented with more severe phenotypes than R86S or R487G mice, with an early deviation in growth and pre-wean lethality by postnatal day 11. D106* mice exhibited a marked reduction in occupied NMJs at end-of-life and reduction in peripheral myelinated axons. Phenotype: respiratory distress, phrenic nerve degeneration, severe neuromuscular changes. Heterozygous mice are similar to WT. +NEMF-null mice produce a phenotype consistent with disease.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_67f2bf82-cc3e-4006-a8e6-3f6f1dcb2513-2023-10-04T160000.000Z,1520,PubMed:32934225 +Validation of the methylation statuses of candidate genes,Functional Alteration Patient cells,"Sheng W, et al., 2014, PMID: 24479926","The concurrent higher methylation of EGFR, EVC2 and NFATC2 might constitute a CpG island methylator phenotype for TOF disease and provide useful cues to understand epigenetic mechanisms in the development of TOF.",Score,0.5 (1),Downgraded to be conservative in awarded points.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6f22ef84-1ac1-412a-a134-bbe7617cf47f-2024-03-11T160000.000Z,1527,PubMed:24479926 +NFIA knockout mouse,Model Systems Non-human model organism,"Lu W, et al., 2007, PMID: 17530927",This mouse model displayed many of the same brain malformations and urinary tract defects seen in human patients.,Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_8d5a5b89-8315-495a-b13d-448f9ba9c553-2022-10-11T160000.000Z,1528,PubMed:17530927 +NFIA important for development of CNS and ureteral systems,Biochemical Function B,"Lu W, et al., 2007, PMID: 17530927","Patients with brain malformations with or without urinary tract defects have a number of brain malformations (ventriculomegaly, corpus callosum dysmorphism, etc.) along with generalized urinary tract defects and renal involvement.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_8d5a5b89-8315-495a-b13d-448f9ba9c553-2022-10-11T160000.000Z,1528,PubMed:17530927 +Mouse KO,Model Systems Non-human model organism,"Oishi S, et al., 2019, PMID: 30503862",Heterozygous deficient mice have phenotype consistent with Malan overgrowth syndrome,Score,0 (2),Heterozygous deficient mice have phenotype consistent with Malan overgrowth syndrome.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5ea5e599-a88b-46de-be18-62e71389c413-2023-05-30T160000.000Z,1530,PubMed:30503862 +Mouse KO,Model Systems Non-human model organism,"Oishi S, et al., 2019, PMID: 30503862","The neuroanatomical changes in NFIX+/- brains likely contribute to deficits in cortically-controlled behavior, which may model intellectual disability and behavioral changes featured in Malan syndrome patients.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9313537f-649e-44b9-9a53-b77a9d7e070c-2023-05-30T160000.000Z,1531,PubMed:30503862 +NFKB1 and B cell survival,Biochemical Function B,"Jacque E, et al., 2014, PMID: 25225457",Defective B cell activation could be one of mechanisms underlying defective antibody production in NFKB1-associated immunodeficiency patients.,Score,0.5 (0.5),Defective signaling through RelA following BCR and CD40 stimulation in the absence of NFKB1 are suggestive of a mechanism underlying disease.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e922c85d-f51a-4394-8906-cf01978d8154-2021-05-14T152859.709Z,1532,PubMed:25225457 +NFKB1 and B cell differentiation,Biochemical Function B,"Jacque E, et al., 2014, PMID: 25225457","Antibodies, specifically antigen-specific antibodies, are produced by plasma cells. The lack of plasmablasts, progenitors of plasma cells, in mice with p50-deficient B cells indicates at least one factor underlying decreased levels of certain antibodies in patients with NFKB1-associated immunodeficiency may be the importance of NFKB1 in mature B cell differentiation.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e922c85d-f51a-4394-8906-cf01978d8154-2021-05-14T152859.709Z,1532,PubMed:25225457 +NFKB1ssaa/ssaa rescue,Rescue Non-human model organism,"Jacque E, et al., 2014, PMID: 25225457","The defect in T-cell dependent B cell antibody production (based on ELISA analysis of mouse sera) observed in NFKB1b ssaa/- mice following stimulation with NP27-CGG was overcome upon expression of p50 in NFKB1ssaa/delta CT mice. Specifically, anti-NP IgM and IgG1 levels were not significantly different between NFKB1ssaa/delta CT and NFKB1 +/- mice, whereas there was a defect in these levels in NFKB1 ssaa/- mice. This indicates increasing the levels of p50 in the mice rescues the antibody deficiency phenotype.",Score,2 (2),Using the default score because increasing p50 levels in a system deficient of p50 restored T-cell dependent antigen-specific antibody production. Decreased IgM and IgG are frequent features in patients with NFKB1-associated CVID.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e922c85d-f51a-4394-8906-cf01978d8154-2021-05-14T152859.709Z,1532,PubMed:25225457 +NFKB1 p50-/- aging,Model Systems Non-human model organism,"de Valle E, et al., 2016, PMID: 27022143","Using aged NFKB1-/- mice, the authors observed an increased incidence of autoimmunity as observed in human patients carrying pathogenic NFKB1 variants. Compared to aged WT mice, a majority of the aged NFKB1-/- mice had organ-specific antibodies, including against the pancreas, thyroid, and liver. Autoimmunity, including diabetes mellitus and hypothyroidism, is a common manifestation in NFKB1-associated CVID patients. Splenomegaly was also observed in the aged NFKB1-/- BM chimera mice (WT BM in irradiated WT mice vs. NFKB1-/-BM in irradiated WT mice) demonstrated the autoimmunity was BM cell derived, as the NFKB1-/- BM chimera mice displayed splenomegaly, lymphadenopathy, and increased multiorgan lymphocytic infiltrates, ANA production, and organ-specific autoantibodies.",Score,1 (2),"Scored down from the default score because the authors only assessed one aspect of the loss of NFKB1 expression (autoimmunity) typically observed in patients and the authors only assessed mice homozygous for the loss of NFKB1, where humans with CVID are heterozygous for pathogenic NFKB1 variants.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e922c85d-f51a-4394-8906-cf01978d8154-2021-05-14T152859.709Z,1532,PubMed:27022143 +Mouse Model I,Model Systems Non-human model organism,"Franzoso G, et al., 1998, PMID: 9432973","Low B cell counts, impaired antibody responses",Score,1 (2),"Null mice were found to have reduced numbers of B cells, were impaired in antibody responses to TD antigens, and were unable to form germinal centers n, decreased B cell counts, and a deficient immunological response to T cell–dependent and –independent antigens. These mutant mice were homozygous the null and NFKB2-related CVID is a dominant disorder. The clinical phenotype in seen in humans was partially recapitulated.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_61b546f1-5683-4588-a5bc-030ebbd5b401-2021-10-13T132601.192Z,1533,PubMed:9432973 +Mouse Model III,Model Systems Non-human model organism,"Caamaño JH, et al., 1998, PMID: 9432976","Low B cell counts, reduced antigen response",Score,1 (2),"Null mice were found to have abnormal B cell production, decreased B cell counts, and a deficient immunological response to T cell–dependent and –independent antigens. These mutant mice were homozygous the null and NFKB2-related CVID is a dominant disorder.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_61b546f1-5683-4588-a5bc-030ebbd5b401-2021-10-13T132601.192Z,1533,PubMed:9432976 +F1- II:1 functional studys,Functional Alteration Patient cells,"Kaiyrzhanov R, et al., 2022, PMID: 36256512","mean activity of the enzyme in the affected individual was low (0.50 nmol/mg protein/min), while the mean activity in the mother was normal (0.82 nmol/mg protein/min, normal range 0.6-0.9 nmol/mg protein/min). +Western blot analysis on fibroblast samples showed that subunits of each complex of the electron transport chain (CI-CIV) were decreased in the affected individual F1-II:1 compared to the heterozygous mother (F1-I:1) and a pediatric control, whereas levels of complex V subunit ATP5A remained relatively unchanged",Score,1 (1),0.5 for PDH deficiency + 0.5 for decreased WB staining of complexes I-V,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1adb01f7-d226-4f55-ab00-adb513c20e80-2023-07-11T160000.000Z,1534,PubMed:36256512 +Inability to activate TRKA,Functional Alteration Non-patient cells,"Carvalho OP, et al., 2011, PMID: 20978020","In the undifferentiated PC12 cells with the variant, the cells do not differentiate and do not have neurite outgrowth.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_f0b3691d-a3d3-42f6-9703-18af08f40688-2023-05-05T160000.000Z,1535,PubMed:20978020 +qRT-PCR from mice DRG,Expression A,"Naftelberg S, et al., 2016, PMID: 27997532",qRT-PCR,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_f0b3691d-a3d3-42f6-9703-18af08f40688-2023-05-05T160000.000Z,1535,PubMed:27997532 +Chantret 2010 Experimental 1,Functional Alteration Non-patient cells,"Chantret I, et al., 2010, PMID: 20668520",Deglycosylation defects due to NGLY1 loss causes CDDG.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3d9f5127-4673-4cc2-99b4-5f220274bc90-2022-10-18T160000.000Z,1536,PubMed:20668520 +Glycogen Metabolism,Functional Alteration Non-patient cells,"Couarch P, et al., 2011, PMID: 21505799","Mutations were obtained from 12 pedigrees where the index patient had PME - sequencing of NHLRC1 identified a mutation in 3 patients who were negative for variants in EPM2A. Testing did not reveal altered expression levels or subcellular mis-localization of the protein. All mutants exhibited decreased interaction with laforin an inability to mediate ubiquitin-dependent proteasomal degradation of R5/PTG (the latter is a positive regulator of glycogen synthesis that is typically downregulated by the laforin-malin complex) leading to the accumulation of glycogen. Notably, not all patients were positive for Lafora bodies on biopsy (1/3 tested). The authors provide several explanations - there is a high false negative rate for this test, the same mutation was positive in another report, and one variant is associated with a milder and more protracted disease course.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c4dbe715-b897-482d-afeb-b05c0653a79a-2020-03-03T170000.000Z,1538,PubMed:21505799 +Mouse Model #2,Model Systems Non-human model organism,"Valles-Ortega J, et al., 2011, PMID: 21882344","LB were present in multiple brain regions (most abundant in hippocampus and cerebellum). They were also detected in skeletal muscle and heart. There was evidence of progressive accumulation when 4m and 11m old mice were compared. The glycogen in these aggregates was poorly branched based on light absorption assays. Pathology also demonstrated a late loss of hippocampal PV+ inhibitory interneurons. +Malin KO mice developed normally and were fertile. They displayed normal gait and showed no significant differences to WT mice in the Rotarod test or in the Beam walking test. They did not present any sign of cerebellar ataxia. Exploratory behaviour of the KO mice was evaluated in an Open Field Test. At 11 months of age, these animals were hyperactive and showed an increase in exploratory behaviour. Significant differences were found in the time spent in the centre of the arena, the distance run and the number of rearings. +In vivo recordings of hippocampal activity in awake mice suggested enhanced synaptic excitability (larger fEPSP amplitudes at higher stimulus intensities). KO mice after a single injection of kainic acid produced spontaneous hippocampal seizures, accompanied on occasions (2 out of 6) by myoclonus. In contrast, no WT animal displayed clonic hippocampal seizures.",Score,1 (2),Does not manifest full phenotype.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c4dbe715-b897-482d-afeb-b05c0653a79a-2020-03-03T170000.000Z,1538,PubMed:21882344 +NHS siRNA,Functional Alteration Non-patient cells,"Brooks SP, et al., 2010, PMID: 20332100","siRNA to NHS were transfected into Caco-2 cells (carcinoma cells, which express NHS1A). The NHS KD cells appeared larger and more round, cell area was 2.5 fold larger than controls. The localization of alpha-catenin was altered, and appeared more diffuse at cell-cell contacts. Actin staining also showed diffuse localization at cell-cell contacts instead of the typical sharp definition. The expression and localiztion of ZO-1, AF-6, E-cadherin and occludin were unchanged. Treatment of MTLn3 cells with NHS siRNA resulted in a similar disorganization of the actin cytoskeleton. The MTLn3 cells also had exessive cell spreading. 2-3 fold higher than controls. The cell spreading was shown to go through the EGF pathway.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a7f57ca3-efb2-4333-9ae1-732aa429f37a-2017-10-20T040000.000Z,1539,PubMed:20332100 +Rescue of siRNA treated cells,Rescue Cell culture model,"Brooks SP, et al., 2010, PMID: 20332100","Re-expression of the NHS-1A isoform reduced the cell surface area, similar to control/WT cells. Also, the lamellapodia phenotype was ameliorated upon re-expression of NHS-1A.",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a7f57ca3-efb2-4333-9ae1-732aa429f37a-2017-10-20T040000.000Z,1539,PubMed:20332100 +RNA-seq meta-analysis of 41 DCM vs 21 controls,Expression B,"Alimadadi A, et al., 2020, PMID: 31948008","NKX2-5 was among the top 50 differentially expressed genes in DCM vs. controls +NKX2-5 was downregulated in DCM heart vs. controls",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6335de7f-71db-4768-8fa0-6faebd0ea0e8-2020-11-06T170000.000Z,1540,PubMed:31948008 +NME5 localizes to the radial spoke neck.,Biochemical Function B,"Pigino G, et al., 2011, PMID: 22065640","NME5 localization to the radial spoke neck is consistent with a role in stabilizing axonemal structure around the central microtubule pair, and may be related to the central pair defects observed in patients harboring NME5 variants.",Score,0 (0.5),No scoring has been recommended as this evidence of a structural role in the radial spoke neck has been previously demonstrated and scored in association with another publication (PMID: 25789548).,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_00efe110-5916-4da0-92ac-cee8c8b18140-2024-02-08T170000.000Z,1542,PubMed:22065640 +Nme5 knockdown in Xenopus embyros,Model Systems Non-human model organism,"Chung MI, et al., 2014, PMID: 24424412",Xenopus embyros with morpholino-based Nme5 knockdown exhibited significantly reduced cilia-based flow rate based upon the movement of latex beads across the epidermis of the embryo (Figure 4 Supplement 2G).,Score,0.5 (2),Down-scoring has been performed because the model has recapitulated one of the cellular features of human patients harboring NME5 defects but has not been examined for other organ-level phenotypes.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_00efe110-5916-4da0-92ac-cee8c8b18140-2024-02-08T170000.000Z,1542,PubMed:24424412 +Naturally occurring Nme5-related canine PCD model,Model Systems Non-human model organism,"Anderegg L, et al., 2019, PMID: 31479451","Alaskan Malamutes harboring the homozygous variant in NME5 exhibit lack of situs inversus, severe bronchial lung pattern with bronchiectasis (Figure 1), hyperemia of the tracheal mucosa with high mucopurulent secretion along the upper and lower airways and nasal cavitiy (Figure 1). Bronchoalveolar bacterial cultures were consistent with chronic infections. Reduced ciliary number and rhinitis were observed in nasal mucosa. Affected animals also showed recurrent bacterial infections, abnormal axonemal organization including extra microtubules, and absent/shortened dynein arms.",Score,2 (2),"The degree of phenotypic match between the affected animals and the NME5-deficient human patients have led to a recommendation of default scoring. The variant was naturally occurring in Alaskan Malamutes rather than a targeted mutation, and has not been observed in an affected human patient.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_00efe110-5916-4da0-92ac-cee8c8b18140-2024-02-08T170000.000Z,1542,PubMed:31479451 +NME5-deficient patient iPSCs exhibit PCD features.,Functional Alteration Patient cells,"von Schledorn L, et al., 2023, PMID: 37296588","The cells exhibit axonemal structural abnormalities such as the absence of the central microtubule pair and/or aberrations in the number of peripheral microtubule pairs (Figures 3A, 3B). Ciliary beat frequencies are higher on average and more variable in cells harboring the variant (Figure 4), while mucociliary clearance is impaired (Figure 5).",Score,1 (1),Default scoring is recommended as the patient cells exhibit functional abnormalities relevant to the subtype of PCD caused by radial spoke defects. Ciliary structure and function are shown to be defective.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_00efe110-5916-4da0-92ac-cee8c8b18140-2024-02-08T170000.000Z,1542,PubMed:37296588 +NMNAT1 enzyme activity,Functional Alteration Non-patient cells,"Falk MJ, et al., 2012, PMID: 22842227","The p.Trp169Ala mutant had no NMNAT1 enzyme activity (n = 6; P = 0.0014), as was previously reported32. The p.Val9Met mutant had significantly lower enzyme activity (37% of wild-type NMNAT1 activity) (n = 7; P = 0.0015). The p.Arg237Cys mutant had 81% of wild-type NMNAT1 activity (n = 6; P = 0.034). The p.Arg66Trp mutant had no NMNAT1 enzyme activity (n = 6; P = 0.0014).",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a6733bc3-489d-413d-9dbe-1bca25f48d49-2021-11-04T160000.000Z,1544,PubMed:22842227 +Li et al. Expression of Notch3 in PAH patients,Expression B,"Li X, et al., 2009, PMID: 19855400","Notch3 mRNA levels in the lungs of human patients with PAH directly correlated with PAH disease severity, measured by pulmonary vascular resistance. In mice, Notch3 hypoxic PH mice displayed a 3-fold increase in Notch3 at mRNA expression and protein (ICD) levels in their lungs compared to normoxic animals. While rats with monocrotaline-induced PH had progressive elevation in steady-state levels of Notch3 mRNA and ICD protein in their lungs compared to controls. Additionally, the authors found that Hes5, a downstream effector target of Notch was increased in human, mouse, and rat lungs with PAH/PH. The severity of PAH also correlated with Hes5 levels. Finally, subcultured small pulmonary artery smooth muscle cells from PAH patients and controls demonstrated that steady-state levels of NOTCH3 mRNA and protein and Hes5 mRNA and protein were higher in individuals with PAH.",Score,1 (0.5),Upscored to 1 point given comprehensive expression level evidence from both lung tissue and small pulmonary artery smooth muscle cells.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d59e2823-a923-4c3e-8976-c3451eaa8666-2022-11-03T160000.000Z,1548,PubMed:19855400 +Knock out Notch3 mice,Model Systems Non-human model organism,"Li X, et al., 2009, PMID: 19855400","The mouse model did not recapitulate the PAH disease phenotype, rather it provided evidence that the absence of notch3 prevents the development of PH. It is likely that if Notch3 is implicated in the development of PAH, evidence suggests that greater Notch3 expression correlates with the disease phenotype instead of Notch3 insufficiency.",Score,0 (2),The mouse model scored at 0 points because it does not recapitulate the PAH disease phenotype.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d59e2823-a923-4c3e-8976-c3451eaa8666-2022-11-03T160000.000Z,1548,PubMed:19855400 +Li et al. sPASMCs infected with Adeno-Notch3 ICD,Functional Alteration Non-patient cells,"Li X, et al., 2009, PMID: 19855400","sPASMC's displayed increased Notch3 ICD protein and Hes5 protein compared to Adeno-lacZ-transduced sPASMCs. sPASMCs transduced with Notch3 ICD displayed increased cell proliferation. Additionally, transfection of Hes5 siRNA was shown to abolish cell proliferation in Notch3 ICD infected cells, suggesting Notch3 upregulation acts upon Hes3 to induce the PAH phenotype.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d59e2823-a923-4c3e-8976-c3451eaa8666-2022-11-03T160000.000Z,1548,PubMed:19855400 +Rescue in MDCK cells,Rescue Cell culture model,"Delous M, et al., 2009, PMID: 19755384",Reexpression of knockdown,Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_abc69434-e9e6-4a2b-96b6-b7186f40021f-2021-01-27T170000.000Z,1549,PubMed:19755384 +Cell culture model,Model Systems Cell culture model,"Delous M, et al., 2009, PMID: 19755384",Cyst formation,Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_abc69434-e9e6-4a2b-96b6-b7186f40021f-2021-01-27T170000.000Z,1549,PubMed:19755384 +Pathogenic variants in NPHP4 also cause nephronophthisis,Biochemical Function A,"Delous M, et al., 2009, PMID: 19755384",PMID:15661758; PMID:12006559; PMID:10739664;PMID: 11493697,Score,1 (0.5),Actual function of NPHP1 is not known and thus it has no functional assay,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_abc69434-e9e6-4a2b-96b6-b7186f40021f-2021-01-27T170000.000Z,1549,PubMed:19755384 +C elegans,Model Systems Non-human model organism,"Yee LE, et al., 2015, PMID: 26540106",The model requires at least two genes involved in cilia structure to be affected to produce cysts. This is consistent with other models,Score,0.5 (2),All the models require that a double mutation in nphp1 alone is not sufficient to produce kidney cysts. A further mutation in a related ciliary gene is also required.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_abc69434-e9e6-4a2b-96b6-b7186f40021f-2021-01-27T170000.000Z,1549,PubMed:26540106 +Rescue in NIH 3T3 cells,Rescue Cell culture model,"Wiegering A, et al., 2018, PMID: 29650680",NPHP1 required for cilia development and function,Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_abc69434-e9e6-4a2b-96b6-b7186f40021f-2021-01-27T170000.000Z,1549,PubMed:29650680 +Cre recombinase rescue in MDCK cells,Rescue Cell culture model,"Delous M, et al., 2009, PMID: 19755384",Excising the sh-RNA led to rescue of more normal ciliary lengths and morphology and also led to rescue of expression of NPHP4,Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_cafd0d51-dd5d-4691-8725-86518345b097-2021-02-10T170000.000Z,1551,PubMed:19755384 +Expression in microglia,Expression A,"Smith C, et al., 2020, PMID: 32100099",Supplementary data fig. 4. NRROS expression in isolated human cortical microglia and cortical whole brain extracts.,Score,0.5 (0.5),Patient pathology includes microgliosis,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ebf06969-1af8-411f-bc64-7f1563851363-2023-09-15T160000.000Z,1563,PubMed:32100099 +Sex-dependent novelty response in NRXN1 mutant mice,Model Systems Non-human model organism,"Laarakker MC, et al., 2012, PMID: 22348092","This evidence suggests that cognition/learning/memory is altered in the context of NRXN1 mutations, however, the phenotype is not extremely similar to the phenotype observed in humans. This is reflected in the significantly downgraded score.",Score,0.5 (2),"As mentioned above, due to the fact that the experimental phenotype was not very similar to the human phenotype, the score for this evidence was downgraded.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_14bb833a-eefd-4f02-b112-c74b6866d5be-2019-07-10T160000.000Z,1564,PubMed:22348092 +NRXN1 Knockdown on Neurodevelopment in Stem Cell Models,Model Systems Cell culture model,"Zeng L, et al., 2013, PMID: 23536886","Exonic deletions in NRXN1, particularly the alpha isoform, have been associated with a number of neurodevelopmental abnormalities, including autism, intellectual disability, epilepsy, and schizophrenia, among others. This model demonstrates that NRXN1 haploinsufficiency has a significant effect on important biological processes in the brain, including altering functional pathways in the synapse, and reducing astrocyte genesis. These cellular phenotypes are similar to what is believed to contribute to complex neurodevelopmental disorder in patients.",Score,0 (1),"After discussion with the Expert Panel, it was decided that only evidence involving animal models, which more reliably model the human phenotype, would be considered.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_14bb833a-eefd-4f02-b112-c74b6866d5be-2019-07-10T160000.000Z,1564,PubMed:23536886 +NRXN1 alpha KO mice: Altered Social Behaviours,Model Systems Non-human model organism,"Grayton HM, et al., 2013, PMID: 23840597","Similar to the deficits in social behaviour observed in humans with NRXN1 variants, these animals had alterations in social behaviour; this is the first report linking a deletion in NRXN1 alpha to alterations in social behaviour (one of the core symptoms in neurodevelopmental conditions such as ASD).",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_14bb833a-eefd-4f02-b112-c74b6866d5be-2019-07-10T160000.000Z,1564,PubMed:23840597 +Mouse 1.5-Mb deletion,Model Systems Non-human model organism,"Migdalska AM, et al., 2012, PMID: 22926222","To identify whether the learning disability of Sotos patients could be observed in adult Df(13)Ms2Dja+/- mice, the mice were subjected to two olfactory discrimination tests and Df(13)Ms2Dja+/- mice show a degree of learning disability.",Score,0 (2),Did not score as deletion encompasses 36 different genes.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_aa1a412a-ee7d-4517-81ba-0ceead9668d1-2018-10-26T160000.000Z,1565,PubMed:22926222 +NSD1 expression in the human growth plate,Expression A,"Visser R, et al., 2012, PMID: 23155469",Immunohistochemistry was employed to study the expression of NSD1 in human growth plate specimens. NSD1 was expressed in the terminally differentiated hypertrophic chondrocytes at different developmental ages.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_aa1a412a-ee7d-4517-81ba-0ceead9668d1-2018-10-26T160000.000Z,1565,PubMed:23155469 +Disruption of NSD2's ability to generate H3K36me2,Functional Alteration Non-patient cells,"Zanoni P, et al., 2021, PMID: 33941880","H3K36me2 levels increased in overexpression of wild-type NSD2 and a cancer-related NSD2 GoF variant (E1099K). Contrarily, apart from C869Y and E1091K, the NSD2 variants significantly reduced H3K36me2 levels were reduced. The S1137F derivative largely behaved like the negative control and the known NSD2 catalytic mutant Y1179A. The variants found by these authors map to three distinct domains of NSD2. The data presented in this publication is consistent with all variants (apart from C896Y) compromising to varying degrees the ability of NSD2 to generate H3K36me2, a key epigenetic modification.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_de3c113b-0a7d-454d-88e3-faf4f1fdb9ac-2021-06-02T060000.000Z,1566,PubMed:33941880 +Knockout mouse model (heterozygous and homozygous),Model Systems Non-human model organism,"Blanco S, et al., 2011, PMID: 22144916",These mice displayed some clinical features of NS,Score,0 (2),"Short stature and craniofacial anomalies could be indicative of a NS phenotype but is barely specific to RASopathies +Of note, no claim was made in this paper but Fahiminya made the claim that this was a model for NS. +Will be counted on the ID/Autism curation",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6442d764-3ff8-41f4-984d-776254226b05-2019-02-04T170000.000Z,1568,PubMed:22144916 +Netrin-G1 regulates behaviors in dissociable neural circuits,Model Systems Non-human model organism,"Zhang Q, et al., 2016, PMID: 27345935","Deletion of NTNG1 in cortical excitatory neurons in mice resulted in altered anxiety-like behavior, but intact fear-like behavior. Conversely, loss of NTNG1 in inhibitory neurons resulted in attenuated fear-like behavior, but intact anxiety-like behavior.",Score,0.5 (2),This score was downgraded because only anxiety-like and fear-like behaviors were reported.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_2c648acf-5801-481b-a1c4-f950e99d4d96-2021-02-02T170000.000Z,1572,PubMed:27345935 +Calvo Patient cell model,Functional Alteration Patient cells,"Calvo SE, et al., 2010, PMID: 20818383","Fibroblasts demonstrated reduced complex I activity (19% of control) which was rescued by wt expression of NUPBL cDNA. Of note, transfection of other control cell lines with wild type NUBPL cDNA did not alter complex I activity.",Score,1 (1),one patient cell culture model with disrupted gene function showing mitochondrial dysfunction in a non-neuronal cell type (Awarded 1 pt),https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_4365ffcd-637c-4862-9fa0-fb8a780a6d25-2020-03-19T195115.036Z,1575,PubMed:20818383 +Yeast model of NUBPL,Model Systems Non-human model organism,"Maclean AE, et al., 2018, PMID: 29982452",The Yeast model demonstrated a biochemical phenotype (reduced complex I and alterations in complex I assembly) that has been reported in individuals with Leigh syndrome,Score,0.5 (2),Scoring was based off of U24 working group model rubric,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_4365ffcd-637c-4862-9fa0-fb8a780a6d25-2020-03-19T195115.036Z,1575,PubMed:29982452 +Formation of the NUP160 subcomplex (NUP107 interaction),Protein Interaction,"Belgareh N, et al., 2001, PMID: 11564755","Forms part of the Nup160 subcomplex in the nuclear pore which is composed of NUP160, NUP133, NUP107 and NUP96. This complex plays a role in RNA export and in tethering Nup98 and NUP153 to the nucleus. To characterize the interaction between hNup133 and Nup107 in human cells. Immunoprecipitation experiments performed on HeLa cell extracts using anti-Nup107 or anti-Nup133 antibodies revealed that these two nucleoporins coprecipitate efficiently with each other. NUP107 = Definitive for nephrotic syndrome, type 11 .",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_2bf3146d-c384-4697-9bf0-09659ac6aec0-2024-06-25T160000.000Z,1576,PubMed:11564755 +Morpholino-mediated gene knockdown in Zebrafish,Model Systems Non-human model organism,"Cianciolo Cosentino C, et al., 2019, PMID: 30894603","Using a morpholino-mediated gene knockdown, it’s demonstrated that partial depletion of Nup133 in zebrafish larvae leads to the formation of kidney cysts, a phenotype that can be rescued by co-injection of wild type mRNA. Analysis of different markers for tubular and glomerular development shows that the overall kidney development is not affected by nup133 knockdown. Likewise, no gross defect in nuclear pore complex assembly was observed in these nup133 morphants. On the other hand, nup133 downregulation results in proteinuria and moderate foot process effacement, mimicking some of the abnormalities typically featured by patients with nephrotic syndrome.",Score,1 (2),Scored at 1 point maximum to reflect that experimental evidence for model systems has been maxed out.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_2bf3146d-c384-4697-9bf0-09659ac6aec0-2024-06-25T160000.000Z,1576,PubMed:30894603 +mRNA expression reduced in Drosophila model,Expression A,"Megat S, et al., 2023, PMID: 36670122",Nup50 in moleads to motor defects in Drosophila substantiates the pathogenic effect of reduced NUP50 levels,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0ce3418e-c7e5-452b-9db6-661571331822-2024-06-27T160000.000Z,1577,PubMed:36670122 +Knockdown of Nup50 in Zebrafish,Model Systems Non-human model organism,"Megat S, et al., 2023, PMID: 36670122","The authors did not observe any significant developmental deficits or non-specific toxicity, as shown at 48 hours post fertilization (hpf) (Fig. 6f, g). However, only upon knockdown of nup50 did they observe reduced swimming bouts in 50 hpf embryos (Fig. 6h); and analysis of the touch-evoked escape response (TEER) showed that nup50 knockdown by AMO led to impaired locomotion with embryos displaying significantly reduced velocity (Fig. 6i). Importantly, The authors observed a significant reduction of zebrafish embryos displaying motor features upon co-expression of nup50 knockdown alongside NUP50 human cDNA (hDNA) as compared to nup50 AMO (Fig. 6g). Similarly, analysis of the velocity from the TEER swimming bouts of nup50 AMO + NUP50 hDNA showed no difference with the control conditions. The loss of function of NUP50 is toxic to motor neurons, and sufficient to lead to motor neuron disease.",Score,0 (2),"Zebrafish model system used. Lower order species used to assess the motor phenotype and the zebrafish models usually are curved when assessing motor phenotype. In this paper, the zebrafish look normal and the scoring is given for the expression data as the authors check the mRNA expression (scored 0.5 in expression data).",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0ce3418e-c7e5-452b-9db6-661571331822-2024-06-27T160000.000Z,1577,PubMed:36670122 +NUP50 depletion on motor phenotype - Drosophila model,Model Systems Non-human model organism,"Megat S, et al., 2023, PMID: 36670122","The authors evaluated the effect of Nup50 knock-down on motor performance by utilizing an automated negative geotaxis climbing assay to evaluate motor performance of 1- and 7-day-old adult flies. Whereas selective Nup50 knock-down in motor neurons (OK371-GAL4) did not significantly affect motor capacities at 1 day of age, 7-day-old flies displayed a significant motor deficit (Fig. 6b, c), indicative of an age-dependent progressive motor phenotype. Finally, the authors evaluated neuromuscular junction (NMJ) morphology in third instar larvae by measuring the length of the NMJs on distal muscle No. 8, as shortening of NMJ length is frequently observed in Drosophila models of (motor) neurodegenerative diseases. Motor neuron-specific Nup50 knock-down significantly reduced NMJ length on muscle 8 (Fig. 6d–f), indicating a length-dependent NMJ phenotype.",Score,0.5 (2),Drosophila model of neurodegenerative diseases.The score is reduced from 2 to 0.5 (lower order species (0.5) and The mRNA expression in motor neurons of drosophila is measured and is scored in experiment type - expression.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0ce3418e-c7e5-452b-9db6-661571331822-2024-06-27T160000.000Z,1577,PubMed:36670122 +Knockdown of NUP50 in mouse neurons,Model Systems Cell culture model,"Megat S, et al., 2023, PMID: 36670122","Nup50 knockdown increased neuronal death in HT22 neurons (Fig. 5g) and in primary cortical neurons (Fig. 5h). Thus, reduced NUP50 expression compromises nuclear pore function and neuronal survival in cultured neurons, recapitulating a subset of ALS pathological features.",Score,0.5 (1),HT22 neurons and in primary cortical neurons from mouse,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0ce3418e-c7e5-452b-9db6-661571331822-2024-06-27T160000.000Z,1577,PubMed:36670122 +Yeast 2 Hybrid,Protein Interaction,"Young P, et al., 2001, PMID: 11448995","The obscurin binding site was mapped on titin by testing +for interaction with titin Z7-Z8 and Z9-Z10. The interaction with obscurin was mapped to Z9-Z10 (Fig. 4 A).",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e1b69281-f3d0-4efe-998d-db080868b57e-2020-11-06T180624.436Z,1580,PubMed:11448995 +Western Blot,Expression A,"Young P, et al., 2001, PMID: 11448995",Western blots were completed and detected obscurin protein,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e1b69281-f3d0-4efe-998d-db080868b57e-2020-11-06T180624.436Z,1580,PubMed:11448995 +Expression in explanted hearts,Expression B,"Marston S, et al., 2015, PMID: 26406308","Obscurin mutants exhibited significantly lower levels of obscurin protein compared with the other DCM samples and controls: (D4, 45±7%, p = <0.0001, n = 8, D14, 48 +±3%, p = <0.0001, n = 21 and D20, 72±6%, p = <0.014, n = 14). The level of obscurin in myofibrils was not significantly different between donor, DCM (no OBSCN mutation) and HCM (myectomy) controls.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e1b69281-f3d0-4efe-998d-db080868b57e-2020-11-06T180624.436Z,1580,PubMed:26406308 +Melanosome Biogenesis in the Melanocyte,Protein Interaction,"Grønskov K, et al., 2007, PMID: 17980020","The P protein, encoded by OCA2, is important or normal biogenesis of melanosomes and for normal processing and transport of the melanosomal proteins: tyrosinase and tyrosinase related protein 1. If OCA2 is not being expressed, tyrosinase, encoded by TYR, and tyrosinase related protein 1, encoded by TYRP1, will not be trafficked out of the developing melanosome. Tyrosinase and tyrosinase related protein 1 play a crucial role in melanogenesis and are both known to be associated with oculocutaneous albinism.",Score,2 (0.5),"The genes TYR and TYRP1 have been implicated previously in oculocutaneous albinism. The protein interaction between OCA2 and TYR and TYRP1 and subsequent albinism phenotypes if OCA2 is not being expressed is strong evidence for the gene-disease relationship between OCA2 and oculocutaneous albinism type 2. Therefore, the General Gene Curation Expert Panel has decided to score this evidence at the top of the range for protein interactions, 2 points.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7433c1e2-a3a6-4351-88e0-cb3edcf39910-2021-08-25T160000.000Z,1581,PubMed:17980020 +Melanin Biosynthetic Pathway,Biochemical Function A,"Grønskov K, et al., 2007, PMID: 17980020","TYR and TYRP1 are trafficked from the ER to the developing melanosome via the golgi apparatus. The OCA2 protein is important for normal biogenesis of melanosomes and for normal processing and transport of the melanosomal proteins: TYR and TYRP1. TYR is a copper-containing enzyme catalyzing the first two steps in the melanin biosynthesis pathway. It converts tyrosine to L-DOPA and subsequently to DOPAquinone. TYR stably expressed in human cells is retained in perinuclear compartments. TYRP1 catalyzes the oxidation of DHICA monomers into melanin. The mislocalization can be reverted if OCA2 is coexpressed. OCA2 exerts at least some of its effects by maintaining an acidic pH in melanosomes. If OCA2 is not being expressed, TYR and TYRP1 will not be trafficked out of the developing melanosome. Melanin biosynthesis is dependent upon OCA2, TYR and TYRP1 in order to produce typical pigmentation.",Score,2 (0.5),"Involvement of TYR and TYRP1, genes known to be involved in oculocutaneous albinism, in multiple steps of melanin biosynthesis pathway is strong evidence for the gene-disease relationship between OCA2 and oculocutaneous albinism type 2. Therefore, the General Gene Curation Expert Panel has decided to score this evidence at the top of the range for biochemical function, 2 points.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7433c1e2-a3a6-4351-88e0-cb3edcf39910-2021-08-25T160000.000Z,1581,PubMed:17980020 +German Spitz Dog,Model Systems Non-human model organism,"Caduff M, et al., 2017, PMID: 28973042","The functional role of the canine OCA2 gene in pigmentation is well known and numerous genetic variants in humans, mice and other vertebrates, lead to oculocutaneous albinism phenotypes that are very similar to the phenotypes observed in the German Spitz dogs. Additionally, accumulation of pigment with age has been described in human OCA2 patients and was observed in the affected dogs as the eye color changed from blue into light green and the coat color darkened.",Score,1 (2),No functional evidence was provided demonstrated that this variant had an effect on the protein product.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7433c1e2-a3a6-4351-88e0-cb3edcf39910-2021-08-25T160000.000Z,1581,PubMed:28973042 +Rhesus Macaque Model,Model Systems Non-human model organism,"Wu KC, et al., 2020, PMID: 32259106","Wu et al identified 6 rhesus macaques with features of albinism including pink skin, red hair, horizontal nystagmus, a difference in the iris pigmentation between affected vs controls, extensive hypopigmentation and absence of foveal centralis, and a loss of pigmentation in the choroid vasculature. The authors pointed out that the rhesus model more closely recapitulates some of the eye phenotypes observed in humans, as they have a fovea in which hypopigmentation and/or absence can be observed, where other animal models do not. The authors first examined melanin formation in HEK293T cells following OCA2 knockdown using shRNA and the co-transfection with both wild type TYR with and without either wild type OCA2 or mutant OCA2. No pigmentation was observed in the OCA2 silenced HEK293T cells overexpressing wild type TYR alone. The simulatneous overexpression of wild type OCA2 and wild type TYR resulted in apparent pigmentation. However, the co-transfection of mutant OCA3 and wild type TYR led to significant depigmentation and reduced melanin production. This demonstrated that the OCA2 variant identified in the 6 rhesus monkeys could biologically affect melanin production.",Score,1 (2),This score was downgraded to 1 point given the presence of the TYR variant in some of the affected animals.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7433c1e2-a3a6-4351-88e0-cb3edcf39910-2021-08-25T160000.000Z,1581,PubMed:32259106 +Zebrafish Model,Model Systems Non-human model organism,"Ramirez IB, et al., 2012, PMID: 22210625","Human patients have seizures, ventriculomegaly, and periventricular cysts. Same findings are also in Zebrafish model.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5140c756-fac0-435b-8f59-a5d4a0b0adb3-2020-07-10T160000.000Z,1582,PubMed:22210625 +Rescue experiment in Zebrafish model,Rescue Non-human model organism,"Ramirez IB, et al., 2012, PMID: 22210625","Phenotype of brain size, apoptosis, and proliferation in OCRL deficient zebrafish embryos can be partially rescued by expression of wild type but not mutant OCRL",Score,1 (2),"Zebrafish cDNA, not human cDNA is used for rescue experiment",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5140c756-fac0-435b-8f59-a5d4a0b0adb3-2020-07-10T160000.000Z,1582,PubMed:22210625 +Zebrafish flanders rescue,Rescue Non-human model organism,"Hjeij R, et al., 2014, PMID: 25192045","25% of the zebrafish (offspring from heterozygote parents) were presumed to be homozygous for the flanders variant. In the uninjected cohort, ~18% had a full tail curl, and ~6% had a bent tail shape. The rest (~24%) were wild type. In another cohort, they injected 100pg of wild type ccdc151 RNA. 1% of these zebrafish had full tail curl, while 19% were bent and 80% were wild type. This improvement in tail shape indicates a partial rescue (p<10E-16).",Score,1 (2),"This rescue was downscored due to lack of important PCD30 disease features (cough, congestion, respiratory infections, etc.) which are unable to be represented by a Zebrafish model.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3238f748-9461-4704-ae35-02115485fab6-2023-03-03T170000.000Z,1585,PubMed:25192045 +Mouse Snbl mutant,Model Systems Non-human model organism,"Hjeij R, et al., 2014, PMID: 25192045",Laterality defects and heart defects are seen in both the mice as well as patients with PCD30. The ciliary dysfunction observed in the mice using TEM and video microscopy confirms the laterality and heart defects are a result of the Ccdc151 mutation.,Score,1.5 (2),"This model was downscored due to lack of important PCD30 disease features (congestion, cough, respiratory infection).",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3238f748-9461-4704-ae35-02115485fab6-2023-03-03T170000.000Z,1585,PubMed:25192045 +Zebrafish flanders,Model Systems Non-human model organism,"Hjeij R, et al., 2014, PMID: 25192045","Humans with PCD30 can show laterality defects. Similar to the zebrafish model, cilia appear immotile or with an irregular beating pattern when observed using video microscopy. ODA loss in humans is visible using TEM.",Score,1 (2),"This model was downscored due to lack of important PCD30 disease features (respiratory infection, congestion, cough, etc.), which are unable to be recapitulated in Zebrafish. Furthermore, this model showed ciliary immotility in the kidney and pronephric cells, which are not tissues typically associated with PCD30 in humans.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3238f748-9461-4704-ae35-02115485fab6-2023-03-03T170000.000Z,1585,PubMed:25192045 +ODAD1 interaction,Protein Interaction,"Hjeij R, et al., 2014, PMID: 25192045","ODAD1 (CCDC114) interacts with ODAD3 (CCDC151), as there are both components of the outer dyenin arm docking complex. In addition to the Co-IP showing their interaction, the authors also showed that localization of ODAD1 to the ciliary axoneme is dependent on a functioning copy of ODAD3. This was demonstrated by the lack of both ODAD3 and ODAD1 in the respiratory cilia of PCD30 patients.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3238f748-9461-4704-ae35-02115485fab6-2023-03-03T170000.000Z,1585,PubMed:25192045 +Zebrafish morphants,Model Systems Non-human model organism,"Xu Y, et al., 2015, PMID: 25860617","This knockdown model caused severe curved body phenotype (Fig 2), defected in the inner ear motile cilia often which led to abnormal otoliths, which are fused, mispositioned, or of wrong sizes or numbers (Fig 3A), exhibited varying extent of defects in the left-right asymmetry (Fig 3G and 3H), and defects in cilia motility (Fig 4A–4D)",Score,1 (2),The model features morpholino-based disruption of the ODAD4 ortholog but does not correspond to a particular human patient variant.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_547fed6e-47df-44b5-bf4a-e31f7b045862-2022-12-08T170000.000Z,1586,PubMed:25860617 +Autophagy promotes cilia biogenesis by regulating OFD1,Biochemical Function B,"Tang Z, et al., 2013, PMID: 24089205",The ciliary organelles are present in many cellular types throughout the human body. Cilia defects adversely affect numerous critical developmental signaling pathways essential to cellular development.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_15e32789-4f24-4870-94d3-b5618e67509f-2018-04-27T165136.294Z,1587,PubMed:24089205 +24 h serum starvation and Immunofluorescence,Rescue Cell culture model,"Tang Z, et al., 2013, PMID: 24089205","If OFD1 accumulation at centriolar satellites is responsible for the +ciliary defects in Atg5-/- MEFs, we would expect that depletion of +OFD1 by RNA interference might rescue these defects. In Atg5-/- +MEFs stably expressing OFD1 short hairpin RNA (shRNA), with +about 50% efficiency of overall depletion of OFD1 (Extended Data +Fig. 8a), OFD1 remained at centrioles but was lost from centriolar +satellites (Extended Data Fig. 8b-d). Primary cilium formation upon +serum starvation was fully restored in these cells; nearly 70% of cells +formed a cilium and the length of these cilia was comparable to those +formed in Atg51/1 MEFs (Fig. 3b).",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_15e32789-4f24-4870-94d3-b5618e67509f-2018-04-27T165136.294Z,1587,PubMed:24089205 +Cilia formation in MCF7 cells,Functional Alteration Non-patient cells,"Tang Z, et al., 2013, PMID: 24089205","OFD1 depletion +at centriolar satellites promotes cilia formation in both cycling +cells and transformed breast cancer MCF7 cells that normally do +not form cilia.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_15e32789-4f24-4870-94d3-b5618e67509f-2018-04-27T165136.294Z,1587,PubMed:24089205 +The OPA1 ortholog promotes mitochondrial fusion in yeast,Biochemical Function B,"Wong ED, et al., 2000, PMID: 11038181","Immunocytochemistry localizes Mgm1 to mitochondria (Figure 6). Subcellular fractionation and western blotting show that Mgm1 localizes to the mitochondrial intermembrane space and peripherally associates with the inner mitochondrial membrane (Figure 5), which is confirmed by cryo-electron microscopy (Figure 7). When combined with evidence that Mgm1-deficient yeast cells exhibit fragmentation of the mitochondrial network (Figure 1) and are unable to undergo mitochondrial fusion (Figure 2), this study reveals the dynamin related GTPase Mgm1 as a positive regulator of inner mitochondrial membrane remodeling and mitochondrial fusion.",Score,0.5 (0.5),"These data demonstrate a function of the yeast OPA1 ortholog Mgm1 in directly promoting mitochondrial inner membrane remodeling and mitochondrial fusion, which helps explain the cellular abnormalities in mitochondrial morphology and function that characterize the human disease state.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_fc3f3ec8-0394-4732-bb4b-d75aaa5bdbcb-2022-11-17T170000.000Z,1589,PubMed:11038181 +CRISPR-Cas9 editing of OPA1 restores mitochondrial function.,Rescue Patient cells,"Sladen PE, et al., 2021, PMID: 34589289",Mitochondrial network fragmentation was assessed by microscopy and was partially rescued by the CRISPR/Cas9 editing of OPA1 (Figure 2B-2D). Mitochondrial bioenergetic function was assessed by oxygen consumption rate and found to be completely rescued by CRISPR/Cas9 editing of OPA1 (Figure 3A-3D). The percentage of wild-type mitochondrial DNA was assessed by PCR and found to be completely rescued by CRISPR/Cas9 editing of OPA1 (Figure 4B). CRISPR/Cas9 editing was also associated with a moderate/partial reversal of the enhanced susceptibility to apoptotic stimuli exhibited by the patient-derived cells (Figure 5D-5E).,Score,1 (1),The default score is appropriate as the rescue was consistently successful across multiple mitochondrial phenotypes characteristic of affected patients at the cellular level. Up-scoring was not performed due to the cell type (iPSC rather than muscle or ocular cell type).,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_fc3f3ec8-0394-4732-bb4b-d75aaa5bdbcb-2022-11-17T170000.000Z,1589,PubMed:34589289 +OPHN1 regulates the RhoA/ROCK pathway,Biochemical Function B,"Khelfaoui M, et al., 2009, PMID: 19401298","Defects in OPHN1 impairs the endocytosis of transferrin, therefore the CME is impaired",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0cb6e45b-501d-4a6f-b76b-b50d92d48f16-2023-08-24T060000.000Z,1591,PubMed:19401298 +E478G microinjection,Functional Alteration Non-patient cells,"Liu Z, et al., 2018, PMID: 30519240","Micro-injection of E478G significantly elevated inflammation in the brains with an increase in astrocyte, microglia and neuronal cell death.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1d8edc80-413c-4c76-bf06-89198175ac65-2022-05-10T170000.000Z,1592,PubMed:30519240 +OPTN Mutants Induce formation of SGs containing High TDP-43,Functional Alteration Non-patient cells,"Kakihana T, et al., 2021, PMID: 34258561","While WT was able to recover KD SG clearance, reduce the amount of TIA1 mRNA/protein expression, reduce the amount of TDP-43 localization to SGs and reduce the amount of ubiquitinated TDP-35, most of the ALS mutants were not able to recover these phenotypes.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1d8edc80-413c-4c76-bf06-89198175ac65-2022-05-10T170000.000Z,1592,PubMed:34258561 +Using mouse model to investigate effects of Optn mutations,Model Systems Non-human model organism,"Chi ZL, et al., 2010, PMID: 20388642","Loss of RGCs and optic nerve cupping are the histological features of the retina of patients with POAG and NTG. It was observed in this study that, after 16 months, histological abnormalities were observed in the retina of the E50K mutant mice with loss of RGCs and thinning of the nerve fiber layer at the optic nerve head",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_22efb828-c989-4584-97f9-e1d795b7468f-2022-11-17T170000.000Z,1593,PubMed:20388642 +Using GFP tagged constructs to evaluate effect of OPTN Mut,Functional Alteration Non-patient cells,"Turturro S, et al., 2014, PMID: 24683533","E50K (NTG) and R96L (ALS) mutations showed prominent phenotypes that include foci formation, Golgi fragmentation, impairment in transferrin uptake and apoptosis. +The 2 bp-AG insertion (691_692insAG) mutation had a nuclear localization, compromised the transferrin uptake and strongly induced apoptosis.",Score,1 (0.5),This is a comprehensive investigation including OPTN variants associated with NTG and ALS as well as the OPTN variants with no disease association. It showed that E50K (NTG) and R96L (ALS) affect all of the optineurin phenotype whereas Q398X (ALS) and 2 bp-AG insertion result in impairment of transferrin uptake and increased apoptosis.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_22efb828-c989-4584-97f9-e1d795b7468f-2022-11-17T170000.000Z,1593,PubMed:24683533 +Generation and Characterization of hPSCs with OPTN(E50K) mut,Model Systems Cell culture model,"VanderWall KB, et al., 2020, PMID: 32531194","OPTN(E50K) and isogenic control RGCs revealed high degree of similarity in neuronal maturation from 1 to 3 weeks. By 4 weeks of maturation, however, OPTN(50K) RGCs displayed deficits in neurite complexity, cell body size, and neurite length; +Expression of the RGCs transcription factors BRN3B and ISLL1 were significantly decreased in OPTN(E50K) RGCs, compared with isogenic controls; +OPTN(E50K) retinal organoid demonstrated autophagy dysfunction through LC3 accumulation.",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_22efb828-c989-4584-97f9-e1d795b7468f-2022-11-17T170000.000Z,1593,PubMed:32531194 +ORAI1 and STIM1 are SOCE Mediators,Biochemical Function A,"Berna-Erro A, et al., 2012, PMID: 21790973","siRNA testing on HeLa cells with active Ca2+ influx through the plasma membrane identified STIM1 and STIM2 as targets when the loss of function resulted in decreased Ca2+ entering the cell. To confirm this finding, an ""add-back"" experiment was performed to test the impact of depleted STIM1 on the SOCE. A significant suppression of Ca2+ influx was observed when HeLa cells were transfected with siRNA against STIM1, STIM2, or both compared to the controls. siRNAs against the 3'UTR also resulted in this suppression of influx, confirming that the STIM proteins were responsible for the SOC mediation.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_bb8d614e-e8ff-4f16-bba3-6fc35ea56e8a-2020-07-13T164919.164Z,1594,PubMed:21790973 +ORAI1 and STIM1 Localization,Protein Interaction,"Berna-Erro A, et al., 2012, PMID: 21790973","HEK293 cells expressing variously tagged ORAI1 and STIM1 were subjected to a variable Ca2+ solution to study the CRAC channel. Coimmunoprecipitation demonstrated the physical interaction between STIM1 and ORAI1 when modulating the intracellular Ca2+ levels, specifically localizing near the plasma membrane.",Score,0.5 (0.5),"As GOF STIM1 and ORAI1 variants are both implicated in Tubular Aggregate Myopathy and act in the same pathway, the physical association between the two proteins provides a default score.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_bb8d614e-e8ff-4f16-bba3-6fc35ea56e8a-2020-07-13T164919.164Z,1594,PubMed:21790973 +ORAI1-KO Cells Demonstrate Impaired SOCE,Functional Alteration Non-patient cells,"Lopez-Guerrero AM, et al., 2017, PMID: 28341841","ORAI1 cells were generated via CRISPR-Cas9 gene editing and frameshift/premature stop codons were confirmed in both valid transcripts. Immunoblot confirmed the loss of ORAI1 expression compared to the control. Thapsigargin and EGF was used to trigger SOCE activation, which was significantly reduced in the ORAI1-KO cells compared to the WT. Overexpression of ectopic ORAI1-mCherry rescued the phenotype and returned SOCE levels to those found in wild-type. Furthermore, the KO cells demonstrated a striking loss of ruffling activity and protrusions formation compared to the WT that was also rescued by expression of the WT ORAI1-mCherry.",Score,1 (0.5),"This experimental data provides significant evidence to show that ORAI1 is essential for not only proper SOCE pathway activity, but also proper cell membrane ruffling and cell migration. Defects in these pathways can be directly regulated to the muscular phenotypes observed in TAM probands, therefore the evidence earns an increased 1.0 points.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_bb8d614e-e8ff-4f16-bba3-6fc35ea56e8a-2020-07-13T164919.164Z,1594,PubMed:28341841 +Stiff_Functional Alteration,Functional Alteration Patient cells,"Stiff T, et al., 2013, PMID: 23516378","∼5% of the EBV plasmids underwent replication in control cells but this was markedly reduced in ORC1, ORC4, ORC6, CDT1, and CDC6-deficient LBLs.",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d00eb95c-5496-4051-a4e1-c327b71fe6e4-2023-05-30T160000.000Z,1595,PubMed:23516378 +Stiff_Biochemical,Biochemical Function A,"Stiff T, et al., 2013, PMID: 23516378","Since ORC1 and ORC6 are also implicated in Meier-Gorlin syndrome, and ORC4 was shown to have similar replication reduction, this evidence can be scored as biochemical function",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d00eb95c-5496-4051-a4e1-c327b71fe6e4-2023-05-30T160000.000Z,1595,PubMed:23516378 +McDaniel_Protein-Protein,Protein Interaction,"McDaniel SL, et al., 2020, PMID: 31818869","To determine if the tissue-specific defects seen in ORC4 Y174C homozygous flies arose from a failure of ORC to form or to associate with chromatin, McDaniel et al. used Cas9 genome-editing to make the analogous mutation in S. cerevisiae (Y232C). Through immunoblots, they demonstrated that the Y232C substitution does not destabilize wildtype ORC4 or ORC1.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d00eb95c-5496-4051-a4e1-c327b71fe6e4-2023-05-30T160000.000Z,1595,PubMed:31818869 +Mouse and rat cochlea expression,Expression A,"Thoenes M, et al., 2015, PMID: 25759012",RT-PCR of mouse and rat cochlea showed presence of OSBPL2 transcript in both. Immunofluorescent staining of mouse organ of Corti showed Osbpl2 present in both OHCs and IHCs. No difference was found in Osbpl2 levels between P20 and 6 month old mice.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a493a4c4-3a9f-431a-a68e-d90d9a11b6f0-2020-02-06T172031.658Z,1597,PubMed:25759012 +El Hakam Animal Model,Model Systems Non-human model organism,"El Hakam Kamareddin C, et al., 2015, PMID: 26636018",Mice had severe vestibular dysfunction and progressive hearing loss (measured by preyer reflex). Morphological analysis of maculae revealed almost absent otoconial membrane of saccular macula. Heterozygotes for the mutation were normal in every test,Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0fac4fd4-d674-4017-a9a6-1d6793162c6b-2018-06-28T160000.000Z,1602,PubMed:26636018 +D127N P2Y12 Kockin Mouse models,Model Systems Non-human model organism,"Dangelmaier C, et al., 2022, PMID: 36232816","The knock-in mouse model of D127N P2Y12 showed the phenotypes of interrupted 2-MeSADP-mediated platelet aggregation, abnormal bleeding and occlusion, which mimic the clinical features of an abnormal aggregate of platelets in response to 2-MeSADP in the proband.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_81c56aba-1414-4365-a8de-847c080251f3-2023-04-03T170000.000Z,1607,PubMed:36232816 +Gene Therapy in PAH Model,Rescue Non-human model organism,"Jung SC, et al., 2008, PMID: 18955797","PAH activity in the livers of treated mice six weeks after treatment recovered to 58.43±5.73% and 89.25±8.79% of the wild-type activity in female and male PAH_enu2 mice respectively compared to <1% WT in untreated mice. Plasma phenylalanine concentration in female PAH_enu2 mice infused with rAAV2/8-hPAH vectors decreased markedly to 110±34.5 µM at two weeks from 2,891±336.2 µM and showed continued significant phenylalanine clearance for six month after rAAV2/8-hPAH infusion. Male PAH_enu2 showed a similar reduction, though they started at a lower base concentration of 1,800.6±233.7 µM. The fur color of treated mice also changed from greyish to black from one week after delivery with sustained fur color changes over the entire six month period. Investiation of effects on pregnant mice revealed a complete recovery of fetus length and body weight compared to the untreated mice (1.746±0.203 cm and 774±144 mg for untreated VS 2.081±0.269 cm and 916±67 mg for treated). Spontaneous abortion rate also normalized to 4.55±5.89% from 30.95±14.27%. The rAAV-hPAH genome was not found in the placentae or fetuses nor did the genome of fetuses affect the development parameters.",Score,2 (2),"This rescue succesfully ameliorates the symptoms indicitave of phenylketonuria, including reversal of fur color, decreased PAH levels, and increased PAH activity/mouse body weight. Therefore, this rescue earns default points.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5a617cb4-94ec-4f34-b97e-10d9808a1581-2020-04-24T160000.000Z,1610,PubMed:18955797 +PAH Variant Rescued by FokI-Cas9,Rescue Cell culture model,"Pan Y, et al., 2016, PMID: 27786189","Western blot analysis performed on cell expressing the wild-type PAH and those treated with differing levels of ODN and RS-1 showed that those treated with the replacement sequence had significantly higher PAH expression than the mutant cells that were not transfected with the vectors. Further, liquid chromatography-electrospray ionization tandem mass spectrometry was used to evaluate PAH activity after repair showing an activity of 22.08 +/- 1.67 % with the RS-1 expressed as opposed to 16.86+/- 1.31 % without the replacement sequence.",Score,0.5 (1),"Although the expression of the wild-type does rescue the reduced PAH activity that the known pathogenic variant causes, there are no further phenotypes to report in this cell system that are indicative of phenylketonuria. Therefore, this rescue is reduced to 0.5 points.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5a617cb4-94ec-4f34-b97e-10d9808a1581-2020-04-24T160000.000Z,1610,PubMed:27786189 +Review of mitochondrial translation disorders,Biochemical Function A,"Boczonadi V, et al., 2018, PMID: 29980628","PMID: 27536729 see MT-TP 5 adults with abnormal muscle biopsy including complex I and IV deficiency consistent with mtDNA translation +Also see: C12ORF65, MT-TP, MT-TI, MT-TK, MT-TL1, MT-TL2, MT-TV, MT-TW",Score,2 (0.5),>10+ genes with mitochondrial disease association implicated in mitochondrial translation,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b8d59b26-84ba-413d-a79f-27903c863356-2022-06-16T160000.000Z,1616,PubMed:29980628 +PAX2 missense mutation mouse,Model Systems Non-human model organism,"Alur RP, et al., 2010, PMID: 20221250","Heterozygous carriers (A220G+/-) had various ocular abnormalities (optic nerve excavation, retinal dysplasia, bending of the retinal vasculature) and renal abnormalities (degenerative tubules on histology and a few mice had unilateral renal hypoplasia). +Missense mutation (A220G) in mouse fibroblast cell line had reduced PAX2 protein expression.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ed6df631-4153-4f76-9bdd-073ed4cb68a2-2021-09-13T023000.000Z,1618,PubMed:20221250 +Spontaneous and novel Missense Pax3 mouse,Model Systems Non-human model organism,"Ohno T, et al., 2017, PMID: 28381738","Both mice and humans with PAX3 variants have been documented to demonstrate pigmentation abnormalities of the hair and eyes. In this case, mice demonstrate white spots with a missense mutation (het) and are not viable with homozygous mutations-embryonic lethality.",Score,1.5 (2),"The missense mutation at this amino acid did not directly affect hearing ability, although deafness is a frequent feature of WS patients and is observed at a rate of about 60% in case of type 1 WS.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_594ef026-3730-43bc-b721-d15cf0bbbf26-2017-11-15T050000.000Z,1619,PubMed:28381738 +Pax5R31Q/E242* and Pax5R31Q/− mouse models,Model Systems Non-human model organism,"Kaiser FMP, et al., 2022, PMID: 35947077","B cell development was partially arrested at the transition from pro-B to pre-B cell in the Pax5R31Q/E242* and Pax5R31Q/− mouse models. Similar to the patient, the frequency of B cells in the peripheral blood of Pax5R31Q/E242* and Pax5R31Q/− mice was strongly reduced compared with control, moreover, total B cell numbers were 3.5-fold reduced in the bone marrow. Pro-B cells were, however, 3-fold increased, while pre-B and immature B cells were 7- and 9-fold decreased in Pax5R31Q/E242* and Pax5R31Q/− mice compared. +When immunized with the T cell–independent antigen Pl4-hydroxy-3-nitrophenylacetyl (NP)–conjugated Ficoll. NP-specific plasma cells were strongly reduced on day 7 after NP-Ficoll immunization in the spleen of Pax5R31Q/− mice compared with Pax5+/+ mice. Immunization with the T cell–dependent antigen NP-keyhole limpet hemocyanin (NP-KLH) in the adjuvant alum demonstrated that no germinal center (GC) B cells were generated in the spleen of Pax5R31Q/− mice on day 14 after immunization. These data demonstrated that the B cell immune responses to T cell–independent and T cell–dependent antigens were largely lost in the Pax5R31Q/− mouse model, consistent with the patient’s diagnosis of hypogammaglobulinemia. +Pax5R31Q/− mice demonstrated substantial motor performance deficits in the Rotarod assay compared with Pax5+/− and Pax5+/+ mice. In the ErasmusLadder test, both Pax5R31Q/− and Pax5+/− mice demonstrated impaired performance as illustrated by the prolonged time required to traverse the ErasmusLadder, the increased frequency of missteps, and the increased time performing short and long steps. Similar motor performance and motor learning deficits were observed in both the patient and the Pax5R31Q/− mouse model. +The three-chamber social interaction assay unveiled hypersociability as a prominent trait of the Pax5R31Q/− mouse, which may reflect the social disinhibition of the patient. Hyperactivity in the mice were also consistent with the restlessness that was reported for the patient. Pax5R31Q/− mice displayed impaired spatial learning in the Y-maze, which is consistent with the observed cognitive impairment of the patient. +Similar to patients, high-resolution MRI of the brains of Pax5R31Q/− and control Pax5+/+ mice revealed significant differences in the volume of the vermal lobules IV/V and VII. Within the midbrain of the patient, there was hypoplasia of several midbrain and subcortical structures, which was most notable in the SN pars compacta (SNc) and pars reticularis (SNr) as well as in the VTA, compared with age- and gender-matched controls. These three regions were also significantly reduced in the midbrain of Pax5R31Q/− mice compared with Pax5+/+ mice. Hence, the same neuroanatomic defects were observed in both the patient and corresponding mouse model. Furthermore, both the patient as well as the Pax5R31Q/− mouse showed structural cerebellar abnormalities, which are a common pathological finding in ASD.",Score,4 (2),"Both Pax5R31Q/E242* and Pax5R31Q/− mutant mice, with patient derived mutations, revealed an early B cell developmental block and impaired immune responses as the cause of hypogammaglobulinemia. Pax5R31Q/− mutant mice were further characterized to display behavioral deficits in all ASD domains. PAX5 deficiency also caused profound hypoplasia of the substantia nigra and ventral tegmental area due to loss of GABAergic neurons, thus affecting two midbrain hubs, controlling motor function and reward processing, respectively.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_111b7453-55ff-4638-9cb7-1936400ec2a4-2023-02-28T170000.000Z,1621,PubMed:35947077 +PTEN regulation,Functional Alteration Patient cells,"Kaiser FMP, et al., 2022, PMID: 35947077","Analysis of EBV-immortalized B cells of the patient and a control revealed that PTEN expression was upregulated, and AKT phosphorylation at Ser473 was strongly reduced in B cells of the patient compared with the control. This was corroborated by stimulating naive mature B cells of the patient and a control for 30 min with anti-IgM, which induced phosphorylation of AKT at Ser473 in the control B cells, but not in B cells of the patient. These data therefore demonstrated that the residual mature B cells of the patient were impaired in their function due to the observed PI3K signaling defect.",Score,1 (1),"Pax5 has recently been shown to fulfill an important function in mature B cells by promoting PI3K signaling by down-regulating the expression of the PTEN protein, a negative regulator of this pathway (Calderón et al., 2021).",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_111b7453-55ff-4638-9cb7-1936400ec2a4-2023-02-28T170000.000Z,1621,PubMed:35947077 +pcare1 mutant zebrafish created by CRISPR/Cas9,Model Systems Non-human model organism,"Corral-Serrano JC, et al., 2018, PMID: 29946172","Mutant zebrafish, homozygous for a frameshift variant (introduced by CRISPR/Cas9) in one of the two pcare genes, pcare1, demonstrated abnormal photoreceptor outer segments, thinning of the inner and outer nuclear layers, visual loss, and a severe reduction in ERG response., thus recapitulating features seen in human individuals with biallelic variants in PCARE. +The authors note that the age of disease onset in patients with PCARE variants ranges from the first to the sixth decade, and that while mutant zebrafish showed a reduced visual response (behavioral and ERG) compared to wild type, the mutant zebrafsh are not completely blind. +This correlates with the human phenotype, since patients do not become fully blind until an older age. +The disease mechanism is the same in the mutant zebrafish and in human patients. In both cases, retinopathy is caused by loss of function of the PCARE gene. Many of the human PCARE disease-causing vareiants as frameshift, like the zebrafish variant that was introducted by CRISPR/Cas9 technology.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_afbc5168-51f6-4f69-bf41-41b9a1d9d665-2022-10-06T160000.000Z,1624,PubMed:29946172 +PCARE yeast two-hybrid,Protein Interaction,"Corral-Serrano JC, et al., 2020, PMID: 32312818","Full length PCARE and the three PCARE fragments were used as bait to screen human and bovine retinal cDNA libraries by yeast two-hybrid assay. Three of the genes indentified as encoding interactors are associated with retinal ciliopathies - CEP290, CEP250, and OFD1. +(See Table S1. PCARE interactors found in the yeast-2-hybrid experiments.) +CEP290 has been classified by the ClinGen Retina GCEP as having a definitive clinical validity for CEP290-related ciliopathy. This disease spectrum includes, per OMIM, ""Leber congenital amaurosis 10"" (MIM# 611755; an early onset retinopathy), ""Joubert syndrome 5"" (MIM# 610188; phenotype includes congenital amaurosis, tapetoretinal degeneration, nystagmus, retinal coloboma, oculomotor apraxia), Meckel-syndrome 4 (MIM# 611134), and Senior-Loken syndrome (MIM# 610189; phenotype includes tapetoretinal degeneration, decreased visual acuity), and possible association with Bardet-Biedl syndrome 14 (MIM# 615991) +CEP250 is associated, in OMIM, with Cone-rod dystrophy and hearing loss 2 (MIM# 618358). +OFD1 has associated with various conditions in OMIM including Joubert syndrome (MIM# 300804). Some patients with this disorder develop retniopathy. OFD1 also has a possible association with ""retinitis pigmentosa 23"" (MIM# 300424). +The phenotypes associated with some of these genes involve more than one orga system, all have been associated with retinal degeneration in some patients, supporting the role of PCARE in retinopathy.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_afbc5168-51f6-4f69-bf41-41b9a1d9d665-2022-10-06T160000.000Z,1624,PubMed:32312818 +Function of PCARE in ciliary expansion,Biochemical Function B,"Corral-Serrano JC, et al., 2020, PMID: 32312818","This study presents data from several different experiments that togehter indicate that PCARE (photoreceptor cilium actin regulator; C2ORF71) plays an important role in delivering actin associated components to the base of the photoreceptor outer segments to regulate the initial development of photoreceptor outer segment disks. This process is summarized in a schematic diagram (Figure 6). +The outer segment (OS) of photoreceptor cells resembles a highly modified primary sensory cilium and is connected to the biosynthetic compartment, the inner segment by a microtubule-based connecting cilium. Each day, about 10% of the rod photoreceptor’s OS disks are shed at the tip and phagocytozed by the retinal pigment epithelium (RPE) cells. New membrane disks are generated at the OS base. This process is known to be critical to the correct function and survival of photoreceptor cells. Disruption of the role of PCARE would be expected to affect the normal process of OS disk reneal, therefore affecting the normal function of phororeceptor cells, causing retinal degeneration and vision loss, as seen in individuals with biallelic loss of function variants in PCARE.",Score,1 (0.5),"The score is increased due the the multiple lines of evidence presented in this paper, not only from the new experimental data provided by the authors, but also based on the previous evidence reviewed in the introduction to the paper.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_afbc5168-51f6-4f69-bf41-41b9a1d9d665-2022-10-06T160000.000Z,1624,PubMed:32312818 +Crystal structure of PCC,Protein Interaction,"Huang CS, et al., 2010, PMID: 20725044","Deficiency of propionyl CoA carboxylase (PCC) results in propionic acidemia. It is well established that PCC is a 750 kDa heterododecamer composed of 6 alpha subunit (encoded by PCCA) and 6 beta subunits (encoded by PCCB) (for review, see Wongkittichote et al. 2017; PMID 29033250). In this study, the crystal structure of a bacterial PCC holoenzyme and cryo-electron microscopy of human PCC revealed that the alpha subunits are arranged as monomers in the holoenzyme, decorating a central beta-6 hexamer. A previously unrecognized domain in the alpha subunit was noted to be crucial for interactions with the beta subunit.",Score,1 (0.5),"It is well-established that PCCA and PCCB encode subunits of propionyl CoA carboxylase (PCC). The interaction of the alpha and beta subunits in generating functional PCC, and the knowledge that variants in PCCB (encoding the beta subunit) supports the association between variants in PCCA and propionic acidemia.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_32a55e25-8632-4f31-84af-3eaf8098ca18-2018-12-13T170000.000Z,1626,PubMed:20725044 +Crystal structure of PCC,Protein Interaction,"Huang CS, et al., 2010, PMID: 20725044","Deficiency of propionyl CoA carboxylase (PCC) results in propionic academia. It is well established that PCC is a 750 kDa heterododecamer composed of 6 alpha subunits (encoded by PCCA) and 6 beta subunits (encoded by PCCB) (for review, see Wongkittichote et al. 2017; PMID 29033250). In this study, the crystal structure of a bacterial PCC holoenzyme and cryo-electron microscopy of human PCC revealed that the alpha subunits are arranged as monomers in the holoenzyme, decorating a central beta-6 hexamer. A previously unrecognized domain in the alpha subunit is crucial for interactions with the beta subunit.",Score,1 (0.5),"The interaction of the alpha and beta subunits in generating functional PCC, and the knowledge that variants in PCCA (encoding the alpha subunit) supports the association between variants in PCCB and propionic acidemia.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1cd49a9b-08c2-49db-8e97-e334f171e34d-2018-12-13T170000.000Z,1627,PubMed:20725044 +PCDH15 and LHFPL5,Protein Interaction,"Mahendrasingam S, et al., 2017, PMID: 29069081","LHFPL5 has been implicated moderately with ARNSHL, however the gene must be definitively associated. Additionally, though this study showed spatiotemporal changes in the distribution of LHFPL5 mice in the absence of PCDH15, this study was done with Ames waltzer mice and therefore the phenotype of the mice cannot be counted as an animal model.",Score,0 (0.5),"The LHFPL5 protein is only moderately associated with hearing loss, and this mouse model has been implicated in Usher so this evidence could not be scored.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_48910592-40d6-4eb7-a53c-4b0883070287-2018-06-19T040000.000Z,1628,PubMed:29069081 +Role of CCT1 in drosophila photoreceptor,Model Systems Non-human model organism,"Haider A, et al., 2018, PMID: 29754800","To assess the requirement for CCT1 in drosophila photoreceptor, CCT1 expression in fly eyes was reduced using two independent strategies. Firstly, siRNA-mediated knockdown using two independent RNAi stocks modestly reduced light responses as assessed by electroretinograms (ERGs), whereas combined use of both resulted in near blindness. +Secondly, FLP-FRT/GMR-hid method was used to generate mosaic flies that have eye tissue specifically homozygous for CCT-null mutant alleles CCT1179 (CCT1 deleted) or CCT299 (both CCT1 and CCT2 deleted), Complete loss of CCT1 or both CCT1 and 2 in the eye essentially eliminated all response to light in the ERG and drastically reduced rhodopsin expression",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_eff306ea-95ff-4b4e-8597-f50849b1b4c2-2021-07-26T183711.748Z,1633,PubMed:29754800 +Murine model of systemic PDC deficiency,Model Systems Non-human model organism,"Pliss L, et al., 2013, PMID: 23840713","Markedly decrease acoustic startle reflexes and impaired PPI = impaired neurological function (ataxia/weakness); similar neuropathological appearance to Leigh syndrome spectrum (neuronal loss, gliosis, reduction in the neocortex thickness); decreased PDC activities in various tissues; neonatal lethal in males",Score,4 (2),"2/3 points given for neuropathological findings; 1/1 score given for biochemical findings (total and active PDC activity reduced by 25-50% in brain; total PDC activity reduced in liver by 25%, no significant decrease in active PDC in liver; total and active PDC activity reduced by 25-40% in muscle); 1/1 point given for neurocognitive/developmental differences (ataxia/weakness) = 4 points",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a579324c-3586-4636-9192-c2ea29391a4e-2019-04-08T161203.224Z,1637,PubMed:23840713 +Reduced PHDC activity in patient cells,Functional Alteration Patient cells,"Ferriero R, et al., 2014, PMID: 25356417","The authors determined the PDHC activity and effect of phenylbutyrate in four fibroblast cell lines with PDHB variants including, p.M101V (hom), p.M101V; p.l266LfsX26 (CH), p.M101V (hom), and p.Y137C (hom). Three of these cell lines showed a reduction in E1-b protein by Western blotting, whereas the nonresponder cell line (p.Y137C) had E1-b levels similar to wild-type levels (Fig. 3B). Phenylbutyrate has been shown to enhance PDHC enzymatic activity in vitro and in vivo by increasing the proportion of unphosphorylated enzyme through inhibition of pyruvate dehydrogenase kinases. Three cell lines showed a statistically significant increase in PDHC activity after phenylbutyrate incubation (Fig. 3A, exception p.Y137C). Two cell lines (p.M101V (hom), p.M101V; p.l266LfsX26) showed an increase in E1-b protein by Western blotting after phenylbutyrate incubation (Fig. 3B). +These results were similar to those observed in patient fibroblast cell lines carrying PDHA1, PDHX, DLAT, and DLD.",Score,1 (1),PDHC activity is reduced in patient fibroblast cell lines carrying PDHB variants and phenylbutyrate increased PDHC enzymatic activity.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_133f688f-b498-4f5e-bd9b-b3406880ddd4-2021-03-11T172853.362Z,1638,PubMed:25356417 +Similar role of genes involved in the pyruvate dehydrogenase,Biochemical Function A,"Rahman J, et al., 2017, PMID: 27977873","PDHC is a multienzyme complex consisting of E1 (PDHA1, PDHB) and E2 (DLAT), which forms the structural core of the complex and E3 (DLD), which is integrated into the complex by E3BP (PDHX). Alteration in these genes result in a similar phenotype.",Score,1 (0.5),Points increased as per scoring guide.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_133f688f-b498-4f5e-bd9b-b3406880ddd4-2021-03-11T172853.362Z,1638,PubMed:27977873 +Mouse model-MGI:6257416,Model Systems Non-human model organism,"Cacheiro P, et al., 2019, PMID: 31127358","The homozygous knockout mice present with abnormal retinal blood vessel morphology, embryonic lethality prior to tooth bud stage, preweaning lethality, incomplete penetrance.",Score,0.5 (2),Reduced scoring for abnormal phenotype and preweaning lethality.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_133f688f-b498-4f5e-bd9b-b3406880ddd4-2021-03-11T172853.362Z,1638,PubMed:31127358 +Leigh map,Biochemical Function A,"Rahman J, et al., 2017, PMID: 27977873","According to Leigh map, 4 other genes that are part of pyruvate dehydrogenase complex are also associated with Leigh syndrome (PDHA1, PDHB, DLAT, DLD).",Score,1 (0.5),shares a function with 2-5 other gene products; scored according to rubric,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3608ac5e-4b1f-4bb5-aa0c-cc42a2262304-2021-03-11T174226.092Z,1639,PubMed:27977873 +Rescue in cell culture model,Rescue Cell culture model,"Perez-Siles G, et al., 2020, PMID: 32504000",E1 hyperphosphorylation and the associated metabolic and mitochondrial abnormalities seen in the CMTX6 patient-derived motor neurons can be pharmacologically reverted to the wild type phenotype. Genetic correction of the R158H variant reverted the CMTX8 phenotype.,Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_508a1db7-0cf1-4c28-9203-89a3f4d7438d-2024-03-14T160000.000Z,1640,PubMed:32504000 +Neuronal model of CMTX6,Model Systems Cell culture model,"Perez-Siles G, et al., 2020, PMID: 32504000",E1 hyperphosphorylation in motor neurons as well as the observed morphological features may be indicative of general mitochondrial dysfunction in the CMTX6-derived motor neurons.,Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_508a1db7-0cf1-4c28-9203-89a3f4d7438d-2024-03-14T160000.000Z,1640,PubMed:32504000 +E1 hyperphosphorylation in patient iPSC CMTX6,Functional Alteration Patient cells,"Perez-Siles G, et al., 2020, PMID: 32504000","E1 subunit hyperphorylation at Ser 293 and Ser 300 was maintained in the CMTX6 derived iPSCs, similar to what was shown in patient's fibroblasts. The phosphorylation was reversed by either gene editing or treatment with a pharmacological inhibitor.",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_508a1db7-0cf1-4c28-9203-89a3f4d7438d-2024-03-14T160000.000Z,1640,PubMed:32504000 +C. elegans CMTX6 knock-in model,Model Systems Non-human model organism,"Narayanan RK, et al., 2021, PMID: 34387338","The C. elegans models generated in this study recapitulate various molecular phenotypes observed in both the CMTX6 fibroblasts and iPSC-derived motor neurons, and motor phenotypes observed in patients.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_508a1db7-0cf1-4c28-9203-89a3f4d7438d-2024-03-14T160000.000Z,1640,PubMed:34387338 +C. elegans CMTX6 overexpression model,Model Systems Non-human model organism,"Narayanan RK, et al., 2021, PMID: 34387338","CMTX6 overexpression mutants displayed both axonal degeneration and neuron loss. The neurodegenerative phenotype observed clearly demonstrate that axon loss precedes neuron loss in the CMTX6 animals, indicating the vulnerability of axons to PDK3 overexpression. The axonal degeneration was progressive, which reflects the age dependent severity reported in patients.",Score,1.5 (2),"This is an overexpression model, also, there was no significant difference in the ATP levels between transgenic and WT animals.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_508a1db7-0cf1-4c28-9203-89a3f4d7438d-2024-03-14T160000.000Z,1640,PubMed:34387338 +Peng mouse model,Model Systems Non-human model organism,"Peng M, et al., 2008, PMID: 18437205","Total knockout of PDSS2 (B6.Zp3/Cre,Pdss2loxP/loxP) was embryonically lethal, with no homozygous embryos surviving beyond 10.5 days of gestation (data not shown). kd/kd mice show nephrotic syndrome, which is observed in human patients but not relevant for Leigh syndrome. +There was a significant reduction in CoQ9 and CoQ10 levels in the kidneys of B6.Pdss2kd/kd mice compared to age-matched B6 controls. B6.Alb/cre,Pdss2loxP/loxP mice had no evidence of disease through 8 months of life, but isolated liver mitochondria respiratory chain capacity in 6 to 8 month old animals was impaired to a similar extent as seen in B6.Pdss2kd/kd missense mice. Specifically, polarography of freshly isolated liver mitochondria showed significantly decreased complex I- and complex II-dependent integrated respiratory chain capacity in both B6.Pdss2kd/kd and B6.Alb/cre,Pdss2loxP/loxP mutants compared with controls (Figure 6, panels A and B). Significantly increased complex IV-dependent respiratory capacity was also observed in both the B6.Pdss2kd/kd and B6.Alb/cre,Pdss2loxP/loxP mutants (Figure 6, panel C). Electron transport chain enzyme activity analyses performed on frozen liver mitochondria from these same animals (Figure 6, Panel D) showed consistent results. +In kidney mitochondria from B6.Pdss2kd/kd, B6.Podocin/cre,Pdss2loxP/loxP, B6.PEPCK/cre, Pdss2loxP/loxP, and B6.Alb/cre,Pdss2loxP/loxP mice, no significant differences were detected in activities of enzyme complex I-III, II-III, III, or IV normalized to citrate synthase activity for any of the mutants in comparison with controls, although a trend toward increase was observed for complex IV enzyme activity in B6.Pdss2kd/kd mice (data not shown). +Histological sections of the brain, retina, liver, and skeletal muscle of B6.Pdss2kd/kd mutants demonstrated no obvious structural abnormalities. Skeletal muscle sections stained with Gomori/trichrome and antibodies to muscle enzymes (ATPase, NADH, SDH) showed no evidence of subsarcolemmal mitochondrial aggregates or other abnormalities. In addition, no differences were observed in bone mineral density or concentration, lean body mass, complete blood count, or liver transaminase (ALT) (data not shown).",Score,1 (2),Homozygous gene KO is embryonic lethal in mice. Homozygous hepatocyte-specific KO mice (albumin promoter) and homozygous missense variant carrying kd/kd mice also show disrupted respiratory chain activity in liver tissue.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5e0928f3-2b7d-4622-bc96-68a4d0078826-2021-03-11T172336.036Z,1642,PubMed:18437205 +Leigh map,Biochemical Function A,"Rahman J, et al., 2017, PMID: 27977873",Leigh map,Score,0.5 (0.5),"In Leigh map, 1 of 2 genes involved in CoQ10 biosynthesis associated with Leigh syndrome (also COQ9). 13 other genes associated with Leigh syndrome are involved in cofactor biosynthesis and metabolism more generally.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5e0928f3-2b7d-4622-bc96-68a4d0078826-2021-03-11T172336.036Z,1642,PubMed:27977873 +PET100 patient cell line,Functional Alteration Patient cells,"Oláhová M, et al., 2015, PMID: 25293719","Fibroblasts showed impaired complex IV activity, associated with a profound defect in cytochrome oxidase assembly, and decreased steady state levels of Complex IV proteins",Score,0.5 (1),A second patient cell culture model with disrupted gene function showing mitochondrial dysfunction in a non-neuronal cell type (Awarded 0.5 pts),https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_33c546f5-a285-424b-9ae2-9ca4fc718c67-2019-05-20T191347.510Z,1645,PubMed:25293719 +PEX12 Complex,Protein Interaction,"Chang CC, et al., 1999, PMID: 10562279","yeast-two hybrid screen showed interaction between PEX12 and PEX10 (Fig. 3A), western blot overlay showed PEX10 was bound by the MBP-PEX12 fusion protein but not by MBP-LacZα, suggesting specific binding between PEX12 and PEX10 (Fig. 3B), fibroblasts transfections confirmed that complex was present in vivo (Fig. 3C)",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c0f7f094-ac3b-4309-ad8f-8e604f006485-2019-12-06T050000.000Z,1647,PubMed:10562279 +Mast_Biochem Function B,Biochemical Function B,"Mast FD, et al., 2011, PMID: 21669930","In patients with mild forms of PBDs, a small number of import-competent, enlarged peroxisomes are observed (from PMID: 20647552)",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_93eacb33-b099-485d-bf8a-782479dc0a3b-2020-01-17T170000.000Z,1649,PubMed:21669930 +iPSC cell line,Model Systems Cell culture model,"Wang XM, et al., 2015, PMID: 26319495",Cells exhibited reduced plasmalogens,Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_124c97b0-92ed-4921-a0b9-2ff33135139d-2019-12-06T170000.000Z,1651,PubMed:26319495 +Mast_FA,Functional Alteration Non-patient cells,"Mast FD, et al., 2011, PMID: 21669930","Most of the GFP signal in S2 cells with knockdown of Pex13 was excluded from punctate bodies. Number of punctate bodies was also reduced. These findings were consistent with those seen in patients with PEX13 mutations. +Experiments in P pastoris system by Gould et al (PubMed: 8858165) showed impaired PTS1 and PTS2 import in pex13 deficient cells. Levels of catalase (PTS1) and thiolase (PTS2) were 3% and 5% in pex13 deficient cells, compared to 55% and 68% in wild-type cells. Analysis with both PTS1-GFP and PTS2-GFP showed that they were mislocalized to the cytoplasm in pex13 deficient cells.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0c662669-4eb8-45e3-8540-c394ea40c1b2-2019-10-04T160000.000Z,1652,PubMed:21669930 +Nakayama_PEX16 Fly model,Model Systems Non-human model organism,"Nakayama M, et al., 2011, PMID: 21826223","Homozygous pex16 mutants were viable, unlike pex3 mutants, with a very small number of peroxisome-like particles. The authors note that this is different from what is seen in mammals, but similar to pex16 yeast mutant, suggesting that the significance of the pex16 ortholog in peroxisome biosynthesis may be different among species. pex16 mutant flies showed reduced body size, rosy eye color, and 2-fold higher levels of VLCFAs compared to wild-type. They showed locomotion defects based on their climbing and flight assessment. Areas of low-density dendrites were observed in the brain, indicating neurodevelopmental abnormality.",Score,1 (2),The model is scored reduced points as it does not typically recapitulate the PBD phenotype.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7506d938-efb4-416c-aafd-221251d00e6e-2020-01-13T170000.000Z,1654,PubMed:21826223 +Aranovich_BF_A,Biochemical Function A,"Aranovich A, et al., 2014, PMID: 25002403","The authors suggest that PEX16 may be involved in trafficking PEX3 via the ER (group I pathway), but that a group II pathway may also serve as an overflow.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7506d938-efb4-416c-aafd-221251d00e6e-2020-01-13T170000.000Z,1654,PubMed:25002403 +PEX3 Interaction,Protein Interaction,"Agrawal G, et al., 2016, PMID: 26833788","PEX3 was found to be required for the budding of RING-domain PEX2 from the ER (Fig. 1) +PEX3 colocalized in ER with PEX2 around the cell periphery, data is suggestive that PEX3 contains intra-ER sorting signal (Figure 2) +Through CO-IP it was determined that PEX19 is required for the interaction of PEX3 and the RING-domain (Figure 7)",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_17bf1c4a-1775-40c6-a499-774c93827343-2020-02-07T170000.000Z,1655,PubMed:26833788 +Nakayama_Fly model,Model Systems Non-human model organism,"Nakayama M, et al., 2011, PMID: 21826223","Homozygous flies with the partial deletion of the pex3 locus as well as compound heterozygous flies with the partial pex3 deletion and a complete deletion of the pex3 locus are reported to have died as larvae. +Overexpression in S2 cells of proteins with peroxisome-targeting signals, PTS1 and PMP70-ECFP, showed co-localization in peroxisomes in the wild-type flies, while almost no positive signals (<1 in 10 cells) were observed in the pex3 homzygous mutants, indicating that pex3 is essential for peroxisome biogenesis.",Score,1 (2),The evidence is scored reduced points as the paper does not present the supporting data.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d53df483-c31a-4672-8a11-04d33d6df336-2019-11-01T160000.000Z,1657,PubMed:21826223 +PEX12 Interaction,Protein Interaction,"Chang CC, et al., 1999, PMID: 10562279","yeast two-hybrid system detected interaction between PEX12 zinc-binding domain and PEX5 (Fig. 2A), protein budding assay which confirmed PEX5-PEX12 binding by showing PEX5 bound byMBP-PEX12 and not MBP-LacZalpha (Fig. 2B), coimmunopreciptation revealed that PEX5 precipitated with PEX12/3xmyc in lysates from human fibroblasts (Fig. 2C)",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b49d9cfd-0e51-4219-84bb-76b4c9b99fa9-2020-01-17T170000.000Z,1658,PubMed:10562279 +Peroxisome dysfunction in fibroblasts,Functional Alteration Patient cells,"Levesque S, et al., 2012, PMID: 22894767","Immunofluorescence on patient fibroblasts (from patient B1 who is homozygous for c.802_815del variant and a PEX6 null cell line) using peroxisomal membrane marker, PMP70, and matrix protein marker, thiolase, revealed a decrease in peroxisome number, abnormally enlarge peroxisomes, and absent matrix protein import into the organelle compared to wild type cells.",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_54df6fb2-b692-4ece-a525-ae0cfe243826-2019-09-06T160000.000Z,1659,PubMed:22894767 +Axon outgrowth,Functional Alteration Non-patient cells,"Wu CH, et al., 2012, PMID: 22801503","In mouse E13.5 primary motor neurons transfected with with WT or mutant (C71G, M114T, or G118V) PFN1, those expressing PFN1 mutations displayed a significant decrease in axon outgrowth. Additionally, PMNs transfected with two mutant PFN1 constructs (C71G and G118V) were stained to detect F- and G-actin localization patterns in the highly dynamic and actin-rich growth cone, finding to a significantly reduced growth cone size (~43-52%) relative to wild-type PFN1. Growth cone morphology was also altered with virtually no filopodia in the mutants. In particular, the C71G mutant expressing PMNs displayed an F-/G-actin ratio of 24.4% relative to wild-type expressing PMNs. These results suggest that mutant PFN1 can inhibit the conversion of G-actin to F-actin within the growth cone region, thus affecting its morphology.",Score,0.5 (0.5),"These results suggest that mutations in PFN1 may contribute to ALS pathogenicity in part by inhibiting axon dynamics. This is in line with the fact that variants in 4 other genes encoding proteins involved in cytoskeletal pathways, peripherin, spastin, NF-H and DCTN1, have earlier been suggested to contribute to ALS pathogenesis. Additionally, those PMNs expressing mutant PFN1 demonstrated ubiquitinated aggregates; aggregates were not observed in cells expressing wild-type. Protein aggregates are a hallmark of ALS pathology.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_948de40f-2cef-4235-ae87-491c01ffe803-2021-04-22T160000.000Z,1661,PubMed:22801503 +Fil (2017) PFN1 Transgenic Mouse Model,Model Systems Non-human model organism,"Fil D, et al., 2017, PMID: 28040732","Since voluntary muscle paralysis is a hallmark of human ALS, authors sought to determine if the expression of mutant profilin1 is sufficient to cause skeletal muscle atrophy and pathology with a possible impact on motor behaviour. hPFN1G118V transgenic mice exhibited progressively deteriorating motor dysfunction with the onset of symptoms at P120–130 and rapid progression to end-stage disease (P165–210). The symptoms began in the hind limbs as an asymmetrical hind limb reflex, a fine tremor, and the appearance of an angle in the hind limb at the ankle joint, where the gastrocnemius and tibialis muscle tendons are attached (Fig. 3). These initial subtle signs were followed by a gradual decline in locomotion, weight loss, kyphosis and finally dragging their hind legs with the help of front limb mobility until the end stage of disease, at which point the mice become non-ambulatory and moribund. + +Other key pathological features were identified that are also consistent with human ALS disease: +2) Mutant profilin1 causes reduced hind limb CMAP amplitude - used to address the decline in motor performance. CMAP amplitudes were drastically reduced in mutant mice compared to controls, which is similar to what occurs in ALS patients as a result of severe muscle atrophy. + + +Mutant profilin1 causes neuromuscular junction and muscle denervation, a finding that correlates with disease pathology in ALS patients. + + +Mutant profilin1 causes loss of ventral horn (lower) spinal neurons and upper motor neurons (corticospinal motor neurons in layer V), mutant profilin1 aggregation, abnormally ubiquitinated proteins, reduced choline acetyltransferase (ChAT) enzyme expression, fragmented mitochondria, and glial cell activation, all of which are also common pathological features of ALS.",Score,2 (2),"Expression of the mutant PFN1 p.G118V in this transgenic mouse model produced ALS-like symptoms including loss of lower and upper motor neurons, mutant profilin1 aggregation, abnormally higher levels of ubiquitinated proteins, glial cell activation, muscle atrophy, weight loss and early death. The phenotype and pathology of these mutant mice closely resembled the phenotype and pathology of human ALS and aligns with other well-characterized transgenic ALS mouse models.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_948de40f-2cef-4235-ae87-491c01ffe803-2021-04-22T160000.000Z,1661,PubMed:28040732 +Lymphoblast cell analysis from patients with PFN1 mutations,Functional Alteration Patient cells,"Giampetruzzi A, et al., 2019, PMID: 31444357","NPC integrity was found to be compromised in patient-derived lymphoblasts. The percentage of cells with abnormal staining of Lamin A/C and RanGAP1 was significantly increased in all 3 lines expressing mutant PFN1, while FG-Nups - recognized by the mAb414 antibody (AbCam) -showed a significant change only in the G118V line. Further, authors found that the nucleocytoplasmic localization of Ran was significantly altered in the C71G lines (fig 3). No changes in the overall levels of all proteins tested, including endogenous PFN1, were detected (Supplementary Fig. 6). These results support the hypothesis that endogenous levels of mutant PFN1 directly affect the nuclear pore structure/stability in ALS patient cells, possibly leading to neuronal degradation.",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_948de40f-2cef-4235-ae87-491c01ffe803-2021-04-22T160000.000Z,1661,PubMed:31444357 +Mutant PFN1 causes functional alteration,Functional Alteration Non-patient cells,"Giampetruzzi A, et al., 2019, PMID: 31444357","Mutations in PFN1 impair nucleocytoplasmic transport (NCT) [Fig 1, supp figures]. In the presence of mutant PFN1, nuclear pore complexes (NPCs) were either reduced in number or structurally compromised because of the lack of essential nucleoporins, and additional key players in NCT are abnormally distributed. + + +Mutant PFN1 alters the structure of the nuclear membrane [Fig 2]. Expression of either V5-tagged or GFP- tagged PFN1C71G in Neuro2a cells led to severe defects in the structure of the nucleus, with the presence of frequent folds, invaginations, and protrusions that were never observed in untransfected or PFN1WT-transfected N2a cells. + + +Nuclear import is greatly reduced by mutant PFN1 [Fig 4]. Expression of mutant PFN1 led to significant reduction in import rates compared to GFP- and PFN1-WT transfected cells as visualized by live cell imaging. + + +Mutant PFN1 alters mRNA post-transcriptional regulation [Fig 5]. The majority of TDP-43 and FUS was nuclear (vs cytoplasmic) in WT-expressing MNs, while mutant PFN1 expression led to a shift in the C:N ratio of both proteins.",Score,1 (0.5),"In addition to the multiple effects of PFN1 mutations shown here, the authors further assessed the causality between nucleocytoplasmic transport (NCT) disturbance, RNA-binding proteins mislocalization, and motor neuron (MN) pathology. They investigated the potential of nuclear export inhibitor KPT-276, a well-established selective inhibitor of XPO16,33,34, to rescue PFN1-dependent defects, finding KPT-276 treatment was able to fully rescue TDP-43 cytoplasmic mislocalization, as well as the axonal outgrowth defects (MNs expressing mutant PFN1 and treated with vehicle alone had significantly shorter axons compared to PFN1WT cells, while KPT-276 treatment fully rescued the defect). Together, these data support a direct link between NCT, mRNA regulation, and PFN1-dependent ALS cellular defects.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_948de40f-2cef-4235-ae87-491c01ffe803-2021-04-22T160000.000Z,1661,PubMed:31444357 +"PHF8 interacts with ZNF711, a XLMR gene product.",Protein Interaction,"Kleine-Kohlbrecher D, et al., 2010, PMID: 20346720","ZNF711 was identified as a protein interactor of tagged-PHF8 by tandem affinity purification in TREX 293 cells. The protein-protein interaction was verified by coimmunoprecipitation in both overexpression and endogenous states in cell culture. A functional interaction between the two proteins was observed in a mammalian two-hybrid assay. Additionally, purified recombinant PHF8 shows increased histone demethylation activity when equimolar amounts of ZNF711 were included in the assay, compared with PHF8 alone. ZNF711 is a XLMR gene (OMIM: 300803)",Score,1 (0.5),"ZNF711 is a XLMR gene (OMIM: 300803). The paper validated the protein-protein interaction by multiple assays, including tandem affinity purification, coimmunoprecipitation in overexpression and endogenous state, mammalian two-hybrid system, and a cell-free functional interaction assay.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b9e94640-1950-4438-bcda-4859545d83d1-2018-11-07T170000.000Z,1665,PubMed:20346720 +Rescue of brain and jaw abnormality in knockdown zebrafish,Rescue Non-human model organism,"Qi HH, et al., 2010, PMID: 20622853","The apoptosis in the developing brain and the neural tube in knockdown zebrafish can be rescued by reintroduction of wild-type but not catalytically inactive zPHF8. Similarly, wild-type but not catalytically inactive zPHF8 showed significant rescue of the craniofacial defects induced by the zPHF8 morpholino.",Score,0.5 (2),This is a rescue experiment of knockdown zebrafish.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b9e94640-1950-4438-bcda-4859545d83d1-2018-11-07T170000.000Z,1665,PubMed:20622853 +Knockdown of zPHF8 in zebrafish,Model Systems Non-human model organism,"Qi HH, et al., 2010, PMID: 20622853","PHF8 mutations have been found in patients with XLMR and craniofacial deformities. PHF8 regulates cell survival in the zebrafish brain and jaw development, as knockdown zebrafish shows apoptosis in the developing brain and the neural tube and craniofacial developmental abnormalities.",Score,0.5 (2),"This is a knockdown zebrafish model (downgraded). This model shows both defects in brain and craniofacial development, while KO mouse model shows cognitive defects without craniofacial problem.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b9e94640-1950-4438-bcda-4859545d83d1-2018-11-07T170000.000Z,1665,PubMed:20622853 +Knockout mouse model recapitulates patient phenotypes,Model Systems Non-human model organism,"Chen X, et al., 2018, PMID: 29317619","PHF8 is a candidate gene for X-chromosome-linked intellectual disability. Phf8 knockout mice displayed impaired learning and memory, and impaired hippocampal long-term potentiation (LTP) without gross morphological defects. These results indicate that loss of Phf8 in animals causes deficient learning and memory.",Score,1.5 (2),"Although a subpopulation of XLID patients with PHF8 mutations display cleft lip and palate, the mouse model does not show any deficits in craniofacial and limb development (Supplementary Fig 3). Another Phf8 knockout mouse model (PMID: 28485378) in a previous study does not show cognitive impairment, although the difference of behavior phenotype in the two studies may be due to different mouse genetic background and subtle difference in the methods for behavioral testing.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b9e94640-1950-4438-bcda-4859545d83d1-2018-11-07T170000.000Z,1665,PubMed:29317619 +Rapamycin rescues cognitive deficits in Phf8 knockout mice,Rescue Non-human model organism,"Chen X, et al., 2018, PMID: 29317619",Pharmacological suppression of mTOR signaling with rapamycin in Phf8 knockout mice recovers the weakened long-term potentiation and cognitive deficits.,Score,1 (2),"A subpopulation of XLID patients with PHF8 mutations display cleft lip and palate, Rapamycin treatment rescues behavioral deficits (Figure 5) and electrophysiological deficit (Figure 6) in Phf8 null mice.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b9e94640-1950-4438-bcda-4859545d83d1-2018-11-07T170000.000Z,1665,PubMed:29317619 +Mouse Model of Glycogen Storage Disease Type IXB,Model Systems Non-human model organism,"Arends CJ, et al., 2022, PMID: 36077341","The phenotype in humans is hepatomegaly which typically has clinical improvement with increasing age. Elevated liver enzymes are observed in humans, this was also observed in the mice. In humans there can also be mild hypoglycemia with prolonged fasting >13 hours. In the mice they observed consistently lower levels of blood glucose compared to WT mice. In humans there is sometimes short stature also observed, which was not observed in the mice.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0bc221ef-fafa-41c6-9b59-fab2b34241c4-2024-03-17T070000.000Z,1667,PubMed:36077341 +siRNA knockdown,Biochemical Function B,"Kim K, et al., 2012, PMID: 23110211","Joubert syndrome (JBTS; OMIM #213300) is neurodevelopment disease which is characterized by malformation in the cerebellum and brainstem, recognizable on axial brain magnetic resonance imaging (MRI) as a “molar tooth sign”the diagnostic hallmark. Patients typically present as infants with hypotonia, abnormal eye movement, respiratory problems, and ataxia multi-system. Additionally JBTS may be manifested in other body systems such as the eyes, kidney, liver, and skeleton. Mutations in the PIBF1 gene impact primary cilia therefore resulting in a classical ciliopathy clinical presentation.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_bf72e5f0-a64d-4fb9-9a9b-07fef481bf56-2023-09-27T160000.000Z,1672,PubMed:23110211 +siRNA knockdown,Functional Alteration Non-patient cells,"Wheway G, et al., 2015, PMID: 26167768","The authors used siRNA knockdown to screen for ciliogenesis across the genome. What they demonstrated for PIBF1 was the exogenous expression of human wild-type PIBF1 rescued ciliogenesis in mIMCD3 cells following siRNA knockdown of endogenous Pibf1, and the expression of PIBF1 containing the p.Asp637Ala Hutterite variant was unable to rescue normal ciliogenesis +Though suggesting that it is a pathogenic missense mutation (Suppl. Figure 4).",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_bf72e5f0-a64d-4fb9-9a9b-07fef481bf56-2023-09-27T160000.000Z,1672,PubMed:26167768 +Xenopus Injection Experiments,Expression A,"Ott T, et al., 2019, PMID: 30858804",PIBF1 was expressed in both the cell and tissue levels of the embryos of the Xenopus,Score,1 (0.5),PIBF1 was expressed in both the cell and tissue levels of the embryos of the Xenopus,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_bf72e5f0-a64d-4fb9-9a9b-07fef481bf56-2023-09-27T160000.000Z,1672,PubMed:30858804 +Mouse Genetic studies,Model Systems Non-human model organism,"Kumar D, et al., 2021, PMID: 34241634","The animal model showed CEP90 (PIBF1) is a key regulator of ciliogenesis, specifically in distal appendage formation,",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_bf72e5f0-a64d-4fb9-9a9b-07fef481bf56-2023-09-27T160000.000Z,1672,PubMed:34241634 +pidd1 knock out mice,Model Systems Non-human model organism,"Sheikh TI, et al., 2021, PMID: 33414379",The phentype of pidd1 mice is not similar to phentype obseved in humans.,Score,0 (2),No similarity of phenotypes were found between mice models and human.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_021d5aa5-6447-4b49-a748-219c4dd356f4-2024-06-04T160000.000Z,1673,PubMed:33414379 +Patch clamp of HEK/293T cells,Functional Alteration Non-patient cells,"Albuisson J, et al., 2013, PMID: 23695678",Expression of mutations was associated with slow inactivation kinetics.,Score,1 (0.5),"Two additional papers (PMID: 28716860, doi.org/10.1182/blood.V124.21.741.741) showed similar results.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6a86cb1d-4eed-4c10-971f-4a9578cb12b1-2023-07-02T040000.000Z,1674,PubMed:23695678 +Expression analysis,Expression A,"Cahalan SM, et al., 2015, PMID: 26001274",Demonstrate expression in murine red blood cells,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6a86cb1d-4eed-4c10-971f-4a9578cb12b1-2023-07-02T040000.000Z,1674,PubMed:26001274 +YODA stimulation of Red Blood Cell,Biochemical Function B,"Cahalan SM, et al., 2015, PMID: 26001274",Both loss of function and gain of function of PIEZO1 is associated with DHS.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6a86cb1d-4eed-4c10-971f-4a9578cb12b1-2023-07-02T040000.000Z,1674,PubMed:26001274 +Calcium imaging and mechanical stimulation,Functional Alteration Non-patient cells,"Syeda R, et al., 2015, PMID: 26001275",Upon mechanical stimulation cells with Piezo1 had increased calcium release determined by calcium imaging which is consistent with increased channel activity.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6a86cb1d-4eed-4c10-971f-4a9578cb12b1-2023-07-02T040000.000Z,1674,PubMed:26001275 +Ektacytometry of patient RBCs,Functional Alteration Patient cells,"Yamaguchi Y, et al., 2021, PMID: 34737711","Ektacytometry determined that patient red blood cells had increased H2O volume, reduced K+, increased Na+ consistent with increased channel activity.",Score,0.5 (1),Reduced score as red blood cell phenotype consistent with DHS has also been described rarely for patients with homozygous loss of function PIEZO1 variants.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6a86cb1d-4eed-4c10-971f-4a9578cb12b1-2023-07-02T040000.000Z,1674,PubMed:34737711 +HEK/239T Stretch-activated current assay,Functional Alteration Non-patient cells,"Yamaguchi Y, et al., 2021, PMID: 34737711",G782S either alone or as double mutation G782S/R808Q showed an increased peak current consistent with a gain of function phenotype.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6a86cb1d-4eed-4c10-971f-4a9578cb12b1-2023-07-02T040000.000Z,1674,PubMed:34737711 +Expression analysis,Expression A,"Cahalan SM, et al., 2015, PMID: 26001274",Demonstrate expression in murine red blood cells,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d37d7a52-269b-4a45-b28e-c6cbdfd7d94e-2023-07-03T160000.000Z,1675,PubMed:26001274 +YODA stimulation of Red Blood Cell,Biochemical Function B,"Cahalan SM, et al., 2015, PMID: 26001274",Both loss of function and gain of function of PIEZO1 is associated with DHS.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d37d7a52-269b-4a45-b28e-c6cbdfd7d94e-2023-07-03T160000.000Z,1675,PubMed:26001274 +Protein localization and expression,Functional Alteration Non-patient cells,"Lukacs V, et al., 2015, PMID: 26387913",Ectopically expressed PIEZO1 variants lead to protein mislocalization and/or reduced expression,Score,0.5 (0.5),Similar results described in PMID 34489534 and PMID 34867393,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d37d7a52-269b-4a45-b28e-c6cbdfd7d94e-2023-07-03T160000.000Z,1675,PubMed:26387913 +Mechanical activation patch clamp,Functional Alteration Patient cells,"Lukacs V, et al., 2015, PMID: 26387913",Loss of mechanical induction scored by patch clamp,Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d37d7a52-269b-4a45-b28e-c6cbdfd7d94e-2023-07-03T160000.000Z,1675,PubMed:26387913 +Mouse model PIEZO1 homozygous endothelial cell knockout,Model Systems Non-human model organism,"Nonomura K, et al., 2018, PMID: 30482854",Mouse models develop ascites similar to humans and lack lymphatic valves leading to back flow.,Score,4 (2),"Two additional papers (PMID 30676326 and PMID 35701867) replicate the loss of valve phenotype using an inducible, lymphatic endothelial specific Prox1-CreERT murine driver.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d37d7a52-269b-4a45-b28e-c6cbdfd7d94e-2023-07-03T160000.000Z,1675,PubMed:30482854 +Stretch activated patch clamp,Functional Alteration Non-patient cells,"Zhou Z, et al., 2021, PMID: 34867393",Loss of channel activity,Score,0.75 (0.5),Additional paper demonstrated another patient variant had the same effect (PMID: 34489534),https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d37d7a52-269b-4a45-b28e-c6cbdfd7d94e-2023-07-03T160000.000Z,1675,PubMed:34867393 +phosphorylation,Functional Alteration Patient cells,"Rivière JB, et al., 2012, PMID: 22729224",Increased phosphorylation,Score,0.5 (1),Patient cell lines,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c670e6ce-97b6-4383-bea6-5c216ab2a4a0-2021-07-29T213157.366Z,1682,PubMed:22729224 +Mouse model,Model Systems Non-human model organism,"Roy A, et al., 2015, PMID: 26633882",The overgrowth displayed in the mouse is similar to that found in the human. Seizures are also a common consequence of the overgrowth,Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c670e6ce-97b6-4383-bea6-5c216ab2a4a0-2021-07-29T213157.366Z,1682,PubMed:26633882 +Clayton_Mouse model,Model Systems Non-human model organism,"Clayton E, et al., 2002, PMID: 12235209","BCR-stimulated B cells from p110δ-deficient mice produced little PIP-3. A marked reduction in the B1 subset resident in the peritoneal cavity, and CD21-hi CD23-lo MZ B cells of the spleen were also significantly reduced in number (B1 total: WT = 10^6; KO mice = 0.08x10^6). In nonimmunized P110δ−/− mice the levels of serum IgM, IgG1, IgG2a, and IgG3 and were significantly reduced, whereas IgG2b and IgA were in the normal range. In response to DNP-KLH, WT mice produced IgM, IgG1 IgG2a, IgG2b, and IgG3 antibodies, while p110δ−/− mice produced significantly less anti-DNP antibody of these subclasses. Purified splenic B cells from p110δ-deficient mice proliferated poorly in response to in vitro stimulation with polyclonal anti-IgM antibody, a potent B cell mitogen. When B cells from p110δ−/− mice were cultured in serum containing media, the spontaneous level of apoptosis was increased when compared with wild-type suggesting survival pathways were defective.",Score,1 (2),Reduced score is awarded as the mouse model recapitulates the human phenotype to some extent.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_00e2cc94-311b-44d8-9c41-e41c12ebd8f2-2022-04-19T192558.184Z,1683,PubMed:12235209 +Avery_CRISPR/Cas9 Knock-in Mouse,Model Systems Non-human model organism,"Avery DT, et al., 2018, PMID: 30018075","Mice expressing the E1020K variant showed increase in basal levels of phosphorylation of Akt and S6 compared to WT mice. Mice homozygous for the E1020K variant showed even greater activation of the signaling pathways indicating a dose-dependent effect of the variant. The increase levels of pAkt and pS6 could be reduced by incubation with leniolisib, a p110δ-specific inhibitor, indicating that the activation was PI3K dependent. This inhibition could paritally rescue defects in B cell differentiation. Analysis of BM revealed an increase in pro-B cells and a decrease in mature recirculating IgD-hi cells in Pik3cdE1020K GOF mice compared with WT controls. Analysis of B cell populations in the circulation revealed comparable proportions of total B cells in Pik3cdE1020K GOF mice, but increased proportions of B1 and transitional B cells and decreased proportions of mature B cells compared with WT mice. Ig class switching was impaired in GOF mice - 50% fewer Pik3cdE1020K GOF follicular B cells were positive for the switched isotypes upon stimulation compared with B cells from WT mice. +Further studied using the same mouse model in PMID: 30738173 describe CD4+ T cell dysfunction. Similar to patients with APDS1 presenting with lymphoproliferation and splenomegaly, spleens of GOF mice had increased total cellularity compared to WT spleens. In older mice, there was an increase in the percentage of CD4+ T cells, a decrease in frequency of naive CD4+ T and corresponding increase in memory cells. Further, authors show that T-follicular helper cells were less efficient than WT Tfh in providing help to B cell and forming an equivalent germinal center, and subsequently in antibody secretion and regulation of Ig isotype switching.",Score,2.5 (2),The mouse model is scored slightly increased points for the recapitulation of the cellular phenotype in a knock-in model using a human-derived variant.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c37954fd-7d7c-4ca9-9cd0-7681c1edf8d3-2022-04-19T150547.546Z,1684,PubMed:30018075 +Stark_Mouse,Model Systems Non-human model organism,"Stark AK, et al., 2018, PMID: 30093657","Authors studied the susceptibility of GOF mice to S. pneumoniae and whether nemiralisib, a PI3Kδ inhibitor would be protective against infection. Treated GOF mice showed prolonged survival compared to mice given vehicle control. Biochemical analyses of B cells and T cells from GOF mice confirmed that the kinase is hyperactive (6x WT). In wild-type and GOF mice derived cells, nemiralisib reduced PIP3 to the background level observed in p110δD910A (knock-out mouse model) cells. Phosphorylation of Akt, ERK, FOXO and S6 were increased. BM of the GOF mice showed significant lymphopenia. GOF mice also showed elevated levels of IgG1, IgG2b, a trend towards increased IgG2c, IgA, IgE and a trend towards hyper IgM syndrome. Infection with S. pneumoniae resulted in accelerated disease onset and increased mortality. The increased susceptibility was driven by B cells in an antibody-dependent manner.",Score,3 (2),Human-derived variant is knocked in to the mouse model showing GOF effect and recapitulation of the human phenotype. Increased points are awarded upon expert review.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c37954fd-7d7c-4ca9-9cd0-7681c1edf8d3-2022-04-19T150547.546Z,1684,PubMed:30093657 +Wray-Dutra_inducible mouse model,Model Systems Non-human model organism,"Wray-Dutra MN, et al., 2018, PMID: 30194267","Mice expressing the E1020K variant displayed diminished frequency and ~50% reduction in absolute BM B cell number. There was also a reduction in the number of small pre- and mature recirculating B cells. GOF mice also exhibited enhanced formation of plasma cells and a 3-fold increase in IgM and IgG3, similar to the hyper-IgM syndrome seen in patients. In addition, GOF mice showed skewed germinal centers and limited Ig class switching.",Score,1 (2),Score is reduced as some recapitulation of the cellular process is addressed using the human-derived variant knocked into the mouse model.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c37954fd-7d7c-4ca9-9cd0-7681c1edf8d3-2022-04-19T150547.546Z,1684,PubMed:30194267 +Pik3cg KO mice,Model Systems Non-human model organism,"Takeda AJ, et al., 2019, PMID: 31554793","Confirmed that bone marrow-derived macrophages from Pik3cg KO mice produced more IL-12 in vitro, as in the patient. +Then sought to replicate the human condition by exposing co-housed WT and Pik3cg KO mice to natural pathogens/microbiota through addition of healthy pet-store mice to their cages. Upregulation of Klrg1 and CD44 with concomitant downregulation of CD62L on CD8 T cells assessed on Day 14 was significantly impaired in KO mice, consistent with activation defects. In line with observations in patient A.1, there was a significantly reduced Treg frequency in Pik3cg KO animals after long-term exposure to pet-store mice. Total serum immunoglobulin levels were assessed in WT and KO animals co-housed for 3–5 weeks with pet-store mice, and all isotypes tested trended lower in KO mice, with IgG1, IgG2a, and IgG3 significantly reduced. +Furthermore, T cell infiltration of the small intestine was significantly greater in KO mice, and a similar trend was observed in the lung but did not reach significance.",Score,2 (2),"observe overlapping phenotypes in human and mouse PI3Kγ deficiency when normal environmental exposure to pathogens occurs, and the major disease features include reduced markers of T cell activation, low Treg cell frequency, low immunoglobulin production, and increased T cell infiltration in the gut, associated with hyper-inflammatory macrophages.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c042f849-508e-4125-be10-cfa6750408ef-2023-07-18T160000.000Z,1685,PubMed:31554793 +AKT phosphorylation,Functional Alteration Non-patient cells,"Thian M, et al., 2020, PMID: 33054089","Created Jurkat PIK3CG knockout cells and found decreased activation as measured by CD69 upregulation upon anti-CD3 stimulation, and reduced AKT phosphorylation at the Ser473 phosphorylation site. These data mimic the phenotypes observed in patient T cells , which when examined for PI3K/AKT signaling found mildly decreased AKT phosphorylation in upon stimulation.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c042f849-508e-4125-be10-cfa6750408ef-2023-07-18T160000.000Z,1685,PubMed:33054089 +T-cell activation alteration,Functional Alteration Patient cells,"Thian M, et al., 2020, PMID: 33054089","Observed functional defects in patient T cells, particularly a poor activation and proliferation in response to anti-CD3 or combined anti- CD3/CD28 stimulation. As expected, TCR-dependent T-cell activation was impaired in PIK3CG-mutated T cells. A gene-rescue experiment on primary patient cells using GFP-labeled wild-type p110γ and showed that the T-cell activation defect could be restored.",Score,1 (1),"This is consistent with the known participation of phosphoinositide 3–kinase γ in T cell receptor–induced T cell activation reported in PMID: 17998387. They found that after TCR ligation, p110γ interacts with Gαq/11, lymphocyte-specific Tyr kinase, and ζ-associated protein. TCR stimulation activates p110γ, which affects 3-phosphorylated polyphosphoinositide levels at the immunological synapse. They showed that TCR-stimulated p110γ controls RAS-related C3 botulinum substrate 1 activity, F-actin polarization, and the interaction between T cells and antigen-presenting cells, illustrating a crucial role for p110γ in TCR-induced T cell activation.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c042f849-508e-4125-be10-cfa6750408ef-2023-07-18T160000.000Z,1685,PubMed:33054089 +Expression of PI3K isoforms,Expression B,"Conley ME, et al., 2012, PMID: 22351933","Expression of p85α and p50α in cells from age-matched disease controls, patients with <1% CD19+ cells in the blood, was identical to that seen in healthy adult controls. The patient had no p85α in T cells, neutrophils, or DCs. The amount of p50α in T cells was normal or slightly increased, whereas the amount in DCs was normal and the amount in neutrophils was decreased. Authors did not identify a truncated form of p85α, encoded by the first six exons of PIK3R1, when using the antibody to the N-terminal portion of p85α to examine the patient’s T cells. Expression of p110δ, the leukocyte-specific partner of p85α, was decreased in T cells, neutrophils, and DCs from the patient. The decreased expression of p110δ indicates that the N-terminal end of p85α contributes to the binding and stabilization of p110 or a 50% decrease in the amount of the p110-binding domain results in more significant loss of p110δ. Expression of other p110 isoforms documented a slight decrease in p110α in the patient’s T cells and the absence of all p110 isoforms as well as p85α and p50α in the patient’s neutrophils.",Score,0.5 (0.5),"Western blot showed markedly decreased p110δ, as well as absent p85α, in patient T cells, neutrophils, and dendritic cells. The absence of p85α in the patient results in an early and severe defect in B cell development but minimal findings in other organ systems.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e019aaad-09a8-44c4-9fc0-12a1d53e79db-2021-05-20T153438.351Z,1686,PubMed:22351933 +phospho-S6 (Ser240/244) blotting and PI-103 inhibitor exposu,Functional Alteration Patient cells,"Rivière JB, et al., 2012, PMID: 22729224",Increased phosphorylation of downstream molecule S6 and resistance to pharmacologic suppression of PI3K activating.,Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_fc9a451e-0e75-47d2-a090-a2409732c465-2021-07-29T213616.452Z,1687,PubMed:22729224 +PIP_3 immunofluorescence,Functional Alteration Patient cells,"Rivière JB, et al., 2012, PMID: 22729224",Increased PIP3 levels on immunofluorescence relative to normal controls and AKT3 mutant.,Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_fc9a451e-0e75-47d2-a090-a2409732c465-2021-07-29T213616.452Z,1687,PubMed:22729224 +Phospho-S6 Western Blotting,Functional Alteration Patient cells,"Negishi Y, et al., 2017, PMID: 28086757",Increased phospho-S6 as a read out of PI3K-AKT-MTOR signaling.,Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_fc9a451e-0e75-47d2-a090-a2409732c465-2021-07-29T213616.452Z,1687,PubMed:28086757 +Recruitment of Parkin,Functional Alteration Non-patient cells,"Narendra DP, et al., 2010, PMID: 20126261","We found that the L347P patient +mutant of PINK1 is unstable (Figure 8C and Figure S6A), as was +reported previously [28], and that L347P failed to reconstitute +YFP-Parkin recruitment to depolarized mitochondria (Figure 8A +and 8B). Of the patient mutations that exhibited stable expression, +A168P and H271Q also failed to reconstitute YFP-Parkin +recruitment at 3 h,",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1999e6c4-eb15-438a-a4ea-98989112dcbb-2023-01-18T190000.000Z,1688,PubMed:20126261 +p-Ser65-Ub signal,Functional Alteration Patient cells,"Ando M, et al., 2017, PMID: 28438176",p-Ser65-Ub signal increased in control cells over time but was undetectable in PINK1 p.I368N mutant cells upon treatment with CCCP,Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1999e6c4-eb15-438a-a4ea-98989112dcbb-2023-01-18T190000.000Z,1688,PubMed:28438176 +PKP2 KO,Model Systems Non-human model organism,"Cerrone M, et al., 2017, PMID: 28740174","Cardiomyocite-specific, tamoxifen-activated PKP2 KO mice: isoprotenerol treatment induced polymorphic ventricular ectopy, couplet, triplets and runs of polymorphic NSVT along, at a structurally-normal heart stage (resembling CPVT). Progression from a normal heart to a cardiomyopathy of RV predominance, to biventricular dilated cardiomyopathy and heart failure. Isoproterenol-induced arrhythmias are prevented by flecainide treatment.",Score,1 (2),"This is a full gene KO model, unlike the heterozygous LOF variants seen in patients in paper by Tester et al. While the mice initially demonstrate CPVT-like phenotypes in structurally normal hearts, they eventually develop a cardiomyopathy phenotype.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1231ec3b-3570-48dd-bea4-f7cd7fc54811-2021-01-20T170000.000Z,1693,PubMed:28740174 +human gene rescue of PKP2 deficient transgenic mouse,Expression A,"Grossmann KS, et al., 2004, PMID: 15479741",https://www.proteinatlas.org/ENSG00000057294-PKP2/tissue,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_2a8e26ad-c4ce-48d7-acab-1198d3b12ce5-2020-10-09T160000.000Z,1694,PubMed:15479741 +Grossmann Mouse Model,Model Systems Non-human model organism,"Grossmann KS, et al., 2004, PMID: 15479741","Confocal microscopy showed that unlike in wt hearts, desmoplakin of mutant hearts did not colocalize with junction proteins (plakoglobin, N-cadherin, beta-catenin, desmogelin Dsg2, alpha-catenin, and p120ctn). Electron microscopy showed that cardiomyocytes of wt embryos were connected by well-organized intercalated disks that were rich in adhering junctions, but the adhering junctions of mutant hearts were hard to distinguish. In the mutant hearts, desmoplakin localization was drastically altered. Mutations in desmoplakin and plakoglobin are known disease mechanisms for ARVC. This mouse model prompted Gerull et al, 2004 to screen for mutations in PKP2.",Score,1 (2),"The mouse model was a null rather than a human variant. It also did not specifically recapitulate the disease phenotype, rather implicated the gene in heart function.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6f97b6cd-5225-4076-b67a-2f609908e6fe-2018-03-08T170000.000Z,1695,PubMed:15479741 +Zhao_Model systems,Model Systems Non-human model organism,"Zhao Z, et al., 2011, PMID: 22046428","These mice developed cerebellar atrophy, severe motor dysfunction associated with the prominent formation of spheroids with tubulovesicular membranes remarkably similar to those seen in human INAD. This report showed the absence of PLA2G6 causes neuroinflammation and Purkinje cell loss and ultimately leads to cerebellar atrophy and that early anti-inflammatory therapy may help slow the progression of cerebellar atrophy in this deadly neurodegenerative disease.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d183700f-e6cc-482f-a3ed-f18f8154f092-2024-03-21T160000.000Z,1696,PubMed:22046428 +Zhou_Biochem function,Biochemical Function B,"Zhou Q, et al., 2016, PMID: 26755131","Genetic or molecular impairment of PLA2g6-dependent Ca2+ signaling is a trigger for autophagic dysfunction, progressive loss of dopaminergic (DA) neurons in substantia nigra pars compacta (SNc) and age-dependent l-DOPA-sensitive motor dysfunction. Overexpression of functional WT PLA2g6(L) can rescue SOCE and improve autophagic flux in idPD cells.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d183700f-e6cc-482f-a3ed-f18f8154f092-2024-03-21T160000.000Z,1696,PubMed:26755131 +Malley_Biochem function,Biochemical Function B,"Malley KR, et al., 2018, PMID: 29472584","The structure will facilitate in depth analysis of known mutants and their effect on biochemical properties. An interesting example of sensitive allosteric regulation is Arg 741 located at the dimerization interface, which is mutated to Trp in INAD, leading to an inactive enzyme, and to Gln in PD with the activity retained. Surprisingly, the A341T mutation in the ANK domain was found to be inactive. This residue is at the ANK/CAT interface and can affect the interactions and stability of the protein.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d183700f-e6cc-482f-a3ed-f18f8154f092-2024-03-21T160000.000Z,1696,PubMed:29472584 +Yu et al.,Functional Alteration Non-patient cells,"Yu S, et al., 2020, PMID: 32238860",PLCE1 KO human podocyte cell clone lines resulted in the loss of terminal arborizations in undifferentiated podocytes and an increased number of stress fibers in differentiated PLCE1 KO podocytes relative to that in control podocytes,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_cf5e85df-45a3-48dc-8b8d-27228d620412-2022-04-10T143000.000Z,1701,PubMed:32238860 +Yu et al.,Functional Alteration Non-patient cells,"Yu S, et al., 2020, PMID: 32238860","PLCE1 knockout and knockdown human podocyte cells showed reduced podocyte migration rates, wound healing and podocyte proliferation when compared to wild type cells.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_cf5e85df-45a3-48dc-8b8d-27228d620412-2022-04-10T143000.000Z,1701,PubMed:32238860 +Yu et al.,Biochemical Function B,"Yu S, et al., 2020, PMID: 32238860","PLCE1 interacts with RAC1 and RhoA that regulate actin cytoskeleton remodelling. (It regulates this small RhoGTPases) +Compared with control podocytes, podocytes transfected with PLCE1 siRNA exhibited a significant decrease in GTP-bound Rac1 and Cdc42 levels",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_cf5e85df-45a3-48dc-8b8d-27228d620412-2022-04-10T143000.000Z,1701,PubMed:32238860 +PLEKHG5 KO Mouse,Model Systems Non-human model organism,"Lüningschrör P, et al., 2017, PMID: 29084947","Plekhg5 gene inactivation in mice results in a late-onset motoneuron disease, characterized by degeneration of axon terminals.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_2f2f5a6d-3b4f-4f4c-b560-50944b4ab34f-2023-09-06T160000.000Z,1702,PubMed:29084947 +Zebrafish Pmm2 knockdown model,Model Systems Non-human model organism,"Cline A, et al., 2012, PMID: 22956764","Morphant zebrafish embryos (with about 33% Pmm2 activity) had developmental abnormalities consistent with PMM2-CDG patients, including craniofacial defects and impaired motility associated with altered motor neurogenesis within the spinal cord. In addition, global N-linked glycosylation and LLO levels were reduced in pmm2 morphants. These phenotypes were rescued by coinjection of pmm2 mRNA, indicating that they were specific to Pmm2 reduction and not potential off-target MO effects.",Score,1 (2),Does not fully recapitulate the phenotype.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a70becbb-336f-4a30-966b-8db1c7832d87-2023-12-12T170000.000Z,1711,PubMed:22956764 +Rescue of mannose metabolism defects,Rescue Patient cells,"Chan B, et al., 2016, PMID: 27053713","Fibroblast cells from a patient who is compound heterozygous for PMM2 p. R141H and p.F119L (cell line CDG-168) were transduced by a lentiviralvector containing wild type PMM2, leading to over-expression of PMM2. Overexpression of wild type PMM2 in CDG-169 cells restored normal intracellular levels of GDP-mannose (Fig. 6B), DLO (Fig. 6C) and global mannosylation (Fig. 6D).",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a70becbb-336f-4a30-966b-8db1c7832d87-2023-12-12T170000.000Z,1711,PubMed:27053713 +Pmm2-R137H/F115L mice,Model Systems Non-human model organism,"Chan B, et al., 2016, PMID: 27053713","There was significant embryonic lethality observed for Pmm2 R137H/F115L mice (Table 1). Postal death was also significantly increased (~50% survival by PND 65). Of the surviving mice, many showed features seen in patients with PMM2-CDG including increased mortality early in life, postnatal growth failure, and additional symptoms such as kyphosis, ophthalmological problems and axial hypotonia. Some Pmm2R137H/F115L mice had hind leg hypotonia, eye defects, and kyphosis. The authors note that ocular anomalies are not often seen in PMM2-CDG. The hind leg hypotonia was classified as a peripheral motor neuropathy, thus contrasting with the central hypotonia seen in children with PMM2-CDG. Like human PMM2-CDG patients, Pmm2R137H/F115L mice had decreased levels of circulating antithrombin III (ATIII), insulin-like growth factor (IGF)-1, IGF binding protein-3 (IGFBP-3) and acid-labile subunit (ALS), in addition to reductions in GDP-mannose and DLO, and in global protein mannosylation, and reduced glycosylation of gp130. However, unlike observations in human PMM2-CDG patients, plasma transferrin glycosylation was normal in Pmm2 R137H/F115L mice, +Note that the molecular features of these mice mimic human patients, as they are compound heterozygous for variants equivalent to the 2 most common pathogenic variants in human PMM2-CDG patients.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a70becbb-336f-4a30-966b-8db1c7832d87-2023-12-12T170000.000Z,1711,PubMed:27053713 +Pmm2 R137H homozygous mice,Model Systems Non-human model organism,"Chan B, et al., 2016, PMID: 27053713","Homozygous Pmm2-R137H/R137H embryos had complete embryonic lethality, consistent with the lack of observation of homozygous PMM2-R141H/R141H human individuals, and lack of Hardy-Weinberg equilibrium for this variant (PMID: 10854097).",Score,0.5 (2),"The score is reduced because there is no detailed phenotype, other than embryonic lethality (assumed in humans) to compare.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a70becbb-336f-4a30-966b-8db1c7832d87-2023-12-12T170000.000Z,1711,PubMed:27053713 +PMP2 I43N Transgenic Mice,Model Systems Non-human model organism,"Hong YB, et al., 2016, PMID: 26828946","Transgenic mouse models were developed for both WT and mutant PMP2. Compared to controls, both mouse lines exhibited normal behavior except for the peripheral neuropathy phenotype. Tail suspension and rotarod tests confirmed that both the WT and mutant lines showed motor defecits compared to the control line. When nerve conduction was examined both lines showed significantly reduced MNCV without decreased CMAP, indicating a likely demyelinating neuropathy rather than an axonal. I43N mice showed a reduced number of large myelinated fibers with the controls and WT showing similar patterns to each other, althouhg both the WT and mutant lines showed increased de/dysmyelinated fibers and a shortened internodal length compared to the controls.",Score,0 (2),"Although this model recapitulates most of the phenotypes observed in the human probands, such as muscle weakness, atrophy, and reduced MNCV without CMAP, the method of development and potential complications via overexpression (as WT overexpression has been shown to cause similar phenotypes to those observed here) and the question regarding the pathogenic mechanism leads to currently unscorable evidence.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_aa4c5730-f807-45d7-afe7-573a3960916f-2021-03-22T201734.319Z,1712,PubMed:26828946 +Joshi_Rescue in patient cells,Rescue Patient cells,"Joshi M, et al., 2016, PMID: 27148589",The PMPCA-rescued cells from the proband revealed a reduction in the unprocessed form of frataxin (23 kDa) and an increase in the levels of the processed (mature) form (18 kDa) in comparison to the control rescue. PMPCA levels increased appropriately in the PMPCA-rescued cells as compared with the control.,Score,1 (1),The PMPCA-rescued cells from the proband revealed a reduction in the unprocessed form of frataxin (23 kDa) and an increase in the levels of the processed (mature) form (18 kDa) in comparison to the control rescue. PMPCA levels increased appropriately in the PMPCA-rescued cells as compared with the control.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6020acad-80ce-430c-adfe-37ed65b0803d-2023-12-18T170000.000Z,1715,PubMed:27148589 +Mouse knock-in Pms2 c.1993A>G equivalent to human c.2002A>G,Model Systems Non-human model organism,"Biswas K, et al., 2021, PMID: 34489406",Germline variant results in an attenuated form of both CMMRD in homozygous state and Lynch Syndrome in heterozygotes.,Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_213ba61e-a4a5-4e4f-945d-f0fef691a9ba-2022-12-30T180000.000Z,1717,PubMed:34489406 +PMS2 Expression,Expression A,"Karlsson M, et al., 2021, PMID: 34321199",Human Protein Atlas- PMS2 is expressed in breast and ovarian tissue,Score,0 (0.5),The score reflects that the gene is expressed in the relevant tissues but is not explicitly evaluated in affected individuals. Discussion with experts in the field identified that the data is not specific enough to score. Points reduced to 0,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_308d8362-7bd9-46a7-b2fa-ab8f671a44c9-2023-12-21T180000.000Z,1718,PubMed:34321199 +Patient derived lymphocytes show abnormal DNA repair,Biochemical Function B,"Shen J, et al., 2010, PMID: 20118933",DNA repair is required for neuron proliferation in early development.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_901a984a-c678-4f35-81c2-9436785d3698-2020-04-17T165304.309Z,1719,PubMed:20118933 +PNKP levels and activity in MCSZ lymphoblastoid cell extract,Functional Alteration Patient cells,"Reynolds JJ, et al., 2012, PMID: 22508754",Reduced rate of DNA strand break repair observed in MCSZ patient cells following γ-radiation.,Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_901a984a-c678-4f35-81c2-9436785d3698-2020-04-17T165304.309Z,1719,PubMed:22508754 +Zebrafish morpholino-mediated knockdown,Model Systems Non-human model organism,"Song Y, et al., 2013, PMID: 22996643",The fewer motor neurons and a higher incidence of axon branching and truncation in the zebrafish morphants is similar to the motor neuropathy phenotype seen in some patients.,Score,1 (2),Reduced score due to zebrafish morphants not showing several major features seen in patients.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_bcc502f3-e49f-4549-ba75-782235974d21-2023-05-30T160000.000Z,1721,PubMed:22996643 +Uchimura et al. POLD1 -/- and POLD1 exo/exo mice,Model Systems Non-human model organism,"Uchimura A, et al., 2009, PMID: 19145245","POLD1 knock out mice are embryonic lethal, specifically between E4.5 and E7.5. POLD1 knock out mice blastocytes displayed a clear deficiency in cellular proliferation and DNA synthesis defects, as well as a high degree of apoptosis. POLD1 exo/exo were not embryonic lethal, but suffered from tumorigenesis. POLD1 knock out mice failed to recapitulate non-severe combined immunodeficiency, as total loss of POLD1 is likely incompatible with life. Variants in POLD1 have been linked to increased risk in the development of cancer however.",Score,0.5 (2),Downscored to .5 point given an inability to recapitulate the disease phenotype of combined immunodeficiency observed in several individuals. It is likely that biallelic loss of function POLD1 variants are incompatible with life.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_73065a32-62bc-4cde-8131-f8f44c09a74f-2023-02-16T180000.000Z,1725,PubMed:19145245 +Structure and role of DNA polymerase delta,Biochemical Function B,"Lancey C, et al., 2020, PMID: 32111820","Evidence from patients have shown deficiencies in DNA polymerase may lead to slower DNA replication and decreased progression through S phase. At least patient, P1 from Cui et al., showed defective S phase replication in T cells as well as restricted V-J gene combinations. It is possible that a deficiency but not total loss of function in DNA polymerase delta leads to non-severe combined immunodeficiency through slower DNA replication of cells throughout the body, and that T cells and the immune system may be particularly affected.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_73065a32-62bc-4cde-8131-f8f44c09a74f-2023-02-16T180000.000Z,1725,PubMed:32111820 +POLD1 modulates cell cycle progression and DNA damage repair,Model Systems Cell culture model,"Song J, et al., 2015, PMID: 26087769","HEK293 cells were transfected with POLD1 shRNA. POLD1 downregulation by shRNA suppressed cell proliferation, cell cycle progression, and DNA synthesis in HEK293 cells. Comet assay also showed that POLD1 down-regulation led to increased DNA damage.",Score,0.5 (1),"Downgrade the score, since this paper showed the function of POLD1 in DNA damage repair, but no more cancer-related phenotypes were reported.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c064a017-9158-4eb5-8ea4-036e53798d2c-2023-07-05T170000.000Z,1726,PubMed:26087769 +"Mur, 2020",Functional Alteration Non-patient cells,"Mur P, et al., 2020, PMID: 32792570","Exonuclease repair ability of POLE in the presence of the variant was tested using yeast system. The number of revertant colonies was significantly higher for p.Leu424Val (positive control),and the variant p.Met294Arg compared with the wildtype (fold change increase of 7–13)",Review,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_8b5306f4-0422-42fc-9f67-2d9b263e4e1e-2023-07-05T170000.000Z,1728,PubMed:32792570 +"Mur, 2020- tumor",Expression B,"Mur P, et al., 2020, PMID: 32792570","Exome sequencing was preformed on DNA extracted from tumors of carriers with POLE variants to assess the presence of hyper or ultramutation and the mutational signatures. Three primary tumors were analyzed (MMR-deficent ovarian cancer, one MMR- deficient endometrial cancer, and one MM-proficent colorectal cancer from the two probands). All three were hyper/ultramutation (10.96-300.885 Mut/Mb). Signature 10 was identified in the colorectal tumor and signature 14 linked to the co-occurrence of MMR deficiency and the POLE exonuclease pathogenic variant in the ovarian tumor.",Review,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_8b5306f4-0422-42fc-9f67-2d9b263e4e1e-2023-07-05T170000.000Z,1728,PubMed:32792570 +POLG Zebrafish model,Model Systems Non-human model organism,"Rahn JJ, et al., 2015, PMID: 26519465","The POLG mutant zebrafish showed a phenotype similar to humans with POLG mutations in that they had delayed development and early mortality. Biochemically, they showed similarities i decreased mtDNA content and respiratory chain defects.",Score,2 (2),Utilized the U24 NICD Leigh Working group animal model scoring rubric (1 pt for phenotype evidence and 1 pt for biochemical evidence),https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1212393e-b517-4430-a8d7-df7e32295aff-2021-06-30T144955.983Z,1729,PubMed:26519465 +Panda Mouse Model,Model Systems Non-human model organism,"Panda SP, et al., 2013, PMID: 24086598","The aberrant development of the skull upon POR deletion in osteoprogenitor cells in this mouse model not only implicates POR in bone development but it recapitulates, at least partially, the observed craniofacial deformities and bone defects leading to fracture in severe POR-deficient human patients",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6275d46a-f005-45f8-b3ec-e9722f8dd39e-2022-03-23T193729.312Z,1733,PubMed:24086598 +Deletion of Porcn in Mice,Model Systems Non-human model organism,"Liu W, et al., 2012, PMID: 22412863","Porcn-ex3-7flox mice have no apparent developmental defects, but chimeric mice retaining the neomycin gene (Porcn-ex3-7Neo-flox) have limb, skin, and urogenital abnormalities. Conditional Porcn inactivation by EIIa-driven or Hprt-driven Cre recombinase results in increased early embryonic lethality. Mesenchyme-specific Prx-Cre-driven inactivation of Porcn produces FDH-like limb defects, while ectodermal Krt14-Cre-driven inactivation produces thin skin, alopecia, and abnormal dentition.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_20fc3afa-d10d-4239-885f-24e91cbb31a8-2020-08-05T124432.168Z,1734,PubMed:22412863 +BOB.1/OBF.1 in distinct T cell subpopulations,Model Systems Non-human model organism,"Betzler AC, et al., 2022, PMID: 35603192","An altered CD4/CD8 T cell ratio in Pou2af1fl/fl x CD4-Cre mice characterized by significantly reduced levels of CD4+ T cells and at the same time increased levels of CD8+ T cells in the periphery provide evidence for a role of BOB.1/OBF.1 in CD4+ T cell biology. A reduced CD4+ T cell compartment was also described analyzing conventional BOB.1/OBF.1-deficient mice. Moreover, we found significantly reduced numbers of TFH cells when BOB.1/OBF.1 expression was deleted in a CD4- or IL21-Cre dependent manner. In particular, the reduction in Pou2af1fl/fl x IL21-Cre mice shows that this is a TFH cell intrinsic defect and not exclusively a consequence of reduced CD4+ T cells prior to GC formation +Reduced TFH cell is similar with what was observed in a single case with POU2AF1 deficiency who had reduced serum TFH cells.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_cfebbac7-4e4e-4bd6-8977-1b490e915f45-2022-09-20T160000.000Z,1735,PubMed:35603192 +Kodokoro gap junction,Protein Interaction,"Kidokoro Y, et al., 2014, PMID: 25259580","In Pou3f4 null mice described in Minowa 1999, gap junctions (Connexin 26 and 30) deteriorated as mice aged. Gap junction plaque lengths were significantly shorter.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_4ab4f4a3-757d-4de3-90e7-42a229c360a0-2018-01-05T170000.000Z,1737,PubMed:25259580 +Raft expression,Expression A,"Raft S, et al., 2014, PMID: 25299585",RNA hybridization,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_4ab4f4a3-757d-4de3-90e7-42a229c360a0-2018-01-05T170000.000Z,1737,PubMed:25299585 +Raft target gene,Protein Interaction,"Raft S, et al., 2014, PMID: 25299585",Loss of function in mice of the Efnb2 gene was an exact phenocopy of Pou3f4 null mice. Double-LoF of both genes had a more severe phenotype than just LoF of Pou3f4. Expression profiles in ear during development. Physical interaction between pou3f4 and a specific non-coding sequence of the Efnb2 gene,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_4ab4f4a3-757d-4de3-90e7-42a229c360a0-2018-01-05T170000.000Z,1737,PubMed:25299585 +Cochlea expression,Expression A,"Yoshimura H, et al., 2014, PMID: 24676347","Mouse cochlea gene expression patterns in apical, middle, and basal turns were assessed by RT-qPCR. Pou4F3 expression was greater in the apex than the base and followed a gradient",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1476f1d9-7538-40bd-b602-b76781630cee-2017-11-21T170000.000Z,1738,PubMed:24676347 +Hair cell expression,Expression B,"Costa A, et al., 2015, PMID: 26697340",Strong evidence that Pou4f3 is involved in hair cell development,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1476f1d9-7538-40bd-b602-b76781630cee-2017-11-21T170000.000Z,1738,PubMed:26697340 +Uptake and clearance of fluorescence labelled transferrin,Functional Alteration Patient cells,"Rehman AU, et al., 2019, PMID: 30520571","Immunofluorescence analysis showed that PP1R21 consistently co-localized with early endosome marker EEA1 (Fig 2A). However, the staining pattern was absent from patient-derived fibroblast (Fig 2B). +Uptake and clearance of fluorescence labelled transferrin (transferrin-488) in patient-derived fibroblast (loss of function PPP1R21) showed unchanged transferrin uptake. However, mildly but statistically significantly delayed clearance was observed (Fig 3B), suggesting mild endo-lysosomal dysfunction",Score,0 (1),Evidence is more for variant characterisation,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d8743574-2fe2-4819-a7bd-40e94d20065e-2023-10-24T160000.000Z,1743,PubMed:30520571 +Investigation of proteasomal activity,Functional Alteration Patient cells,"Hentschel A, et al., 2023, PMID: 36692708","Proteomic findings indicative for activation of ubiquitin-proteasome system +Treatment with MG132 (proteasome inhibitors) showd pronounced activation of proteasome (Fig 4A) in patient-derived fibroblast - most likely correlates in terms of cellular attempt to elevate protein clearance capacity to facilitate break-down of protein aggregates +MTT-assay revealed decreased cellular proliferation (Fig 4D) – observation in agreement with known function of PP1 in cell cycle regulation, accompanied with increased cellular toxicity burden (Fig 4E) +Altered orientation of actin bundles and altered formation of filopodia in patient-derived fibroblast cytoskeleton (Fig 6B) – likely due to dysregulation of various proteins that play crucial role in proper cytoskeleton",Score,0 (1),Evidence is more for variant characterisation,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d8743574-2fe2-4819-a7bd-40e94d20065e-2023-10-24T160000.000Z,1743,PubMed:36692708 +Hentschel_Biochemical Function,Biochemical Function A,"Hentschel A, et al., 2023, PMID: 36692708","Since other PP1 subunits have been linked to disease, the GCEP has elected to score this as biochemical evidence.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d8743574-2fe2-4819-a7bd-40e94d20065e-2023-10-24T160000.000Z,1743,PubMed:36692708 +B56δ-Aα subunits interaction,Protein Interaction,"Lenaerts L, et al., 2021, PMID: 33106617","The protein encoded by PPPR1A, Aα subunit interacts with B56δ regulatory subunit encoded by the PPP2R5D gene. De novo pathogenic variants in PPP2R5D are associated with intellectual disability (PMID: 26576547).",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1aae8155-7cb1-44ee-9cee-17bb22e6a0ad-2022-11-16T170000.000Z,1744,PubMed:33106617 +Ito Animal Model,Model Systems Non-human model organism,"Ito H, et al., 2015, PMID: 25070536","conditional knockout mouse of PQBP1 in neural stem cells using nestin-Cre. Brain weight was decreased about 70% compared to background or floxed mice. No obvious differences in cerebral contrex layer structure or thickness of cortical layers. No change in cell death of ventricular zone (evaluated by Tunnel staining). No microcephaly was observed in synapsin-1-Cre derived PQBP1-cKO mice, suggesting that mutations in neural crest stem cells, and not neurons, cause microcephaly.",Score,1 (2),downgraded because this is a conditional KO and there was no behavioral phenotyping.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_8128f36b-f273-49ee-bfd8-bee64b4df921-2018-11-09T170000.000Z,1745,PubMed:25070536 +PRG4 KO mouse model,Model Systems Non-human model organism,"Coles JM, et al., 2010, PMID: 20191580","Synovial fluid from patients with CACP show no ability to lower friction in a latex-onglass bearing, which can be effectively lubricated by normal synovial fluid. Friction and elastic modulus in cartilage of Prg4 -/- KO and WT mice at ages 2, 4, 10, and 16 weeks exhibited significant changes in articular cartilage properties, including enlargement and roughening of the surface layer, irregularities in cartilage structure, and age-related changes in the compressive modulus. Cartilage of KO mice was also characterized by a pericellular loss of proteoglycans and delayed tidemark progression. This degenerative cartilage phenotype caused by the lack of PRG4 is similar to that observed clinically in patients. This model demonstrates structural and biomechanical changes in cartilage following gene KO.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3b4be938-664c-421e-922b-dc6ac83e5dec-2021-07-30T130737.801Z,1748,PubMed:20191580 +Ghosh Western Blot,Expression A,"Ghosh TK, et al., 2019, PMID: 31784580",Western blot analysis shows expression in mouse embryonic heart tissue,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1dc39882-3a53-46eb-aa2f-0d92ed03605b-2024-04-30T160000.000Z,1756,PubMed:31784580 +Ghosh TBX5 protein interaction,Protein Interaction,"Ghosh TK, et al., 2019, PMID: 31784580","Luciferase-reporter assay shows that PRKD1 relieves repression of TBX5, the MYH6 promoter.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1dc39882-3a53-46eb-aa2f-0d92ed03605b-2024-04-30T160000.000Z,1756,PubMed:31784580 +Ghosh TBX5 protein interaction,Protein Interaction,"Ghosh TK, et al., 2019, PMID: 31784580","Luciferase-reporter assay shows that PRKD1 relieves repression of TBX5, the MYH6 promoter.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_913dec3f-cd09-45c7-8cd4-3441ddb5dd77-2024-04-30T160000.000Z,1757,PubMed:31784580 +Ghosh Western Blot,Expression A,"Ghosh TK, et al., 2019, PMID: 31784580",Western blot analysis shows expression in mouse embryonic heart tissue,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_913dec3f-cd09-45c7-8cd4-3441ddb5dd77-2024-04-30T160000.000Z,1757,PubMed:31784580 +Waheed-Ullah Mouse Model,Model Systems Non-human model organism,"Waheed-Ullah Q, et al., 2024, PMID: 38419169",83.3% of mice homozygous for a null variant in PRKD1 present with embryonic congenital heart defects,Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_913dec3f-cd09-45c7-8cd4-3441ddb5dd77-2024-04-30T160000.000Z,1757,PubMed:38419169 +PRKDC -/- Null Zebrafish Model,Model Systems Non-human model organism,"Jung IH, et al., 2016, PMID: 27566103","SCID PRKDC knockout demonstrated abnormal growth, abnormal thymus and lymphoid development, susceptibility to spontaneous infection. SCID zebrafish had no functional T and B lymphocytes.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_fff25ca1-bbe5-47d3-b672-4b675a9fa6f7-2022-02-01T151658.605Z,1758,PubMed:27566103 +Parkin recruitment to mitochondria and/or Parkin-induced mit,Functional Alteration Non-patient cells,"Narendra DP, et al., 2010, PMID: 20126261","Patient Mutations in PINK1 and Parkin Disrupt PINK1/Parkin Pathway at Distinct Steps +As was reported previously, wild-type YFP-Parkin is recruited to mitochondria in the majority of HeLa cells (94.7±5.8%) by confocal microscopy, following treatment with 10 µM CCCP for 1 h (Figure 9A and 9B). Pathogenic mutations in the UBL domain (R42P and R46P), deletion of the UBL, or mutation of a key residue (I44A) in the interaction of UBLs with UBDs [47], all cause a moderate deficit in Parkin recruitment to depolarized mitochondria (34±5.3% and 26.5±6.6% for R42P and R46P, respectively) (Figure 9A and 9B and Figure S7A–S7E). Mutations in conserved cysteines of the RING domains (the patient mutations C253Y, C289G, and C441R and the engineered mutation C332S) completely disrupt recruitment at 1 h of CCCP treatment, as do mutations (patient mutation Q311X and engineered mutation T415X) that result in loss of RING2 (Figure 9A and 9B). Mutations K211N and C212Y, which lie within a highly conserved region of Parkin that is likely a novel RING-like domain [41] (Figure S5A), similarly blocked the recruitment of Parkin to mitochondria (Figure 9B), consistent with the importance of this region for Parkin's activity. Mitochondrial recruitment was seen for several of the conserved cysteine RING mutants (C289G, C332S, and C441R) after 24 h of CCCP exposure, suggesting that recruitment is not completely disrupted with these mutations (Figure S8A and S8B). Interestingly, the R275W mutation in RING1 exhibited only a mild deficit in recruitment (81.7±2.1%) (Figure 9A and 9B). The recruitment of YFP-Parkin R275W was verified in a live-cell imaging experiment (Figure S8C). Although under control conditions some mutants formed visible aggregates (Figure S8D), no mutant, including R275W, colocalized with mitochondria (Figure 9B and Figure S8E).",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6b39c4a0-f6bd-4afc-b2a7-f234eab5a667-2023-01-18T190000.000Z,1759,PubMed:20126261 +mitophagy defects in dopaminergic parkin mutant patient neur,Functional Alteration Patient cells,"Schwartzentruber A, et al., 2020, PMID: 32968089","There was significant cell death occurring throughout differentiation specifically in the PRKN mutant patient derived DA neurons; the percentage of cells surviving until the end of the differentiation was significantly reduced (mean ± SD, controls 83.62 ± 4.8; parkin mutants 52.72 ± 11.98) +We observe the same mitochondrial fragmentation at the end stage +of differentiation accompanied by an increase in mitochondrial number (Fig. 3A mitochondrial interconnectivity: controls 0.07 ± 0.003; PRKN mutants 0.04 ± 0.005 p < 0.05; Fig. 3B mitochondrial number (% normalised to controls): controls 100 ± 3.4; PRKN mutants 204 ± 35; p < 0.0001).",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6b39c4a0-f6bd-4afc-b2a7-f234eab5a667-2023-01-18T190000.000Z,1759,PubMed:32968089 +PROC/PROS1,Protein Interaction,"Huttlin EL, et al., 2017, PMID: 28514442","Affinity purification-mass spectrometry in HEK293T cells with affinity tagged PROC was used to elucidate protein interactions. PROS1 was identified, by LC-MS as an interacting protein with a CompPASS score of 0.789 (above the >0.75 threshold).",Score,0.5 (0.5),"PROS1 encodes a vitamin K-dependent plasma protein that functions as a cofactor for the anticoagulant protease, activated protein C (APC) to inhibit blood coagulation. Deficiency in either PROS1 or PROC can cause thrombophilia.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c6fe2f63-36ad-40c2-beb6-8804de17409d-2020-01-22T170000.000Z,1760,PubMed:28514442 +EGFP-immunostained fibers in suprachiasmatic nucleus,Biochemical Function B,"Zhang C, et al., 2009, PMID: 19784373","LOF in PROK2 would lead to failure to modulate GnRH function, causing hypogonadotropic hypogonadism.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_2305ec95-325d-4ebe-9401-121705e49660-2022-03-22T160000.000Z,1762,PubMed:19784373 +Loss of one copy of PROK2 disrupts estrous cycles,Model Systems Non-human model organism,"Xiao L, et al., 2014, PMID: 24633064","This mouse model supports that PROK2 variation interrupts the pre-ovulatory GnRH surge, partially controlled by circadian outputs from the SCN to GnRH neurons.",Score,1 (2),"This is the same mouse model used in Li et al. 2006. PMID:17093083. Therefore, this evidence is scored for 1 point as this mouse model detailed by Li et al. is scored for 1 point as well, for a total of 2 points.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_2305ec95-325d-4ebe-9401-121705e49660-2022-03-22T160000.000Z,1762,PubMed:24633064 +Splice Variant Mouse Model,Model Systems Cell culture model,"Robertson J, et al., 2003, PMID: 12642616","The authors showed that peripherin isoform Per 61 is neurotoxic when expressed in motor neurons in primary culture. The viability curve shows that Per 61 is extremely toxic to motor neurons. In addition, motor neurons expressing Per 61 appeared shrunken with few neuritic processes, changes consistent with neurotoxicity and neuronal death This evidence suggests that expression of neurotoxic splice variants of peripherin may contribute to the neurodegenerative mechanism in ALS. The Per 61 antibody also labeled pathological lesions in the lumbar spinal cord of ALS cases but not of control. +Additionally, they showed that Per 61 is expressed in motor neurons of mutant SOD1G37R transgenic mice, demonstrating that the disease mechanism of mutant SOD1G37R includes expression of a neurotoxic splice variant of peripherin.",Score,0 (1),"No gene alteration was performed, they used one of the normal isoforms, Per 61 for these studies.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3d11b04d-508a-4f91-9d9a-b5016fd0b940-2022-12-13T170000.000Z,1767,PubMed:12642616 +Overexpression Mouse,Model Systems Non-human model organism,"Beaulieu JM, et al., 1999, PMID: 15132161",Sustained overexpression of wild-type peripherin in mice provokes massive and selective degeneration of motor axons during aging.,Score,1 (2),Degeneration of motor axons is consistent with ALS but relevance of the overexpression mechanism to human disease is unknown.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3d11b04d-508a-4f91-9d9a-b5016fd0b940-2022-12-13T170000.000Z,1767,PubMed:15132161 +RT-PCR for RNA samples from blood lymphocytes,Expression B,"Almoguera B, et al., 2014, PMID: 25491489","The in silico analysis using ESEFinder predicted this +mutation to alter the recognition pattern of splicing +RNA proteins compared to the wild type sequence. To +confirm this, PRPS1 expression analysis was performed +in RNA samples from blood lymphocytes from three +affecteds and one unaffected (IV:1). RT-PCR analysis +yielded no differences on the expression of PRPS1 transcripts +between carriers of p.Ser16Pro and the non-carrier +(Figure 1E), and no additional splicing transcripts were +found. Notably, further sequencing of mRNA transcripts +evidenced the mutation in homozygosis in the index +patient (Figure 1E).",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9416f6e2-8de3-48b0-9a1c-9bd11a59315c-2020-02-14T170000.000Z,1769,PubMed:25491489 +p.Ser16Pro leads to PRS deficiency in female affected eryth,Functional Alteration Patient cells,"Almoguera B, et al., 2014, PMID: 25491489","Showed decreased PRS activity in erythrocytes f affected patients and found that Arts syndrome patients had no activiyt whle CMTX5 and DFN2 had decreased activity. Cite de Brouwer et al. 20101 when they note that in Arts syndrome the ATP site and allosteric sites I and II are affected, in CMTX5, the ATP site and allosteric site I are affected.",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9416f6e2-8de3-48b0-9a1c-9bd11a59315c-2020-02-14T170000.000Z,1769,PubMed:25491489 +In situ hybridization of PRPS1a and b in zebrafish inner ear,Expression A,"Pei W, et al., 2016, PMID: 27425195","In situ hybridization of PRPS1a and PRPS1b in zebrafish was found to be relatively enriched in the inner ear, embryonic brain and caudal hematopoiteic tissue.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9416f6e2-8de3-48b0-9a1c-9bd11a59315c-2020-02-14T170000.000Z,1769,PubMed:27425195 +Transfected PRRT2 shRNA Constructs in Mouse Brains,Rescue Non-human model organism,"Liu YT, et al., 2016, PMID: 27172900","The neurons in the brain electroporated with PRRT2 shRNA exhibited a delay in neuronal migration from the ventricular zone, subventricular zone, and intermediate zone. Quantification of the cells at day 3 revealed significantly reduced numbers of neurons in the CP as most of the cells reamined in the VZ. The migration delay was partially rescued by expressing PRRT2 in knockdown cells.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_62af25b8-b9a4-421f-b897-4fc222569618-2020-01-21T213814.191Z,1771,PubMed:27172900 +HEK293T Cells Transfected with EGFP-PRRT2 or Mutant,Functional Alteration Non-patient cells,"Liu YT, et al., 2016, PMID: 27172900","WT PRRT2 predominately localized to the plasma membrane consistent with pattern observed for endogenous PRRT2 in culutred mouse neurons. In contrast, 6 truncated PRRT2 mutants were mostly retained in the cytoplasm with some mutant proteins (Pro91GlnfsX, Glu199X, Arg240X) were found in the nucleus indicating abnormal intracellular trafficking of the mutant proteins.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_62af25b8-b9a4-421f-b897-4fc222569618-2020-01-21T213814.191Z,1771,PubMed:27172900 +PRRT2 Polyclonal Antibody to Detect Presence of PRRT2,Expression A,"Liu YT, et al., 2016, PMID: 27172900","A polyclonal antibody against the extracellular domain of the PRRT2 protein was tested in rat and mouse brain lysates. Using the antibody, endogenous PRRT2 was shown to localize at the cell membrane of mouse cortical neurons. +Synaptic membrane fractionation and post synaptic density from adult rat brain lysates were carried out with several pre and post synaptic markers to confirm if PRRT2 is present on synapses. PRRT2 was enriched in the synaptic membrane fraction but was also detected in the synaptic vesicle and post synaptic density fractions indicating presence of PRRT2 at both pre and post synaptic membranes.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_62af25b8-b9a4-421f-b897-4fc222569618-2020-01-21T213814.191Z,1771,PubMed:27172900 +Transgenic mouse expressing R122H human PRSS1 gene,Model Systems Non-human model organism,"Selig L, et al., 2006, PMID: 17069643","Transgenic mice carry the construct comprising the -205 to 8+ region of the elastase promotor, R122H trypsinogen cDNA and the bovine growth hormone (bGH) polyadenylation signal. After induction of pancreatitis with cerulein, Lipase, amylase and MCP1 levels are significantly elevated in R122H animals. Pancreatitis was more severe in R122H transgenic animals after repetitive intraperitoneal cerulein injection.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d271c52b-b0bb-4e9b-a745-ea03dc716fa0-2020-07-30T205014.833Z,1772,PubMed:17069643 +Prosapin B-deficient knock in mice,Model Systems Non-human model organism,"Sun Y, et al., 2008, PMID: 18480170","Like human patients with metachromatic leukodystrophy due to saposin B deficiency, saposin B-deficient mice exhibit a progressive, neurological phenotype, with ataxia, head tremor, impaired coordination, as well as evidence of storage in neurons, and elevated sulfatides in urine and body tissues.",Score,3 (2),"The score is increased due to the recapitulation of the clinical phenotype, biochemical, features, and knock in of a variant identified in humans.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_4e24c4e4-a97d-4d08-abd9-e190fb001b9d-2023-07-20T160000.000Z,1775,PubMed:18480170 +Saposin C knockout mouse,Model Systems Non-human model organism,"Sun Y, et al., 2010, PMID: 20015957","Saposin C knockout mice show absent saposin C protein and normal levels of saposins A, B, and D, cellular accumulation of glucocerebroside, and neurologic impairment including hind limb weakness, impaired hippocampal long-term potentiation, and progressive ataxia, recapitulating key features of the human disease phenotype",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e949cb92-7d76-471e-9e37-44fd7f00964b-2023-06-26T160000.000Z,1777,PubMed:20015957 +Ptchd1 knockout mouse model,Model Systems Non-human model organism,"Wells MF, et al., 2016, PMID: 27007844","Patchd1 knockout mice demonstrate distractibility, hyperactivity, impaired learning, motor deficits, and aggressive behavior. These features recapitulate what is seen in individuals with loss-of-function variants in PATCHD1",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_05d36fe2-0026-4bbc-af4b-6d952490969b-2018-08-15T160000.000Z,1785,PubMed:27007844 +Ptchd1 mRNA expression studies,Expression A,"Wells MF, et al., 2016, PMID: 27007844","mRNA in situ hybridization was performed with 20 μm cryosections from freshly frozen P0, P15, and P35 brain tissue from male mice using a mixture of two digoxigenin (DIG)-labelled probes against mouse Ptchd1 cDNA. Ptchd1 expression was confined to the thalamic reticular nucleus at birth, but expressed in striatum, cortex, cerebellum by postnatal day 15.",Score,0.5 (0.5),"Together with expression data from PMID 20844286, 0.5 points awarded.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_05d36fe2-0026-4bbc-af4b-6d952490969b-2018-08-15T160000.000Z,1785,PubMed:27007844 +Immunohistochemical expression of COX-1 （PTGS1）in tissues,Expression A,"Zidar N, et al., 2009, PMID: 18657230","The gene for COX-1 (PTGS1) is preferentially expressed constitutively at high levels in selected cells, including endothelium, monocytes, platelets, renal collecting tubules, and seminal vesicles.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d979e26e-bf9b-4f6a-a37c-2df0f2d35129-2023-02-01T170000.000Z,1787,PubMed:18657230 +eicosanoid production,Functional Alteration Patient cells,"Chan MV, et al., 2021, PMID: 32299908","Incubation of blood from healthy volunteers with collagen or TRAP-6 amide greatly increased the levels of TXB (a stable breakdown product of TXA2), 11-dehydro-TXB (11-dH-TXB, a dehydrogenation product of TXB), PGE, PGD, 15-HETE, 11-HETE and 12-HETE. In the PTGS1-deficient proband 12-HETE production was unaffected but there was an absence of TXB, PGE, PGD and 15-HETE.",Score,1 (1),This case models the specific loss of platelet COX-1 activity and provides a benchmark of COX- 1’s role in platelet function and eicosanoid metabolism.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d979e26e-bf9b-4f6a-a37c-2df0f2d35129-2023-02-01T170000.000Z,1787,PubMed:32299908 +Protein expression,Expression B,"Chan MV, et al., 2021, PMID: 32299908","Western blots and quantification of COX-1 (PTGS1) and GAPDH expression were done in platelet lysates, isolated from the controls, the proband (IV-1), homozygous (III-1 and III-2) and unaffected (III-3, III-4, III-5 and IV-2) family members. The authors showed that the COX-1 protein in platelet lysates from the proband and her homozygous relatives was absent. In III-3 and III-4, expression was present but reduced and was at normal levels in III- 5 and IV-2 (Figure 2A). The absence of COX-1 protein in platelets from the proband and homozygous relatives (Figures 2Ci, Figure 2Di) compared to a healthy control (Figures 2Bi) was confirmed with immunohistochemical analysis. COX-1 expression, however, was retained in leukocytes from all those tested (Figure 2Cii, Figure 2Dii).",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d979e26e-bf9b-4f6a-a37c-2df0f2d35129-2023-02-01T170000.000Z,1787,PubMed:32299908 +nimbus mouse,Model Systems Non-human model organism,"Andrews TD, et al., 2012, PMID: 22724066",Mice homozygous for the Ptprc-nim mutation indeed had almost no CD45 protein on the surface of their B-lymphocytes (2% of wild-type controls) as measured by flow cytometric staining with antibodies to CD45. Nimbus mutant animals displayed a fourfold reduction in the percentage of CD3+ T cells.,Score,0.5 (2),"The lymphopaenia in nimbus homozygotes is stated to match that in mice and humans with other null or severe loss-of-function mutations in Ptprc, however they also note a decrease in B cells in the blood which differs from patients.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_f4b09bbc-c749-45be-9f2a-1a54813b2906-2021-12-22T205504.201Z,1788,PubMed:22724066 +KO mouse model,Model Systems Non-human model organism,"Mangum JE, et al., 2016, PMID: 27197761",recapitulation of myopathy and mitochondrial dysfunction in muscle but not anemia,Score,1 (2),"Pus1−/− mice were born at the expected Mendelian frequency and were non-dysmorphic. At 14 weeks the mutants displayed reduced exercise capacity. Examination of tibialis anterior (TA) muscle morphology and histochemistry demonstrated an increase in the cross sectional area and proportion of myosin heavy chain (MHC) IIB and low succinate dehydrogenase (SDH) expressing myofibers, without a change in the size of MHC IIA positive or high SDH myofibers. Cytochrome c oxidase activity was significantly reduced in extracts from red gastrocnemius muscle from Pus1−/− mice. Transmission electron microscopy on red gastrocnemius muscle demonstrated that Pus1−/− mice also had lower intermyofibrillar mitochondrial density and smaller mitochondria. However, in contrast to MLASA patients, there appears to be no overt hematological phenotype in Pus1p deficient mice. Certain pseudouridine modifications were missing in cytoplasmic and mitochondrial tRNAs from Pus1−/− animals. Absence of Pus1p activity in the Pus1−/− mice was confirmed via pseudouridinylation assays (Fig. 2). +recapitulation of myopathy and mitochondrial dysfunction in muscle but not anemia",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_821f6d18-025f-477b-8ba2-b4aad502670c-2022-08-01T160000.000Z,1792,PubMed:27197761 +Yan_Pxdn KO mouse,Model Systems Non-human model organism,"Yan X, et al., 2014, PMID: 24895407","Authors report on the expression of Pxdn during embryonic development. At E17.5, peroxidasin is expressed in the whole lens (lens epithelium and at the posterior pole of the lens) and inner neuroblast layer. During development, the lens size of mutant mice is significantly reduced and the anterior segment is severely impaired. Postnatally at P21, mutant mice showed severe ocular phenotypes including smaller eyes and lenses. lens-cornea adhesion, which may be a potential risk for developing glaucoma and retinal damage.",Score,2 (2),The mouse model due to a LOF variant in the Pxdn gene recapitulates the features of anterior segment dysgenesis due to PXDN variation in humans and is scored default points.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_905b07f8-ed15-4c25-9579-edac5521c699-2023-06-15T160000.000Z,1793,PubMed:24895407 +Pxdn CRISPR mouse,Model Systems Non-human model organism,"Kim HK, et al., 2019, PMID: 31817535","No changes in size and external morphology in most organs, including the brain, heart, lung, spleen, kidney, and testis, except for the eyes were observed. KO mice had small eyes. KO mice had completely or almost closed eyelids, and some of them had severe cataracts in the eyes, whereas the heterozygous and WT mice born from the crossing had normal eyelids. H&E staining of eye sections revealed that lenses were completely missing or remained in trace. Disorganization of retinal structure, such as retinal folds or rosette-like structures, and retinal dysplasia were also observed. Furthermore, even eyeball formation was absent in the KO mouse. Western blot showed that KO mice did not express Pxdn in the eye tissue.",Score,1 (2),The CRISPR-mediated Pxdn knock-out mouse model shows a more severe eye phenotype compared to human patients. The authors do not comment on the anterior segment dysgenesis in KO mice. Reduced score is awarded.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_905b07f8-ed15-4c25-9579-edac5521c699-2023-06-15T160000.000Z,1793,PubMed:31817535 +Zebrafish knockout,Model Systems Non-human model organism,"Liang ST, et al., 2019, PMID: 31091804","KO fish exhibit premature aging phenotypes, such as dwarfism, slow swimming ability, loss of fertility at the age of six months, and increased mortality.",Score,1 (2),"This model is consistent with the progeroid symptoms in humans, such as growth delay, but does not fully recapitulate skin and bone defects observed in patients.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ca242cd8-1f57-4c7b-ba97-5ec0c97b425b-2020-05-21T191607.864Z,1794,PubMed:31091804 +Rab18 knockout mice (genetrap),Model Systems Non-human model organism,"Carpanini SM, et al., 2014, PMID: 24764192",Congenital cataract and progressive neurological decline are shared between the mouse model and humans.,Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_4f09a474-8789-4f05-8f7e-611698d30936-2023-09-30T160000.000Z,1800,PubMed:24764192 +Neuronal migration assay,Model Systems Non-human model organism,"Wu Q, et al., 2016, PMID: 26879639",Abnormal migration is seen in humans in the form of polymicrogyria.,Score,1 (2),This is not a knockout mouse model.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_4f09a474-8789-4f05-8f7e-611698d30936-2023-09-30T160000.000Z,1800,PubMed:26879639 +Mouse brain in situ hybridization and immunohistochemistry,Expression A,"Wu Q, et al., 2016, PMID: 26879639","Rab18 mRNA and protein are abundantly expressed in the mouse cerebral cortex during development at E14,5, E17.5, and P0.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_4f09a474-8789-4f05-8f7e-611698d30936-2023-09-30T160000.000Z,1800,PubMed:26879639 +Open brain mouse,Model Systems Non-human model organism,"Hasan MR, et al., 2020, PMID: 32662771","The mice had coronal, parietal-temporal, frontonasal, and lambdoid craniosynostosis as well as preaxial polydactyly of the forelimbs and preaxial polysyndactyly of the hindlimbs. Multisutural craniosynostosis, syndactyly, and polydactyly are cardinal features of Carpenter syndrome in humans.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_46756b21-4bb5-4384-a42c-cf10c76e98c8-2021-04-22T160000.000Z,1801,PubMed:32662771 +Expression in mouse skull and sutures,Expression A,"Hasan MR, et al., 2020, PMID: 32662771","In situ hybridization and immunohistochemical staining showed that Rab23 mRNA was expressed in mouse calvaria and sutures (frontal, sagittal, and lambdoid).",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_46756b21-4bb5-4384-a42c-cf10c76e98c8-2021-04-22T160000.000Z,1801,PubMed:32662771 +RAB28 in intraflaggelar transport,Biochemical Function B,"Jensen VL, et al., 2016, PMID: 27930654","The authors identify Rab28 as a ciliary protein in C. elegans, with exclusive expression in ciliated neurons. They show that GFP-labeled RAB-28 undergoes continuous, bidirectional, intraflagellar transport (IFT)-like movement along ciliary axonemes at IF-associated velocities. They reported that binding of GTP to RAB-28 targets RAB-28 to the periciliary membrane and facilitates its association with IFT trains. Overexpression of either GTP or GDP-preferring RAB-28 (i.e. T49N and Q95L respectively) induced functional and ultrastructural defects in the cilia and sensory organs of the nematode C. elegans suggesting that similar ciliary defects in human patients with deleterious variants in RAB28 could be involved in retinal dystrophy. +Ciliary transport is important in photoreceptors, in order to transport proteins to the outer segments. Deleterious variants in many other ciliary genes have been reported to result in retinal degeneration (see PMID 28289063 for review), supporting a similar mechanism for RAB28 in cone-rod dystrophy.",Score,0.5 (0.5),"Also see the entry for Akella et al, 2020, PMID 32101165, which provides results of follow up studies on the role of Rab28 in C. elegans ciliated neurons.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e8e3c7bd-3ee5-404d-98b0-75af6ec257d1-2021-11-04T160000.000Z,1802,PubMed:27930654 +Rab28 function in C. elegans neurons,Biochemical Function B,"Akella JS, et al., 2020, PMID: 32101165","10% of the photoreceptor outer segments daily undergoes a renewal process that involves disc shedding and phagocytosis the retinal pigmented epithelium (RPE) cells. Defects in this process can cause photoreceptor dysfunction. In this study, the authors built upon a previous report (PMID 27930654). By conducting experiments in series of C. elegans mutants, they deduced a ciliary trafficking pathway in amphid and phasmid neurons in which activated (GTP-bound) RAB-28 is targeted to the pericilliary membrane (PCM) by the BBSome, and to a lesser extent ARL-6. PDL-1 (prenyl-binding protein phosphodiesterase 6 subunit delta, PDE6D) is required for loading RAB-28 onto IFT trains, a step inhibited by ARL-6 (summarized in Figure 1 schematic). They found that Rab28 and the BBSome are key in vivo regulators of extracellular vesicle (EV) production at the periciliary membrane. They noted accumulation of EV cargo markers in the ciliary region of rab-28 and BBSome gene mutants which suggested defects in ciliary EV biogenesis and shedding into the lumens of sensory organs. The authors propose that the EV shedding defects in C. elegans rab-28 and bbs-8 gene mutants, and the reduced disc shedding and/or phagocytosis previously reported in Rab28 knockout mice (see entry for Ying et al, 2018), may involve a shared Rab28 mechanism. However, they also note that the precise nature of this mechanism is not known.",Score,0.5 (0.5),"Taken together, the results from studies of C. elegans mutants, showing defects in ciliary vesicle biogenesis, as well as the reduced cone outer segment disc shedding in Rab28 knock out mice and zebrafish indicate that Rab 28 has a role in cone disc shedding. Such a role would be consistent with cone dysfunction and degeneration.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e8e3c7bd-3ee5-404d-98b0-75af6ec257d1-2021-11-04T160000.000Z,1802,PubMed:32101165 +Rab28 null Zebrafish,Model Systems Non-human model organism,"Carter SP, et al., 2020, PMID: 32258030","At 5 dpf, rab28 -/- zebrafish had only ""subtle differences"" in visual behavior compared to wild type (slightly elevated activity in the dark, but reduced activity in light conditions, compared to sibling controls). Unlike human patients with cone-rod dystrophy, there was no sign of retinal degeneration by 12 mpf. Notably, the number of cone phagosomes was found to be reduced in rab28-/- zebrafish, by ∼44% compared to siblings at 1-2 mpf. The authors offer various explanations for the lack of retinal degeneration including that the level of OS shedding is sufficient to maintain vision, mechanisms compensating for NMD (e.g. increased transcipriton of related genes), genetic redundancy, and persistent neurogenesis in the zebrafish retina.",Score,0 (2),"No score given because, although there are defects in Zebrafish cones i.e. reduced outer segment shedding as had previously been reported in mice (PMID 30228185), the phenotype does not recapitulate the findings in humans e.g. cone degeneration was not found. The authors provide several possible explanations. Thus, which this study does not provide strong suport for the relationship between RAB28 and cone-rod dystrophy, it is also not considered as conflicting evidence. The data will be used to support the biochemical function of the RAB28 - as important in OS shedding.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e8e3c7bd-3ee5-404d-98b0-75af6ec257d1-2021-11-04T160000.000Z,1802,PubMed:32258030 +in vitro nucleotide exchange activity,Biochemical Function A,"Gerondopoulos A, et al., 2014, PMID: 24891604","Both subunits were required for this Rab18 GEF activity, and neither subunit, alone stimulated GDP release above the basal level seen with other nontarget Rabs (Fig 1c)",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a322fa3e-2985-4f60-9b4b-87f333cf9431-2023-11-28T200000.000Z,1804,PubMed:24891604 +ER localization,Biochemical Function B,"Gerondopoulos A, et al., 2014, PMID: 24891604","Control and patient fibroblasts were fixed and stained with antibodies to CLIMP-63 and reticulon 4 (Rtn4). In comparison to control fibroblasts, CLIMP-63 spread away from the perinuclear region into the cell periphery and clearly defined Rtn4-positive tubules were lost in both the Rab18 L24Q and Rab3GAP1 (c.649-2A>G) patient cell lines (Fig. 7 a). Measurements of the area occupied by CLIMP- 63 indicated that ER sheet volumes increased from 20% of the cell area to 60–70% in cells with mutant Rab18 or Rab3GAP1 (Fig. 7 b). Spread of ER sheets and a loss of fragmentation of ER +tubules were therefore observed in patient fibroblasts.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a322fa3e-2985-4f60-9b4b-87f333cf9431-2023-11-28T200000.000Z,1804,PubMed:24891604 +immunofluorescence,Expression A,"Cogli L, et al., 2013, PMID: 23179371",Immunofluorescence shows RAB7A localization in the cell body and in axonal projections where it co-localize with peripherin. RAB7 is also widely distributed in the scietic nerve.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_222dbfa6-db75-42a0-bab6-338b46a316c3-2022-02-10T021034.172Z,1806,PubMed:23179371 +Zebrafish models with RAB7A mutations,Model Systems Non-human model organism,"Ponomareva OY, et al., 2016, PMID: 26791407",zebrafish expressing 3 different mutants showed significant reduced axonal branching of sensory neurons. Axonal transport of endosomes were imaged in vivo by confocal microscopy. The speed of endosomes were significantly reduced in 2 of the mutants. And the other mutants showed a significant reduction in the number of stationary vesicles.,Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_222dbfa6-db75-42a0-bab6-338b46a316c3-2022-02-10T021034.172Z,1806,PubMed:26791407 +Autophagy evaluation in patient fibroblasts,Functional Alteration Patient cells,"Colecchia D, et al., 2018, PMID: 29130394",Patient fibroblasts show decrease co-localization between RAB7A and the autophagy marker LC3B and reduced autophagic flux.,Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_222dbfa6-db75-42a0-bab6-338b46a316c3-2022-02-10T021034.172Z,1806,PubMed:29130394 +RAC1-TRIO Interaction,Protein Interaction,"Barbosa S, et al., 2020, PMID: 32109419","TRIO acts as a key regulator of neuronal migration, axonal outgrowth, axon guidance, and synaptogenesis by activating the GTPase RAC1 and modulating actin cytoskeleton remodeling; TRIO variants are associated with ID. Patient variants in specific TRIO domains (spectrin and GEFD1) either cause hyper- or hypo-activation of RAC1, respectively, and result in opposite effects on RAC1 activation levels and macrocephaly (spectrin variants) or microcephaly (GEFD1 variants) in patients",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_da151217-aee4-4a00-9ae1-d8b610eb216e-2023-09-20T160000.000Z,1807,PubMed:32109419 +Mouse Rac1 constitutively active model (Rac1-G12V),Model Systems Non-human model organism,"Gahankari A, et al., 2021, PMID: 34557485","RAC1 constitutively active mouse model leads to increased proliferation rate, altered cell density, and migration pattern of neural crest cells and disruption of ventral midbrain dopaminergic neuron precursors",Score,1 (2),Downgraded due to lack of behavioral or additional phenotype information,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_da151217-aee4-4a00-9ae1-d8b610eb216e-2023-09-20T160000.000Z,1807,PubMed:34557485 +Drosophila Rac1-Y64D transgenic model,Model Systems Non-human model organism,"Banka S, et al., 2022, PMID: 35139179","Drosophila Rac1-Y64D model displayed abnormal axonal growth and morphology, abnormal axonal organization, and abnormal dendritic branching of sensory neurons",Score,1 (2),Downgraded due to non-mammalian model organism,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_da151217-aee4-4a00-9ae1-d8b610eb216e-2023-09-20T160000.000Z,1807,PubMed:35139179 +RAC1 variants promote activation of downstream targets,Functional Alteration Non-patient cells,"Banka S, et al., 2022, PMID: 35139179","Activating RAC1 switch II variants (Y64D, Y64C and R68G) in fibroblasts promotes activation of downstream signalling targets (WRC and PAK) involved in regulating lamellipodia assembly in fibroblasts and axonal growth as well as initiation of collateral branches on axons and dendrites in neurons (WRC), and cell survival, proliferation and metabolism (PAK)",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_da151217-aee4-4a00-9ae1-d8b610eb216e-2023-09-20T160000.000Z,1807,PubMed:35139179 +RAC2 role in T cell proliferation,Biochemical Function B,"Yu H, et al., 2001, PMID: 11581314",A significant decrease in the T cell population has been observed in patients with RAC2-associated disease. These experiments indicate RAC2 has a role in T cell proliferation and thus could be involved in the smaller population of T cells observed in patients.,Score,0.5 (0.5),These experiments indicate RAC2 has a role in T cell proliferation. Disruption of this function may be involved in the T cell population downsizing noted in patients with RAC2-associated disease.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a6c1e0b1-de02-4899-9825-acc950bedcc3-2021-10-19T155522.241Z,1809,PubMed:11581314 +Hi2529 mutant zebrafish,Model Systems Non-human model organism,"Xu B, et al., 2015, PMID: 25378554","Poor growth, congenital heart disease, and small head size are features of CdLs.",Score,1 (2),Downgraded for zebrafish model.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_30ad5023-6c68-42ab-b8ea-a601a134eaf6-2020-01-08T170000.000Z,1811,PubMed:25378554 +RAD50 Foci in Cancer Patient Fibroblasts,Functional Alteration Patient cells,"Djuzenova C, et al., 2004, PMID: 15150571","Cancer patients had an adverse, early reaction to radiation treatment. Cultured fibroblasts from these patients displayed significantly more RAD50 foci and altered distribution of it than did fibroblasts from cancer patients that did not have an adverse reaction to radiation.",Score,0.25 (1),"Reducing points because the alteration in RAD50 is not known (if there is one or not) in the cancer patients that displayed extreme radiation hypersensitivity. +This was scored as 1 in the 2017 curation. Curator notes are as follows: ""Irregular expression of RAD50 in irradiated skin biopsies of radiosensitive cancer patients. in vitro irradiated cells from radiosensitive patients exhibited a significantly higher number of nuclei with focally concentrated Rad50 protein than in both control groups. The observed alteration of the distribution of radiation-induced Rad50 foci in cells derived from cancer patients with acute side reactions to radiotherapy might contribute to their radiation therapy outcome""",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1f16b58f-c6b5-45ef-bb4a-a9fa5fe8ac35-2023-03-14T170000.000Z,1812,PubMed:15150571 +Medaka model,Model Systems Non-human model organism,"Chisada S, et al., 2023, PMID: 37098078",Histology was examined of thyroid,Score,0 (2),"A 2-base pair deletion in the RAD50 gene (c.1515_1516 del AA, p.I505fs*5) was introduced into medaka using the CRISPR/Cas9 system (also used a 9 base pair deletion that retained some RAD50 function). The mutant fish were analyzed histologically for tumorgenicity and hindbrain quality and swimming behavior. There was tumorigenesis in 8 out 10 of the histologically analyzed fish and a decrease in median survival. Not scored, since no ovarian cancer developed.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ef809b24-cdc2-4d5c-a1ab-5a9c2f35da54-2024-02-23T180000.000Z,1813,PubMed:37098078 +Ramanagoudr-Bhojappa et al. Zebrafish,Model Systems Non-human model organism,"Ramanagoudr-Bhojappa R, et al., 2018, PMID: 30540754","Knockout zebrafish exhibited a partial sex reversal with the numbers of females greatly reduced in numbers compared to males. Authors note that the reversal illustrates that the FANCO gene is important for gonadogenesis and may reflect the commonly observed hypogonadism in FA probands. Authors also showed that at 21 dpf knockout fish were undifferentiated and contained gonocytes. By 45 dpf testicular differentiation was apparent. Heterozygotes showed both ovarian or testicular differentiation at the same time point. +In FA patients, problems associated with gonadogenesis such as hypogonadism, and infertility +are common, particularly male infertility is noted in additional literature.",Score,1 (2),Points are reduced because zebrafish only exhibited partial phenotypic overlap and did not exhibit key features consistent with FA seen in humans.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ea7ea36f-955c-4478-b5f6-12ff0a0dbf0b-2023-12-20T180000.000Z,1815,PubMed:30540754 +Tomaszowski et al. Mouse Model,Model Systems Non-human model organism,"Tomaszowski KH, et al., 2023, PMID: 36906610","The double KO model mouse demonstrates phenotypes more closely related to phenotypes seen in FA probands including DNA replication instability, higher spontaneous chromosomal aberrations, bone marrow failure, leukemia, reduced survivability.",Score,1 (2),While this model does replicate FA better than the monogenic model it does have a double KO with BRCA2. Authors do compare the monogenic model data to this model and do make a strong case for showing the role of RAD51C in FA probands.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ea7ea36f-955c-4478-b5f6-12ff0a0dbf0b-2023-12-20T180000.000Z,1815,PubMed:36906610 +Genes within the same pathway,Biochemical Function A,"Thompson B, et al., 2019, PMID: 31796115","GDR for STR6 in the GenCC is Definitive for autosomal recessive syndromic microphthalmia / Matthew Wood syndrome by TGMI and Strong by BabySeq and Invitae. +GDR for ALDH1A3 in the GenCC is Strong for autosomal recessive isolated microphthalmia by Invitae. +GDR for RBP4 in the GenCC is Moderate for autosomal recessive isolated microphthalmia with coloboma.",Score,1 (0.5),"Scored 0.5 for STR6 and 0.5 for ALDH1A3 to get a total of 1 point. +Did not score RBP4 because the GDR for this gene is Moderate.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_8fde1ee7-8deb-49e3-a335-0c47c5e77e52-2023-04-25T160000.000Z,1825,PubMed:31796115 +Zebrafish morphants,Model Systems Non-human model organism,"Kalaskar VK, et al., 2020, PMID: 31816153","Zebrafish morphants had microphthalmia and coloboma, both of which are also seen in patients.",Score,1 (2),Reduced score to 1 because the zebrafish morphants are loss of function whereas patients have missense variants most which have been shown to have gain of function effects.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_8fde1ee7-8deb-49e3-a335-0c47c5e77e52-2023-04-25T160000.000Z,1825,PubMed:31816153 +shared protein function,Biochemical Function A,"Diodato D, et al., 2014, PMID: 24639874","Aminoacyl-tRNA synthetases (aaRSs) are key enzymes in the translation of the genetic information. In fact, they catalyze the specific attachment of each of the 20 amino acids (aa) to a cognate tRNA, through a two-step reaction, where they first activate the amino acid with ATP, forming an intermediate aminoacyl-adenylate, and then transfer the aminoacyl group to the 3'-end of its own tRNA. There are 19 mt-aaRSs, which are enoded by nuclear genes, imported into mitochondria, and their interaction with cognate tRNAs seems to be essential for their amount and stability. Biallelic variants in 16 of these genes (table 1) have been associated with human disease including: AARS2 (OMIM#612035, OMIM#614096, 615889), CARS2 (OMIM#612800, OMIM#616672), DARS2 (OMIM#610956, OMIM#611105), EARS2 (OMIM#612799, OMIM#614924), FARS2 (OMIM#611592, OMIM#614946, 617046), GARS (OMIM# 600287, OMIM#600794), HARS2 (OMIM#600783, OMIM#614926), KARS (OMIM#60142, OMIM#613641), LARS2 (OMIM#604544, OMIM#617021, 615 300), MARS2 (OMIM#609728, OMIM#616430, 611 390), NARS2 (OMIM#612803, OMIM#616239), RARS2 (OMIM#611524, OMIM#611523), SARS2 (OMIM#612804, OMIM#613845), TARS2 (OMIM#612805, OMIM#615918) VARS2 (OMIM#611390, OMIM#615917), YARS2 (OMIM#610957, OMIM#613561).",Score,2 (0.5),>10 products with gene disease association. Can score at 2 points as per LSS scoring rubric.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1bdeaf04-f6ce-42f1-9ee0-037f1ead77fb-2022-05-04T160000.000Z,1826,PubMed:24639874 +Rescue in patient cells,Rescue Patient cells,"Canault M, et al., 2014, PMID: 24958846","The patient’s cells infected with the vector containing only EGFP showed a defect in fibrinogen binding when stimulated by 10 and 50 µM TRAP-6, thereby confirming that the CALDAG-GEFI defect extended to megakaryocytes. Expression of the wild-type form of CalDAG-GEFI in the patient’s megakaryocytes restored fibrinogen binding at a level observed in control megakaryocytes transduced with the vector containing EGFP alone.",Score,1 (1),"To unequivocally attribute the integrin activation defect to the p.G248W transition in CalDAG-GEFI, rescue experiments were performed with megakaryocytes from the patients and healthy individuals. These were obtained from differentiated CD34+ cells transduced with a vector containing the EGFP and the wild-type form of RASGRP2 sequences or the EGFP alone.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_f4401e99-145a-4b93-aa73-6854b8037895-2019-09-27T135300.165Z,1827,PubMed:24958846 +Patient Platelet,Functional Alteration Patient cells,"Canault M, et al., 2014, PMID: 24958846","RASGRP2 encodes CalDAG-GEFI which is a guanine nucleotide exchange factor that is critical for Ras-like GTPase activation whose target is mainly Rap1 in platelets. Patient platelets showed a strongly reduced Rap1 activation; no activation was seen with ADP and a reduced activation with TRAP-6. Additionally, a strong reduction in Rac1 (a regulator of platelet cytoskeleton dynamics, which cooperates with Rap1) activation was also observed. This is consistent with the observations in patient platelets, which have reduced binding of soluble fibrinogen in the presence of ADP or TRAP-6 and diminished adhesion to surface-bound fibrinogen in the absence of agonists. Furthermore, during spreading platelets from patients exhibited a reduced number of filopodia and failed to form lamellipodia either when platelet on fibrinogen alone or in the presence of ADP and TRAP-6.",Score,1 (1),The loss of Rap1 activation and resulting spreading defect in platelets may explain the bleeding phenotype in patients.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_f4401e99-145a-4b93-aa73-6854b8037895-2019-09-27T135300.165Z,1827,PubMed:24958846 +TALEN rb1 somatic inhibition in zebrafish,Model Systems Non-human model organism,"Solin SL, et al., 2015, PMID: 26345384","At 1.5 years post fertilization, tumor penetrance in rb1 exon 2 and exon 3 TALEN injected fish was 33% (29/87 adults) and 11% (29/275), respectively (Table 1). +Individuals with somatic mutations or gremline mutations in RB1 develop retinoblastoma, tumors of neuroectodermal origin in the eye.",Score,3 (2),"I increased the score to 3, as this is the first time that tumors have been shown to develop in zebrafish. Furthermore, unlike mouse models of RB1 mutation which require inactivation of other genes (like p53) to develop cancer, the zebrafish only had somatic mosaic mutation of rb1 (either heterozygous or homozygous) to develop the cancers, showing the strength of the rb1 mutation alone to developing tumors.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_f8c79621-7ace-4c0c-874e-a315a2e6c872-2020-07-30T213929.219Z,1828,PubMed:26345384 +HLHS right ventricular tissue,Functional Alteration Patient cells,"Verma SK, et al., 2016, PMID: 27485310","immunohistochemistry, western blot",Score,0 (1),"Postnatal tissues, no unaffected tissues",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ed2c6ea3-402b-482d-ba7e-24e8cf2fb681-2024-05-14T160000.000Z,1829,PubMed:27485310 +Mouse in situ,Expression A,"Cibi DM, et al., 2019, PMID: 31241461",In situ expression in outflow tract of heart during mouse development,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ed2c6ea3-402b-482d-ba7e-24e8cf2fb681-2024-05-14T160000.000Z,1829,PubMed:31241461 +3'UTR Binding,Biochemical Function A,"Begg BE, et al., 2020, PMID: 32807990",Reviewed in PMC3804413,Score,0.25 (0.5),In vitro and not in relevant cell type,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ed2c6ea3-402b-482d-ba7e-24e8cf2fb681-2024-05-14T160000.000Z,1829,PubMed:32807990 +Mouse knockout,Model Systems Non-human model organism,"Verma SK, et al., 2022, PMID: 35137168",Thin ventricular wall but no structural CHD,Score,0.5 (2),No structural CHD,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ed2c6ea3-402b-482d-ba7e-24e8cf2fb681-2024-05-14T160000.000Z,1829,PubMed:35137168 +Zebrafish rescue,Rescue Non-human model organism,"Huang M, et al., 2022, PMID: 36198703",Rescue of ventricular size and contractility,Score,1 (2),Double knockout model,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ed2c6ea3-402b-482d-ba7e-24e8cf2fb681-2024-05-14T160000.000Z,1829,PubMed:36198703 +Functional alterations caused by RBM20 mutations,Functional Alteration Non-patient cells,"Murayama R, et al., 2018, PMID: 29895960",R636W substitution (equivalent to R634W in human) diminished splicing regulation activity of RBM20. The RBM20 R636W protein was almost undetectable with the anti-phospho-RBM20 antibody and was excluded from the nuclei consistent with the idea that phosphorylation of the RSRSP stretch is necessary for nuclear localization of RBM20,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3e123751-078a-4d30-9f83-847119982342-2020-08-20T160000.000Z,1831,PubMed:29895960 +Zebrafish Knockdown,Model Systems Non-human model organism,"Albers CA, et al., 2012, PMID: 22366785",At the highest dosage the embryos died within 24hrs post-fertilization while the lower doses had gross developmental defects at 78 hpf. These effects were more extensive than those seen from similar experiments for other genes implicated in hemopoiesis and are compatible with rbm8a being required for early zebrafish development.,Score,0.5 (2),"This is consistent with the genotypes observed in human patients, with compound inheritance of one null allele and one low frequency SNP; two null alleles have not been reported which may be consistent with the high dosage morpholino knockdown lethality. However, this zebrafish does not model TAR phenotypes so only receives the minimum score.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_56c276a7-3068-48db-9baa-6f178eb9c3a7-2020-05-15T160000.000Z,1832,PubMed:22366785 +Expression in hemopoietic lineages,Expression A,"Albers CA, et al., 2012, PMID: 22366785","RBM8A gene expression was determined to be present in all 8 hematopoietic lineages assayed by qPCR. Furthermore, expression was reduced in TAR patient platelets which may contribute the presence of thrombocytopenia.",Score,0.5 (0.5),Expression in hematopoietic lineages is consistent with the tissue enhanced expression in blood reported by The Human Protein Atlas.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_56c276a7-3068-48db-9baa-6f178eb9c3a7-2020-05-15T160000.000Z,1832,PubMed:22366785 +Expression human retina,Expression A,"Coppieters F, et al., 2016, PMID: 27486781",Targeted qPCR-based expression analysis of mRNA from RCBTB1 shows strong expression in retina and limited expression in RPE (compared to positive control genes CEP290 and CRB1),Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_f356649e-e6d6-4ab6-9e78-3774404794ff-2022-06-02T160000.000Z,1833,PubMed:27486781 +Expression in murine retina,Expression A,"Coppieters F, et al., 2016, PMID: 27486781",RCBTB1 immunoreactivity in the murine retina mainly localized to the inner retina,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_f356649e-e6d6-4ab6-9e78-3774404794ff-2022-06-02T160000.000Z,1833,PubMed:27486781 +Cilia anomalies in patient cells,Functional Alteration Patient cells,"Huang Z, et al., 2021, PMID: 34617687",Development of RPE barrier function impaired and mean cilium length is reduced (though not significant). SEM analysis of cultured RPE cells showing morphology in patient‐derived and control RPE cells and surface microvillus densities in patient‐derived and control RPE,Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_f356649e-e6d6-4ab6-9e78-3774404794ff-2022-06-02T160000.000Z,1833,PubMed:34617687 +Expression in patient-derived iPSC,Expression B,"Huang Z, et al., 2021, PMID: 34617687",RCBTB1 expression reduced in patient RPE compared to control,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_f356649e-e6d6-4ab6-9e78-3774404794ff-2022-06-02T160000.000Z,1833,PubMed:34617687 +Immunohistochemistry,Expression A,"Aravindan S, et al., 2017, PMID: 29030614","They custom-synthesized an anti-human RD3 antibody, characterized its specificity, and investigated the expression and localization of RD3 in several human tissues. In the retina, the strongest immunoreactivities were located in the internal half of the photoreceptor layer and the external half of the outer plexiform layer. Both nuclear and cytoplasmic immunoreactivities were observed. In the photoreceptor layer, some cells were more strongly reactive than others. The distribution of immunoreactivities was not homogeneous, with the strongest immunoreactivity seen in the inner half of the cytoplasmic portion of the photoreceptor layer, where rods and cones are found, and the external half of the outer plexiform layer.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_67c894eb-2c16-4598-8e92-8345e562d91c-2022-01-06T050000.000Z,1834,PubMed:29030614 +eyeIntegration RNA-seq data,Expression A,"Swamy V, et al., 2019, PMID: 31343654","Data from the eyeInegration database (https://eyeintegration.nei.nih.gov/), which integrates RNA-seq data from GTex (for non-eye tissues) and RNA-seq data from various databases for eye tissues, showed that RDH5 is most highly expressed in RPE, and also in adipose tissue and breast tissue. Any expression in the remaining tissues is around background level. Specifica expression in RPE was also noted on nothern analysis of bovine tissues when the bovine RDH5 cDNA was first cloned (PMID 7544779).",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5399fd62-ca69-4665-b3ba-c15ceefbf6d9-2021-09-02T160000.000Z,1836,PubMed:31343654 +Kitajiri Expression,Expression A,"Kitajiri S, et al., 2004, PMID: 15314067",Radixin expression was detected in one row of IHC sterocilia and three rows of OHC stereocilia in mouse cochlea by immunofluorescent microscopy and by scanning EM. There was also expression detected in the hair cell stereocilia of the crista ampullaris of the vestibule,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_2cf494e5-7335-4e2a-8b50-75cf8412a9d0-2018-01-02T170000.000Z,1837,PubMed:15314067 +Kitajiri Animal Model,Model Systems Non-human model organism,"Kitajiri S, et al., 2004, PMID: 15314067","Rdx null mice were deaf- absent Preyer's reflex and absent ABR. Heterozygous null mice had normal hearing. No obvious gross morphological malformations of cochlea were seen in null mice. Scanning EM of Rdx null mosue organ of Corti showed defective stereocilia in both IHCs and OHCs, however cellular arrangement of IHCs and OHCs as well as supporting cells appeared normal. Mice also had hyperbilirubinemia. No evidence so far of liver phenotype in human cases",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_2cf494e5-7335-4e2a-8b50-75cf8412a9d0-2018-01-02T170000.000Z,1837,PubMed:15314067 +Shin Protein Interaction,Protein Interaction,"Shin JB, et al., 2013, PMID: 23334578",Proteomic analysis of chicken vestibular hair bundle showed RDX was a hub protein that interacts with many bundle proteins.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_2cf494e5-7335-4e2a-8b50-75cf8412a9d0-2018-01-02T170000.000Z,1837,PubMed:23334578 +RECQL Knock Out Mouse,Model Systems Non-human model organism,"Sharma S, et al., 2007, PMID: 18074021","Cancer cells display defective DNA repair and damage responses, as do the MEF cells from RECQL knock-out mice.",Score,0.5 (2),"""RECQL knockout mice are viable, fertile, and apparently not tumor prone under normal colony conditions. However, it should be emphasized that small numbers of mice were evaluated in each group and no genetic or environmental carcinogenic stimuli were used in these initial studies""",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_777b2a5c-459f-4eee-8a6d-e8bf15b88aca-2023-03-13T170000.000Z,1838,PubMed:18074021 +RECQL Defective G2/M Checkpoint Following IR,Biochemical Function B,"Sharma S, et al., 2007, PMID: 18074021",Cancerous cells often have dysfunctional / disrupted cell cycle progression.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_777b2a5c-459f-4eee-8a6d-e8bf15b88aca-2023-03-13T170000.000Z,1838,PubMed:18074021 +RECQL depleted Hela DNA damage Assay,Functional Alteration Non-patient cells,"Sharma S, et al., 2007, PMID: 18074021","With decreased RECQL levels, cell survival declined upon exposure to ionizing radiation because cells could not repair damage compared to normal cells without RECQL loss.",Score,0 (0.5),Not scoring because DNA damage repair function is already scored elsewhere.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_777b2a5c-459f-4eee-8a6d-e8bf15b88aca-2023-03-13T170000.000Z,1838,PubMed:18074021 +TNF-induced apoptosis,Functional Alteration Patient cells,"Badran YR, et al., 2017, PMID: 28600438","Compared with controls, the patients’ fibroblasts exhibited significantly more TNF-induced cell death and caspase-8 cleavage, with significantly less NF-κB activation and secretion of the NF-κB–regulated cytokine IL-6. PBMCs from the patients, but not from the healthy father, also had significantly impaired IL-6 secretion after TNF stimulation. The patients’ lymphocytes did not undergo increased apoptosis after TNF exposure, consistent with their normal lymphocyte counts. RelA haploinsufficiency, therefore, results in increased stromal cell apoptosis in response to TNF but permits sufficient NF-κB activation for the maintenance of intact lymphocyte numbers and host immunity.",Score,1 (1),The pathogenic mechanism is explained by increased sensitivity of mutant fibroblasts to TNF-induced apoptosis.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1e0145f5-c001-420c-9591-c6583862a7ca-2023-09-21T160000.000Z,1842,PubMed:28600438 +Rela+/− mice,Model Systems Non-human model organism,"Badran YR, et al., 2017, PMID: 28600438","TNF stimulation of Rela+/− splenocytes resulted in significantly impaired up-regulation of Il6, Tnfaip3, and Traf1; all which depend on NF-κB activation. A low-dose, s.c. TNF injection had no effect on WT mice but resulted in cutaneous ulceration in Rela+/− mice, which was notable for epidermal skin loss and a predominance of neutrophils and macrophages in the dermis and hypodermis. This is consistent with the cutaneous (oral and genital) ulcers observed in patients.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1e0145f5-c001-420c-9591-c6583862a7ca-2023-09-21T160000.000Z,1842,PubMed:28600438 +Gene expression,Rescue Patient cells,"Badran YR, et al., 2017, PMID: 28600438","To investigate the molecular mechanisms driving the patients’ defective stromal survival, the authors analyzed gene expression in patient and control fibroblasts, with and without TNF stimulation. Most transcripts encoding NF-κB–dependent antiapoptotic proteins and cytokines were decreased in patient cells. The expression of WT RelA in the patient fibroblasts restored the expression of BCL2A1 and IL-6 in response to NF-κB–activating stimuli.",Score,1 (1),"Collectively, these data indicate that RelA haploinsufficiency results in impaired up-regulation of NF-κB antiapoptotic genes, thus providing a mechanistic rationale for the cell death induced in patient fibroblasts by in vitro TNF exposure.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1e0145f5-c001-420c-9591-c6583862a7ca-2023-09-21T160000.000Z,1842,PubMed:28600438 +"Expression of DelL16, L381P and WT of renin in zebra fish.",Model Systems Non-human model organism,"Schaeffer C, et al., 2019, PMID: 31406136","In model_ At 5 days post fertilization (dpf) no significant alterations in the head, heart, and swim bladder were detected. 60% of embryos injected with the L381P renin variant showed pronephric alteration: 43% were characterized by reduced, partial convolution of the pronephric tubules and 17% showed absence of tubular convolutions. A similar phenotypic distribution was observed in embryos injected with the L16del. By contrast, only 9% of embryos injected with wild type renin showed alterations of pronephric tubules. +Observed changes in zebra fish model correspond to tubulointerstitial changes observed in patients with autosomal dominant mutations in renin and ADTKD-REN.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_cae92b57-f5b9-4000-9a42-72161f2d7dd3-2020-10-28T160000.000Z,1846,PubMed:31406136 +Mouse model,Model Systems Non-human model organism,"Kim BJ, et al., 2013, PMID: 23451234","Mice homozygous for a null Rere allele died between E9.5 and E11.5 from failure of cardiac looping and subsequent cardiac failure. These embryos also had defects in somitogenesis, fusion of the telencephalic vesicles, defects of the optic vesicles, and failure of anterior neural tube closure, and were given the name 'openmind' (om). Mice compound heterozygous for om and eyes3, a hypomorphic Rere allele causing autosomal recessive microphthalmia, had a high level of perinatal mortality, postnatal growth deficiency, brain hypoplasia, decreased numbers of hippocampal neurons, hearing loss, cardiovascular malformations, spontaneous development of cardiac fibrosis in adulthood, and renal agenesis. Fregeau et al. (2016) observed that om/eye3 compound heterozygous mice also had ventriculomegaly and incomplete closure of the optic fissure, suggestive of coloboma. Kim and Scott (2014) showed pre- and postnatal delayed development of the principal fissures in the cerebellum, which was associated with decreased proliferative activity of granule cell precursors and delayed maturation and migration of Purkinje cells. These abnormalities were associated with a decrease in the expression of SHH, which is secreted from Purkinje cells and is required for normal proliferation. This model recapitulates multiple phenotypes observed in human patients.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_bdf18409-7db7-4934-9bc7-99eea21d9058-2023-03-21T160000.000Z,1847,PubMed:23451234 +Conditional Knockout of RFX6,Model Systems Non-human model organism,"Piccand J, et al., 2014, PMID: 25497096","Rfx6 is required for normal b cell identity, sustaining the expression of signature b cell genes (Gck, +Abcc8) and repressing that of disallowed genes. These findings raise the possibility that changes in RFX6 expression may contribute to b cell failure in type 2 diabetes (T2D) in humans.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d0636b0f-5a63-4905-86c9-92ef57eb77d3-2024-05-10T160000.000Z,1855,PubMed:25497096 +Transcriptional assay,Functional Alteration Non-patient cells,"Imaki S, et al., 2021, PMID: 33721395",RFX6(R652X) failed to activate the human insulin promoter,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d0636b0f-5a63-4905-86c9-92ef57eb77d3-2024-05-10T160000.000Z,1855,PubMed:33721395 +Subcellular localization,Functional Alteration Non-patient cells,"Imaki S, et al., 2021, PMID: 33721395","Subcellular localization of RFX6 (R652X) revealed that the p.R652X mutation had little +effect on nuclear localization of the protein",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d0636b0f-5a63-4905-86c9-92ef57eb77d3-2024-05-10T160000.000Z,1855,PubMed:33721395 +Mice carrying RHBDF2 p.P189L (p.P159L in mice),Model Systems Non-human model organism,"Hosur V, et al., 2017, PMID: 28655741","Rhbdf2 P159L/P159L mice showed alopecia, rapid cutaneous wound healing, hyperplasia, and hyperkeratosis (Fig. 2). ELISA quantitation of AREG levels indicated increased AREG secretion in Rhbdf2 P159L/P159L mice (Fig. 2). +Immunohistochemical analyses of skin sections from Rhbdf2 P159L/P159L mice revealed increased activity of downstream effectors of the EGFR signaling pathway, including phospho-ERK1/2 and phospho-AKT (Fig. 3). +AREG deficiency restores the normal skin phenotype in Rhbdf2P159L/P159L mice, suggesting AREG drives the skin disease phenotype in Rhbdf2P159L/P159L mice (Fig. 4).",Score,2 (2),"Rhbdf2 P159L/P159L mice recapitulates the phenotype of TOC patients, suggesting that Rhbdf2 P159L is a GOF mutation, and that this GOF mutation enhances secretion of AREG and leads to constitutive activation of EGFR signaling to cause TOC.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b7e72765-1a53-44fb-bfee-9e5923507bbe-2020-07-30T212232.808Z,1859,PubMed:28655741 +Mouse model (heterozygotes have mild phenotype),Model Systems Non-human model organism,"Zhao B, et al., 2016, PMID: 27269051",Both affected humans and mutant mice have mild hearing loss.,Score,0.5 (2),Only mild hearing loss was seen in the heterozygous mutant mice.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_64425d70-9de8-4b24-946d-338d86cecf48-2024-05-15T160000.000Z,1865,PubMed:27269051 +Rlbp1−/−  mouse model,Model Systems Non-human model organism,"Lima de Carvalho JR, et al., 2020, PMID: 32188692","Sibling pair compound het for variants in RLBP1 and their asymptomatic carrier parents showed reduced SW-AF intensities, measured as quantitative fundus autofluorescence (qAF). This indicated chronic impairment in 11-cis-retinal availability and provided information on mutation severity. Hypertransmission of the SD-OCT signal into the choroid together with decreased near-infrared autofluorescence (NIR-AF) provided evidence for retinal pigment epithelial cell (RPE) involvement. +In Rlbp1/Cralbp-/- mice, reduced 11-cis-retinal levels, qAF and NIR-AF intensities, and photoreceptor loss were consistent with the clinical presentation of the affected siblings. These findings indicate that RLBP1 mutations are associated with progressive disease involving RPE atrophy and photoreceptor cell degeneration. In asymptomatic carriers, qAF disclosed previously undetected visual cycle deficiency.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d8c69db5-8d29-40af-85f0-59471ce0c62c-2021-06-03T160000.000Z,1866,PubMed:32188692 +Mouse model,Model Systems Non-human model organism,"Bohgaki T, et al., 2011, PMID: 21552324","Both patients with RIDDLE syndrome and RNF168 knock out mice show immunodeficiency, specifically impaired class switch recombination, and increased cellular sensitivity to radiation. Neither have defects in T- or B- cell numbers but have significantly lower serum IgG concentration (Figure 5A). Class switch recombination of various IgG isotypes in knockout mice is also impaired (Figure 5B, 5C, 5D). Knockout lymphocytes demonstrate a significant increase in the sensitivity to infrared radiation and ultra violet treatment (Figure 1A).",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_2eab353f-d7ed-4f22-883e-0b62c7bc4f9b-2022-08-08T170000.000Z,1872,PubMed:21552324 +Pietrucha functional alteration,Functional Alteration Patient cells,"Pietrucha B, et al., 2017, PMID: 29255463","The formation and disappearance of 53BP1 repair foci were monitored over time in both lymphoblastoid cells and fibroblasts from both patients. The fibroblasts from both patients failed to form any detectable 53BP1 foci (Figure 3; Table 1). Similarly, we could not detect any 53BP1 foci after irradiation in lymphoblastoid cells from both patients.",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_2eab353f-d7ed-4f22-883e-0b62c7bc4f9b-2022-08-08T170000.000Z,1872,PubMed:29255463 +RNF43 mutants impact in intestinal organoid growth,Model Systems Cell culture model,"Tsukiyama T, et al., 2020, PMID: 32934222","Expression of RNF43(3SD) during short-term culture of organoids in the ENR condition significantly suppressed organoid growth. +Expression of RNF43(3SA) improved their viability. These results suggest that phospho-regulation of RNF43 is required for the survival and the growth of crypts, and that this regulation occurs independently of the RNF43-Rspo-Lgr regulatory module.",Score,0.1 (1),Reduced since not related to serrated polyps.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9abf2a1d-21a7-4ef7-99c7-b0b37d5acf38-2022-12-30T180000.000Z,1874,PubMed:32934222 +Zebrafish rescue,Rescue Non-human model organism,"Patil SB, et al., 2011, PMID: 21738648",Retinopathy phenotype rescued - preservation of photoreceptor morphology and expression of rod and cone-specific proteins in the retina.,Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_75e3203d-3841-49eb-84d4-e6238eda55ea-2022-03-02T214941.540Z,1883,PubMed:21738648 +shRNA-based knockdown of RPGR in an RPE cell line,Functional Alteration Non-patient cells,"Murga-Zamalloa CA, et al., 2010, PMID: 20631154","Cells transfected with RPGR-targeting shRNA exhibited significant shortening of the primary cilia, consistent with a role in the assembly of the primary cilium (Figures 4B-4D).",Score,0.5 (0.5),The finding is consistent with a role for RPGR in the assembly of the primary cilium.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_57ad94c7-d914-4a84-ab33-597c8d4bafdd-2022-08-05T160000.000Z,1886,PubMed:20631154 +Rescue of Rpgr-deficient mice with human RPGR,Rescue Non-human model organism,"Fischer MD, et al., 2017, PMID: 28549772",ERG analyses show significant rescue of rod function and a rescue of cone function that is trending towards statistical significance (Figures 5B and 5C).,Score,0.5 (2),"The experiment shows convincing rescue in two mouse models, but has been down-scored for the absence of unaffected control animals for comparison, and for the absence of information on the rescue of other phenotypes from these models at the microscopic level.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_57ad94c7-d914-4a84-ab33-597c8d4bafdd-2022-08-05T160000.000Z,1886,PubMed:28549772 +Figure 7,Model Systems Non-human model organism,"Wiegering A, et al., 2018, PMID: 29650680",The similar kidney phenotype,Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ab4cfcff-be99-4c82-ab33-8451b5ed5b0c-2024-04-24T160000.000Z,1887,PubMed:29650680 +Figure 8,Functional Alteration Non-patient cells,"Wiegering A, et al., 2018, PMID: 29650680","The amount of Nphp1, Invs and Cep290 was decreased at the ciliary TZ, the cilia length is increased.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ab4cfcff-be99-4c82-ab33-8451b5ed5b0c-2024-04-24T160000.000Z,1887,PubMed:29650680 +Figure 1.,Biochemical Function B,"Wiegering A, et al., 2018, PMID: 29650680",The disease occurs due to dysfunction of cilia.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ab4cfcff-be99-4c82-ab33-8451b5ed5b0c-2024-04-24T160000.000Z,1887,PubMed:29650680 +Inducible mouse model,Model Systems Non-human model organism,"Kazerounian S, et al., 2019, PMID: 32309614","After two weeks of treatment with doxycycline in drinking water, a subset of treated shRNA Rpl5+/- adult mice developed mild anemia while control mice had normal complete blood counts. Similarly, treated shRNA Rpl5+/- mice developed reticulocytopenia and bone marrow erythroblastopenia.",Score,1 (2),Downgraded as the model is a knockdown without rescue,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_edb6a96b-92d7-4c57-8613-e055d1bdd678-2023-05-30T160000.000Z,1888,PubMed:32309614 +ENU mouse model,Model Systems Non-human model organism,"Yu L, et al., 2021, PMID: 34464976","Mutants showed growth and skeletal defects, cardiac malformations, and increased mortality which is consistent with DBA phenotypes in human. Mutants were smaller and had a kinky tail. They had a profound delay in erythroid maturation and increased mortality at embryonic day (E)12.5, which improved by E14.5. Surviving mutant animals had macrocytic anemia at birth, as well as evidence of ventricular septal defect (VSD) which is common in human patients as well",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_edb6a96b-92d7-4c57-8613-e055d1bdd678-2023-05-30T160000.000Z,1888,PubMed:34464976 +"Gregory et al., 2007",Protein Interaction,"Gregory LA, et al., 2007, PMID: 17726054","The RPS19 protein was analyzed, in terms of its crystal-like shape, using Pyrococcus abyssi. The protein creates a five alpha-helix structure surrounding an amphipathic alpha-helix, which correlates with the DBA mutation hot spot (basic regions A and B). DBA mutations were analyzed for their degree of impact on protein folding and surface characteristics. A yeast cell-culture revealed that when analyzed on IgG sepharose, wild-type RPS19 co-precipitated with 18S rRNA and 25S rRNA (large subunit), demonstrating that RPS19 is integrated into developed ribosomes. Mutations in basic region A, (Arg57Glu, Arg57Gln, and Arg63Glu) and basic region B (Arg102Glu and Arg122Glu) reduced such co-precipitation, indicating the integral role of these areas of the protein.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_bceef5ee-7596-4a90-91ce-b36385f9669b-2023-05-30T160000.000Z,1889,PubMed:17726054 +GTEx expression data,Expression A,"Gregory LA, et al., 2007, PMID: 17726054","This data was found in GTEx, not a particular paper.",Score,0.5 (0.5),"This is not really from a paper, but from the RPS19 page on GTEx.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_bceef5ee-7596-4a90-91ce-b36385f9669b-2023-05-30T160000.000Z,1889,PubMed:17726054 +small interfering RNA depletion of RPS20 in HeLa cells,Functional Alteration Non-patient cells,"Nieminen TT, et al., 2014, PMID: 24941021","a significant increase of 21S pre-rRNAs (which are distributed in 2 close bands in this cell type), as well as an accumulation of 18S-E pre-rRNAs",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_258ec9c5-12bb-4d8b-9bc2-d5747b52660c-2024-03-22T170000.000Z,1890,PubMed:24941021 +Drosophila knockout leads to neuronal defects,Functional Alteration Non-patient cells,"Beck K, et al., 2015, PMID: 26398944",histochemical and electrophysiological analyses were used to show defects in subcellular localization on neurons and alterations to the electrophysiological properties of the neurons,Score,0.5 (0.5),Showed defects in subcellular localization on neurons and alterations to the electrophysiological properties of the neurons,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_af32a931-1d55-432f-82cf-ce87f6c26580-2019-05-28T040000.000Z,1891,PubMed:26398944 +Cryo-electron tomography reveals RSPH1-/- ciliary defects,Functional Alteration Patient cells,"Lin J, et al., 2014, PMID: 25473808","The cryo-tomograms revealed a variety of CPC abnormalities in a subset of RSPH1 mutant cilia. This was consistent with previous studies of PCD caused by mutations in putative RS head proteins, which revealed a subset of cilia that lacked the CPC (9+0 axoneme) or had one of the nine DMTs translocated to the centre of the axoneme ((8+1)+0). PCD cilia with an apparently normal 9+2 microtubule arrangement (Fig. 5d), with one of the CPC microtubules missing (9+1; Fig. 5e), with the entire CPC missing (9+0; Fig. 5g), with the CPC replaced by one DMT ((8+1)+0; Fig. 5h), or with a doubled CPC with 4 singlet microtubules (9+4; Fig. 5f) were detected.",Score,1 (1),"The experiment presented the native 3D structures of normal and PCD- causing RSPH1-mutant human respiratory cilia, revealing the resulting defects in radial spokes, and uncovering a mechanism for the milder RSPH1-PCD-phenotype.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_f2bdb2e5-9659-46af-b306-e01207f31174-2022-06-07T110000.000Z,1894,PubMed:25473808 +mouse model - ciliary ultrastuctural and motility defects,Model Systems Non-human model organism,"Yoke H, et al., 2020, PMID: 32203505","same things on EM and HSVM and IF. also hydrocephalus is linked to PCD, although noy specific.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6f876804-e14a-4c7e-a826-232c7f445c7f-2022-04-05T150444.668Z,1896,PubMed:32203505 +Cryo–electron tomography (cryo-ET) and subtomogram averaging,Functional Alteration Patient cells,"Zhao Y, et al., 2021, PMID: 33852348",Patient cilia show RS head defects and CPC defects.,Score,0 (1),not scoring as we use this evidence to score the patients with this variant instead.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6f876804-e14a-4c7e-a826-232c7f445c7f-2022-04-05T150444.668Z,1896,PubMed:33852348 +RUNX1 function in the development of hematopoietic cells,Biochemical Function B,"Liakhovitskaia A, et al., 2014, PMID: 25139854","Runx1 is required for progression of CD41+embryonic precursors into HSCs. (Figure 1 and Figure 2). RUNX1 has a primary role in the development of all hematopoietic cell types (definitive erythroid cells, granulocytes, macrophages, and lymphoid cells);",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_06aed341-58db-459b-a750-7142e29b420b-2018-06-04T170000.000Z,1898,PubMed:25139854 +Western blot,Expression A,"Cacheux M, et al., 2015, PMID: 27858745",Western blot shows expression of RYR1 in skeletal muscle in both the control and patient.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_fbd82373-705c-4b60-8b73-147ed461d357-2020-10-26T160000.000Z,1902,PubMed:27858745 +Western blot,Expression B,"Cacheux M, et al., 2015, PMID: 27858745",Y4864H variant has a rare hypomorphic effect in patients that are heterozygous for this variant.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_fbd82373-705c-4b60-8b73-147ed461d357-2020-10-26T160000.000Z,1902,PubMed:27858745 +Stanczyk Protein Interaction,Protein Interaction,"Stanczyk PJ, et al., 2018, PMID: 29930088","First evidence for RYR2–MYBPC3 complex. The direct interaction involves the C-terminus of MYBPC3 binding with the RYR2 N-terminus in the absence of fibronectin-like domain. In cardiac tissue, a complex formation between both recombinant MYBPC3 and RYR2 was also observed. N-terminal fragment residues 1–906 BT4L RyR2 as the ‘bait’ to screen a human heart cDNA library showing positive interaction (Table 1). To reinforce Y2H observations, co-immunoprecipitation (co-IP) was performed (Figure 1).",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3ac9dd09-674f-4d67-94da-234ffb4e5070-2022-12-14T170000.000Z,1903,PubMed:29930088 +Kohno Model Systems,Model Systems Non-human model organism,"Kohno M, et al., 2020, PMID: 33244105","Compared to mutant mouse models (homozygous RYR2 V3599K), WT mouse LV chamber was markedly enlarged showing hypertrophy and reduced contractile function and insterstitial fibrosis present in cardiomyocytes. Similar phenotypes have been observed in humans with hypertrophic cardiomyopathy.",Score,1 (2),Mutation of mouse model (homozygous RYR2 V3599K) has not been reported in humans.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3ac9dd09-674f-4d67-94da-234ffb4e5070-2022-12-14T170000.000Z,1903,PubMed:33244105 +Calcium Sparks in Tail Muscle from RyR3-Depleted Zebrafish,Functional Alteration Non-patient cells,"Perni S, et al., 2015, PMID: 25667412","Silencing of RyR3 leads to an absence of parajunctional feet and markedly reduced numbers of spontaneous calcium sparks in fibers isolated from zebrafish larvae tail muscle compared to uninjected wild type zebrafish larvae tail muscle. Furthermore, the sparks that were observed in RyR3-depleted tail muscle had altered kinetics (reduced amplitude, duration, and size) when compared to those observed in wild type fibers.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_f234219f-23fd-449f-9d7e-4c1731af3309-2023-08-28T160000.000Z,1905,PubMed:25667412 +Boczonadi review,Biochemical Function A,"Boczonadi V, et al., 2018, PMID: 29980628","Variants in at least 18 aminoacyl-tRNA synthetase genes have been associated with primary mitochondrial disease, these disorders are associated with a spectrum of clinical presentations.",Score,2 (0.5),>10+ genes with a function in mitochondrial translation associated with PMD,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d49e2a27-bd5f-4bc5-8d41-e3f0b4b043ad-2022-06-06T160000.000Z,1908,PubMed:29980628 +shRNA SARS2 knockdown in CD34+ culture system,Functional Alteration Non-patient cells,"Colin E, et al., 2021, PMID: 34407605","SARS2 depletion in early erythroblasts results in decreased proliferation rate and differentiation arrest due to increased apoptosis. (Fig 2) +Increased apoptosis in SARS2-depleted cells is mitochondria-mediated. (Fig3). Mitochondrial depolarization in a subset of SARS2 depleted cells and increased caspase 3 and caspase 9 cleavage. +Note: COXII and ATP8 levels comparable to controls, no increase in ROS",Score,0 (0.5),"Reviewed at the GCEP meeting 6th June 2022, panel decided this data was too weak to score.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d49e2a27-bd5f-4bc5-8d41-e3f0b4b043ad-2022-06-06T160000.000Z,1908,PubMed:34407605 +GWAS in dog breeds with hereditary neuropathy,Model Systems Non-human model organism,"Granger N, et al., 2019, PMID: 31772832","Phenotype reproduced, LOF is a shared mechanism",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_01893bf4-e95d-4206-9d2e-e3822f778b7a-2021-03-22T201309.257Z,1911,PubMed:31772832 +Patch-clamp in transfected HEK cells,Biochemical Function A,"Lin Z, et al., 2016, PMID: 27556810","E.g. Meents et al., 2019, PMID: 30720580",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_abe8c0db-503c-46fa-a2a6-e4d6071219d0-2022-02-25T020007.355Z,1913,PubMed:27556810 +SCN11A KI mouse,Model Systems Non-human model organism,"Ebbinghaus M, et al., 2020, PMID: 32817686","In addition to Leipold et al., Ebbinghaus et al. show a reduced grip-strength and more scratching bouts in SCN11A mutant mice. CGRP-release is reduced, potentially explaining delayed wound-healing.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_abe8c0db-503c-46fa-a2a6-e4d6071219d0-2022-02-25T020007.355Z,1913,PubMed:32817686 +SCN11A KI mouse,Model Systems Non-human model organism,"Matsubara Y, et al., 2021, PMID: 32970203","Allodynia, especially aggravated by cold, has been described as a recurrent phenotype in association with SCN11A variants.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_abe8c0db-503c-46fa-a2a6-e4d6071219d0-2022-02-25T020007.355Z,1913,PubMed:32970203 +hiPSC model,Model Systems Cell culture model,"Moreau A, et al., 2018, PMID: 30218094",The iPSC-CM model could recapitulate the human DCM phenotypes.,Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_53c90d2e-4d40-48ab-8761-b0158102c977-2020-11-06T181622.881Z,1922,PubMed:30218094 +Animal Model,Model Systems Non-human model organism,"Wagnon JL, et al., 2015, PMID: 25227913","Generated genetic locus specific knockin mice of the EIEE patient derived mutaiton N1768D, using TALON technology. These mice express the mutation in a heterozygous state, and are not a transgenic overxpression. The heterozygous mice develop seizures after 3 months of age, and eventually die from SUDEP at 14 weeks (on average). The mice also display deficits in the accelrating rotarod compared to WT mice, indicative of motor dysfunction as seen in patient with EIEE. The homozygous N1768D mice show an enhance/ accelerated rate of seizure onset and death, indicating a dosage dependent outcome. Lopez-Santiago et al., 2017 showed: Dissociated hippocampal neurons from mutant mice exhibited increased persistent current; recordings from brain slices from mutant mice revealed early after-depolarizations and spontaneous firing in hippocampal neurons",Score,4 (2),"no changes to open field, sociability or fear conditioning were observed. Given that the mice express a patient derived mutation and fully recapitulate the disease, I will give full points for the model.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_f52993aa-ddee-483d-b15e-dbf21608d5a9-2018-07-18T125000.560Z,1926,PubMed:25227913 +Function PI,Protein Interaction,"Wagnon JL, et al., 2016, PMID: 26900580",C-terminus of Nav1.6 interacted with Navb1 (Scn1b),Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_f52993aa-ddee-483d-b15e-dbf21608d5a9-2018-07-18T125000.560Z,1926,PubMed:26900580 +Sco1 Mouse Heart knockout studies + G115S knockin,Model Systems Non-human model organism,"Baker ZN, et al., 2017, PMID: 28973536","Lethality was observed in both (heart and muscle) models due to a combined COX and copper deficiency that resulted in a dilated cardiomyopathy +Sc1 hrt/hrt had 0% survival by day 2 +Sco1hrt/hrt hearts also exhibited a severe COX deficiency when compared with wild-type hearts +the Sco1hrt/hrt heart had a slight, but statistically significant reduction in total copper content when compared with the wild-type heart +Msk specific knockout Sco1stm/stm +Sco1stm/stmhearts had a significant reduction in COX activity and COX IV protein levels when compared with the hearts of wild-type littermates (Fig. 3A and D, Supplementary Material, Fig. S2C). +Sco1stm/stmhearts had significantly lower total copper levels than wild-type hearts, in the absence of changes in the total abundance of iron and zinc (Fig. 3C). +Sco1G115S/G115S hearts exhibited a severe, combined COX and copper deficiency, like the knockout mouse model (Fig. 6A and B). The copper deficiency was not attributable to changes in the steady-state levels of CTR1 or ATP7A, and was not accompanied by changes in CCS abundance (Fig. 6B).",Score,3 (2),"0.5 (cardiomyopathy phenotype) + 0.5 (specific complex IV deficiency + Copper deficiency) x 3 (knockout muscle, knock out heart, knockin G115S)",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_90d9d757-a45e-4d35-af68-c1345e1d8c65-2022-02-17T170000.000Z,1929,PubMed:28973536 +SDHA and SDHB are complex II subunits,Protein Interaction,"Alston CL, et al., 2012, PMID: 22972948","See PMID: 20226277 for overview, PMID: 15989954 for crystal structure",Score,0.5 (0.5),The encoded protein interacts with one gene product (SDHB) whose dysfunction is known to cause Leigh syndrome.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_4c5801d0-5839-47d9-81cc-a53cea959b57-2019-05-20T190935.665Z,1933,PubMed:22972948 +Patient 3 Cell Studies,Functional Alteration Patient cells,"Ohlenbusch A, et al., 2012, PMID: 22995659",Complex II activity measured in (SDH residual activity normalized to CS) fibroblasts was 18% relative to controls.,Score,0.5 (1),This is the second patient derived cell culture model demonstrating mitochondrial dysfunction.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0baf56d2-40f8-465a-9b50-22f57481a5cb-2020-02-12T201133.569Z,1934,PubMed:22995659 +Part of complex II,Biochemical Function A,"Fullerton M, et al., 2020, PMID: 33162331",Table 1 lists the pathogenic variants in the above genes involved in complex II deficiency.,Score,1 (0.5),Four proteins encoded by 4 genes are part of SDH complex.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e421e4d0-9618-4fad-bf20-a509d8d527ed-2023-12-04T050000.000Z,1935,PubMed:33162331 +C.elegans model,Model Systems Non-human model organism,"Saskői É, et al., 2020, PMID: 32859697","sdhb-1(gk165) deletional worm was used to generate two transgenic lines carrying either the Arg244His mutation (equivalent to human Arg230His, associated with pheochromocytomas (PHEOs) and paragangliomas (PGLs ) or its genomic wild-type SDHB as a control. +KO and Arg230His showed reduced lifespan, KO worms showed arrested development at L2, R244H homozygous worms reached adulthood at day 4-5, indicating delayed development. Both models showed elevated succinate levels, +Using mitotracker, both mutants showed reduced mitochondrial number. +Bioluminescent ATP assay demonstrated a reduction in ATP production in null and Arg244His strain. +Treatment with protonophore FCCP failed to stimulate oxygen consumption as measured by Seahorse XF96 Metabolic Analyser.",Score,1 (2),"delayed development, shortened lifespan, attenuated ATP production, reduced mitochondrial number, elevated succinate. 1pt (0.5 biochemical dysfunction/ mitochondrial dysfunction + 0.5 developmental differences.)",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_53015cfb-c54a-4436-9ebd-79ae3fdbf613-2022-03-07T170000.000Z,1937,PubMed:32859697 +Review: mitochondrial complex II deficiency,Biochemical Function A,"Fullerton M, et al., 2020, PMID: 33162331","SDHA: Moderate GDR for Leigh syndrome spectrum, Fullerton review found 32 patients with PMD. +SDHAF1: Limited GDR for Leigh syndrome spectrum, Fullerton review found 16 patients with PMD. +SDHD: not yet curated, at least two cases in the literature.",Score,1 (0.5),1 pt (2-3 gene products with shared biochemical relationship),https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_53015cfb-c54a-4436-9ebd-79ae3fdbf613-2022-03-07T170000.000Z,1937,PubMed:33162331 +Complex II structure,Biochemical Function A,"Fullerton M, et al., 2020, PMID: 33162331","Pathogenic variants in these genes are associated with Leigh syndrome: +SDHA- GDR is moderate by ClinGen SOP v6 +SDHB- GDR is moderate by ClinGen SOP v8 +SDHD - +SDHAF1-GDR is limited by ClinGen SOP v7",Score,0 (0.5),Not scored at this time due to lack of genetic evidence. Can be scored upon availability of genetic evidence.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_909982e0-a53c-4a87-bf28-cdb563c8ae62-2022-03-07T170000.000Z,1940,PubMed:33162331 +Complex II structure,Biochemical Function A,"Fullerton M, et al., 2020, PMID: 33162331",All the above genes are structural components of complex II.,Score,1 (0.5),1 point as per LSS GCEP rubric,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9010c629-a86c-4f55-a45b-212b7aabdb6f-2022-04-04T160000.000Z,1941,PubMed:33162331 +knockdown of SDHD in HEK293 cells,Model Systems Cell culture model,"Bandara AB, et al., 2021, PMID: 34118887","Similar to the human phenotype, in response to treatment with succinate, Complex II-mediated oxygen consumption was significantly repressed in mutant cells compared to parent cells (p = 0.0002), further confirming the effect SDHD mutation. The mutant also had decreased OXPHOS.",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9010c629-a86c-4f55-a45b-212b7aabdb6f-2022-04-04T160000.000Z,1941,PubMed:34118887 +Bolar_Zebrafish,Model Systems Non-human model organism,"Bolar NA, et al., 2016, PMID: 27392076","Embryos at 4 dpf showed an overall percentage of 70% of affected embryos that included 30% with an absence of convolution of the pronephric tubules and 40% with partial convolution. Tubular atrophy was observed in the morphants, which the authors suggest was unlikely to be driven by overall developmental delay. Similar convolution defects (V-shaped and straight tubules in 55% of F0 founders) were observed in CRISPR mutants.",Score,0.5 (2),"Since the clinical phenotypes associated with SEC61A1 variants cannot be modeled in the zebrafish in early development, authors studied the structure of the nephron, which is conserved between human and zebrafish. Minimum points are awarded as there is not a typical recapitulation of the phenotype.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1ff61d15-19f9-42a2-8dc4-0a4071b562eb-2021-07-27T154837.287Z,1944,PubMed:27392076 +Bolar_Subcellular mislocalization,Functional Alteration Patient cells,"Bolar NA, et al., 2016, PMID: 27392076","In the kidney biopsy from the patient with the SEC61A1 Thr185Ala variant, the mutant protein was present in coarsely granular structures. It was localized in the ER and a significant proportion of the protein was also localized in the Golgi. In control kidney sections, SEC61A1 was present in finely granular structures and was located exclusively in the ER. Quantitative western blot analysis in HEK293 cells showed reduced expression of the protein. In addition, IF and colocalization studies showed that WT protein was present in granular structures, localized exclusively in the ER; whereas the mutant proteins formed intracellular clumps localized in the ER but also partly in the Golgi.",Score,1 (1),Default score is awarded for the mislocalization evidence as SEC61A1 functions in the ER membrane.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1ff61d15-19f9-42a2-8dc4-0a4071b562eb-2021-07-27T154837.287Z,1944,PubMed:27392076 +Van Nieuwenhove_ER stress and Calcium leak studies,Biochemical Function B,"Van Nieuwenhove E, et al., 2020, PMID: 32325141","Single-cell transcriptomics analysis on red blood cell-depleted bone marrow from the proband and healthy sex-matched control. Primary fibroblasts from the patient demonstrated upregulation of both DDIT3, encoding CCAAT/enhancer-binding protein homologous protein (CHOP), and HSPA5, encoding immunoglobulin heavy chain binding protein (BiP), with primary PBMCs showing a similar fold increase for CHOP. Likewise, the patient's cells upregulated both CHOP and BiP following 16 days of in vitro neutrophilic differentiation, indicating ER stress.",Score,0.5 (0.5),ER stress (and increased calcium leakage) is noted as a mechanism of disease and demonstrated in patients and experimental systems.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1ff61d15-19f9-42a2-8dc4-0a4071b562eb-2021-07-27T154837.287Z,1944,PubMed:32325141 +Zebrafish sec63-st67,Model Systems Non-human model organism,"Monk KR, et al., 2013, PMID: 22864019","Increase in ER stress. Abnormal liver development - fragmentation and swelling of the ER, smaller mitochondria, regions of empty cytoplasm, large lysosomes filled with debris. Development of liver steatosis. Translates to missense mutation in region conserved in humans.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_76312e16-e3b1-400a-8a22-4c0cca5e6918-2020-09-23T040000.000Z,1946,PubMed:22864019 +Mouse Model,Model Systems Non-human model organism,"Rederstorff M, et al., 2011, PMID: 21858002",Both humans and mice exhibit histological abnormalities in skeletal muscles and similar spinal abnormalities.,Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7485529e-a573-4a47-aa0f-7c0d7067ae49-2020-04-27T190000.000Z,1947,PubMed:21858002 +mRNA expression of SEMA4A in different human tissues,Expression A,"Schulz E, et al., 2014, PMID: 25307848",GTEx data show SEMA4A is widely expressed including normal colonic tissue,Score,0 (0.5),Not a colon tissue-specific protein. The expression data is also not necessary to be linked to cancer formation.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_af6942d6-a886-4ef0-a979-bce7a971e111-2024-03-22T170000.000Z,1948,PubMed:25307848 +Bupp_Mouse model,Model Systems Non-human model organism,"Bupp S, et al., 2021, PMID: 34354123","Silica nanoparticles were used to simulate acute HAE attacks as they have been shown to activate FXII. With ACEi captopril pretreatment, intravenous injection of silica nanoparticles induced a reversible decrease in blood pressure and markedly decreased locomotor activity in serping1−/−. Use of ecallantide, an HAE therapeutic agent, prior to injection of silica nanoparticles, showed mitigation of attacks. Vascular permeability in these models were shown to be increased in prior studies (PMID: 11956243).",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_bb571a69-47a6-4e28-a837-b9df492526c9-2022-12-15T170000.000Z,1954,PubMed:34354123 +Drouet_C1Inh function,Biochemical Function B,", , PMID: 35958943","The diagnosis of HAE with C1-INH deficiency (C1-INH-HAE) is established on a decreased C1-INH function. It may be classified as type-1 HAE (HAE-1), where C1-INH-HAE results from the failure to synthesize the protein, or type-2 HAE (HAE-2) where an abnormal, dysfunctional protein is synthesized. Honda et al, 2021 (PMID: 33614375) provide cut-off values for diagnosis of C1-Inh deficiency. C1-INH-HAE shares a common kinin dependency with other HAE situations: F12-HAE, PLG-HAE, ANGPT1-HAE, etc.",Score,1 (0.5),The function of C1-Inh encoded by SERPING1 is well described and the deficiency of the protein is the primary phenotype associated with HAE with C2Inh deficiency.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_bb571a69-47a6-4e28-a837-b9df492526c9-2022-12-15T170000.000Z,1954,PubMed:35958943 +PC12 cell expression of variant neuroserpins,Functional Alteration Non-patient cells,"Miranda E, et al., 2008, PMID: 18267959","The steady-state level of neuroserpin was decreased for variant neuroserpins compared to WT neuroserpin. This seems to be due to ER-associated degradation of S52R and G392E neuroserpin, because three cell lines expressed similar levels of protein when assessed by the pulse-chase analysis. Immunoprecipitation with the 1A10 monoclonal antibody followed by endoglycosidase H digestion showed that there are two different species of neuroserpin that can be differentiated after immunoprecipitation: monomeric wild-type and S52R neuroserpin, which are insensitive to endoglycosidase H diges- tion and run as single bands on non-denaturing PAGE, and polymers of S52R and G392E neuroserpin, which are endogly- cosidase H sensitive and form high molecular mass ladders on non-denaturing PAGE. The trafficking of neuroserpin was then assessed in PC12 cells that were differentiated into neurons by plating on col- lagen and treatment with nerve growth factor prior to the expression of neuroserpin. The distribution of total neuroser- pin was characterized with an anti-neuroserpin polyclonal antibody while neuroserpin polymers were identified with the 7C6 monoclonal antibody. There was strong staining for wild-type neuroserpin in the periphery of the cells and the tips of neurites where it co-localized with chromogranin A, a marker for dense core vesicles. In contrast, G392E neuroserpin was found mainly in the cell body of PC12 cells where it formed punctate accumulations typical of mutant neuroserpin. These inclusions stained positive for both total neuroserpin and neu- roserpin polymers. The analysis of PC12-S52R cells showed a mixture of the staining seen for wild-type and G392E neuroserpin. Wild-type neuroserpin did not co-localize with calreticulin in the ER or ERGIC-53/p-58 in the ER Golgi intermediate compartment (ERGIC) and only some cells showed co-localization with GM130 in the Golgi compartment. G392E neuroserpin co-localized with calreticulin within the ER even when the punctate inclusions were found within the neurites, but there was no co-localization with the ERGIC or Golgi markers. Regulated secretion of neuro- serpin from each cell line upon stimulation with 55 mM KCl for 15 min was assessed. Treatment with Kþ resulted in the secretion of 30% of the wild-type neuroserpin, 20% of S52R neuroserpin (detectable only by ELISA) and no neuroserpin from cells expressing G392E neuroserpin.",Review,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1b31db78-6595-440d-a3f1-b3b5ca361611-2022-06-05T190000.000Z,1955,PubMed:18267959 +COS-7 cell experimental data,Functional Alteration Non-patient cells,"Miranda E, et al., 2008, PMID: 18267959","H338R and G392E variant protein formed punctate inclusions in ER. Unlike Wt neuroserpin that is found in ER as well as Golgi, the H338R and G392E neuroserpin was not detected in Golgi. Digestion of proteins labelled with 35S-methionine and -cysteine with endoglycosidase H showed that WT neuroserpin was undetectable in cell lysate after 6h chase, but found in the media. However, there was an intracellular band of 50 kDa in cells transfected with both mutants of neuroserpin that shifted to 45 kDa after digestion with endoglycosidase H showing that it still contained unmodified poly- mannose N-glycans typical of ER proteins. Wild-type neuroserpin in the culture media contained an additional lower band due to pro- teolysis over the 6 h chase period, while both mutant forms of neuroserpin were resistant to proteolysis due to their polymeric conformation. Non-denaturing PAGE showed that WT neuroserpin is present as a monomer in the media, but H338R, G392E, S49P, and S52R neuroserpins formed polymers in cytoplasm as well as media. the polymer specific monoclonal antibody did not detect WT neuroserpin but detected the variant proteins by immunocytochemistry. There was a correlation of accumulation of intracellular neuroserpin and the severity of the disease.",Review,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1b31db78-6595-440d-a3f1-b3b5ca361611-2022-06-05T190000.000Z,1955,PubMed:18267959 +Drosophila expressing variant neuroserpin,Model Systems Non-human model organism,"Miranda E, et al., 2008, PMID: 18267959",Both Drosophila and humans showed motor deterioration. neuroserpin polymer accumulation seen in the flies is similar to the polymer found in neuroserpin inclusion bodies seen in humans. Also the severity of motor phenotypes and polymer formation in flies correlated well with the severity of human phenotypes.,Review,0 (2),"No seizure phenotypes, Can be used as a variant-level experimental data.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1b31db78-6595-440d-a3f1-b3b5ca361611-2022-06-05T190000.000Z,1955,PubMed:18267959 +SET depletion affects embryonic stem cell differentiation,Functional Alteration Non-patient cells,"Edupuganti RR, et al., 2017, PMID: 28966118","SET depletion slows down cells in the G2/M phase, and SET overexpression increased ESC proliferation rates by ∼1.4-fold. +Additionally, knockdown cells affects cell growth and aberrant neuronal differentiation. SET-knockdown cells failed to upregulate many genes involved in neurogenesis.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_4d7c9aa2-0a9a-4359-af98-6097cc6a3b91-2021-11-17T170000.000Z,1956,PubMed:28966118 +Interactions with proteins involved in ID,Protein Interaction,"Bayarkhangai B, et al., 2018, PMID: 29749127","SET interacts with numerous proteins involved in histone modification, some of which are encoded by known autosomal dominant intellectual disability genes (e.g., CREBBP, CTCF, EP300, KMT2A, SETBP1, RAC1, TREX1) (Table 1). Additional function and related information was reviewed in Uniprot. +SET also interacts with microcephalin (MCPH1) participate in the regulation of chromosome condensation [PMID: 20800572, Kim et al].",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_4d7c9aa2-0a9a-4359-af98-6097cc6a3b91-2021-11-17T170000.000Z,1956,PubMed:29749127 +SET domain-containing histone lysine methyltransferases,Biochemical Function A,"Edmunds JW, et al., 2008, PMID: 18157086","Other genes encoding SET domain-containing histone lysine methyltransferases have also been implicated in neurodevelopmental disorders, including SETD1A (OMIM#: 611052), SETD1B (OMIM#: 611055), and SETD5 (OMIM#: 615743).",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_12443e12-a359-40fb-afbf-b334e9b87b1d-2023-10-04T160000.000Z,1960,PubMed:18157086 +SET domain-containing histone lysine methyltransferases,Biochemical Function A,"Edmunds JW, et al., 2008, PMID: 18157086","Other genes encoding SET domain-containing histone lysine methyltransferases have also been implicated in neurodevelopmental disorders, including SETD1A (OMIM#: 611052), SETD1B (OMIM#: 611055), and SETD5 (OMIM#: 615743).",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c8d0235a-b48e-4609-8c61-09586a83d1f2-2023-10-04T160000.000Z,1961,PubMed:18157086 +Paul_Rescue,Rescue Cell culture model,"Paul BT, et al., 2019, PMID: 31873120","Mitochondrial Fe-S proteins SDHB and ACO2, and cytosolic Fe-S cluster proteins PPAT and POLD1, were all reduced following SFXN4 knockout, as was their activity +Reintroduction of SFXN4 into SFXN4 knockout cells restored protein levels of Fe-S proteins and aconitase activity supporting the attribution of the effects observed to SFXN4 itself. +Hemoglobin synthesis: Induced erythroid differentiation in K562 SFXN4 knockout cells and scrambled controls using sodium butyrate and measured hemoglobin (Hb) levels using non-denaturing electrophoresis. +SFXN4 knockdown substantially reduced hemoglobin levels (sufficient to result in a visible loss of red color in the cell pellets) +Reintroduction of SFXN4 into SFXN4 knockout cells restored hemoglobin synthesis",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_02ff9212-9668-4899-bdc9-b726564aeefe-2023-11-20T170000.000Z,1967,PubMed:31873120 +Paul_Functional alteration (non-patient cells),Functional Alteration Non-patient cells,"Paul BT, et al., 2019, PMID: 31873120","Knock down of SFXN4 in various cell lines affected Fe-S cluster formation, mitochondrial respiratory chain enzyme activity, iron metabolism, and hemoglobin synthesis",Score,1 (0.5),"Knock down of SFXN4 in various cell lines affected Fe-S cluster formation, mitochondrial respiratory chain enzyme activity, iron metabolism, and hemoglobin synthesis",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_02ff9212-9668-4899-bdc9-b726564aeefe-2023-11-20T170000.000Z,1967,PubMed:31873120 +Jackson_Functional alteration (non-patient cells),Functional Alteration Non-patient cells,"Jackson TD, et al., 2022, PMID: 35333655","Knock-out of SFXN4 in a cell line led to isolated complex I assembly defect and showed SFXN4 interacts with the core components of the mitochondrial complex I intermediate assembly (MCIA) complex, and that SFXN4 is required for the incorporation of the ND6 subunit in the ND2 assembly module of complex I",Score,1 (0.5),"Knock-out of SFXN4 in a cell line led to isolated complex I assembly defect and showed SFXN4 interacts with the core components of the mitochondrial complex I intermediate assembly (MCIA) complex, and that SFXN4 is required for the incorporation of the ND6 subunit in the ND2 assembly module of complex I",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_02ff9212-9668-4899-bdc9-b726564aeefe-2023-11-20T170000.000Z,1967,PubMed:35333655 +B cell–specific CIN85 knockout mice,Model Systems Non-human model organism,"Kometani K, et al., 2011, PMID: 21708930","Loss of SH3KBP1 expression in human B cells compromised distinct effector mechanisms of BCR signal transduction that are known to be critical for proper B cell activation. B cell-specific ablation of SH3KBP1 in genetically engineered mice caused the same defects with impaired T cell–independent type II antibody responses (determined by immunization with NP-Ficoll, resulting in barely detectable responses in terms of NP-specific IgM and IgG3) in vivo and diminished IKK-β activation and cellular responses to BCR cross-linking (confirmed by an in vitro kinase assay of the IKK complex).",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3cc42cdd-5484-467b-9e35-7529716114dd-2021-11-16T170000.000Z,1970,PubMed:21708930 +BCR-induced Ca2+ mobilization,Functional Alteration Non-patient cells,"Keller B, et al., 2018, PMID: 29636373","As observed for primary B cells, loss of wild-type CIN85 in DG75 cells strongly compromised BCR-induced Ca2+ mobilization and the signaling-incompetent version of CIN85 completely failed to restore a normal Ca2+ response.",Score,0.5 (0.5),These results reinforce the indispensable role of CIN85 for proper activation of human B cells.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3cc42cdd-5484-467b-9e35-7529716114dd-2021-11-16T170000.000Z,1970,PubMed:29636373 +induction of the NF-κB pathway,Functional Alteration Patient cells,"Keller B, et al., 2018, PMID: 29636373","On BCR stimulation, patient B cells consistently showed moderately reduced Ca2+ flux compared with healthy control B cells and striking differences were, observed for BCR-induced NF-κB activation. Although the majority of CIN85 wild-type B cells had degraded the inhibitor IκBα after 40 min upon BCR ligation, only very few B cells of patient no. 1 showed degradation. Additionally, on CIN85-deficient B cells, BCR-induced CD86 and ICAM-1 up-regulation was diminished.",Score,1 (1),"Loss of CIN85 expression in human B cells compromised distinct effector mechanisms of BCR signal transduction that are known to be critical for proper B cell activation, consistent with the immunodeficiency observed in the patients.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3cc42cdd-5484-467b-9e35-7529716114dd-2021-11-16T170000.000Z,1970,PubMed:29636373 +Rat sciatic nerve immunofluorescence,Expression A,"Vijay S, et al., 2016, PMID: 27068304",Immunofluorescence of rat sciatic nerve shows SH3TC2 expression in Schwann cells,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_8d2b214f-3086-4012-bf4b-a6e651618f0b-2022-02-10T020711.223Z,1972,PubMed:27068304 +Gene replacement therapy in a model of CMT4C neuropathy,Rescue Non-human model organism,"Schiza N, et al., 2019, PMID: 30907403","Treated mice show improved motor performance in rotarod and foot grip test. Morphological analysis of the nerve showed improved myelination, the g-ratio was significantly decreased, and myelin thickness was increased.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_8d2b214f-3086-4012-bf4b-a6e651618f0b-2022-02-10T020711.223Z,1972,PubMed:30907403 +SHANK2 isoforms are differentially expressed in human tissue,Expression A,"Leblond CS, et al., 2012, PMID: 22346768","Figure 1. Genomic structure, isoforms, and expression of human SHANK2.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_911cb9ff-e68e-4b47-8639-f6a63ab11b3e-2019-07-17T160000.000Z,1974,PubMed:22346768 +review on the available SHANK2 Mouse models(n=10),Model Systems Non-human model organism,"Eltokhi A, et al., 2018, PMID: 30072871",SHANK2 mouse models show cognitive and social impairments (Autistic like behavior),Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_911cb9ff-e68e-4b47-8639-f6a63ab11b3e-2019-07-17T160000.000Z,1974,PubMed:30072871 +iPSC cells from affected individuals with SHANK2 variants,Model Systems Cell culture model,"Zaslavsky K, et al., 2019, PMID: 30911184",It is not clear how to compare the cell culture phenotype to human phenotype; however the effect of the mutation seems to affect the cortical neuron properties.,Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_911cb9ff-e68e-4b47-8639-f6a63ab11b3e-2019-07-17T160000.000Z,1974,PubMed:30911184 +Spine induction,Functional Alteration Non-patient cells,"Durand CM, et al., 2012, PMID: 21606927","To analyze the role of Shank3 in actin cytoskeleton +regulation in dendritic spines, we overexpressed the different constructs in hippocampal neurons and studied their effects on the organization and shape +of postsynaptic spines. +Overexpression of Shank3WT significantly increased the +number of spines compared with the control and reduced the number of filopodia +in rat hippocampal neurons. However, the overexpression of +Shank3STOP had a reduction in +the number of spines compared with Shank3WT and +with the control (2.6±0.2 spines per 20 mm; +P < 0.001 compared with Shank3WT and P < 0.05 compared with the control).",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e941703a-0f30-4f4c-a997-bc3b4295f289-2018-12-12T170000.000Z,1975,PubMed:21606927 +Dendritic tree analysis,Functional Alteration Non-patient cells,"Cochoy DM, et al., 2015, PMID: 26045941","To assess neuronal morphology of transfected neurons, we +first analyzed the dendritic tree. Subsequent Sholl analysis showed that +dendritic tree complexity was identical in Control and with +overexpressed SHANK3. However, overexpression +of either G1527A or 2497delG resulted in a much +lower complexity of the dendritic tree when compared to +either Control or SHANK3 indicating +severely impaired dendritic branching. +Further assessment of neuronal morphology included +the evaluation of spines and filopodia among secondary dendrites of transfected neurons. Overexpression +of either G1527A or 2497delG resulted in a +strong reduction in spine density when compared to either +Control or SHANK3, while filopodia density +remained unchanged.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e941703a-0f30-4f4c-a997-bc3b4295f289-2018-12-12T170000.000Z,1975,PubMed:26045941 +Autistic behavior rescue,Rescue Non-human model organism,"Mei Y, et al., 2016, PMID: 26886798","Because striatal defects have been strongly linked +to repetitive and compulsive behaviours and Shank3 KO mice show +signs of overgrooming, we filmed WT, TM and KO mice after treatment, +and quantified their grooming time. The results indicated that +while there was a significant increase in the percentage of time spent +grooming in the KO mice compared to WT mice, TM mice exhibited a +significantly reduced grooming time. +In addition, during the +tamoxifen treatment, we noticed that some Shank3fx/fx:CreER+/− mice that had initially developed lesions began to heal and regrow their lost +fur, providing further support that the repetitive/excessive grooming +phenotype is reversible in the Shank3fx/fx mice.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e941703a-0f30-4f4c-a997-bc3b4295f289-2018-12-12T170000.000Z,1975,PubMed:26886798 +Mouse model,Model Systems Non-human model organism,"Wang X, et al., 2016, PMID: 27161151","Mice presented with behavioral phenotypes that resemble features of SHANK3-related ASDs and PMS, such as increased repetitive behaviors, impaired USV communication and +aberrant social behaviors, as well as common comorbidities associated with SHANK3 deficiency.",Score,1 (2),Downgraded as only ID/Autism phenotypes reported for mouse model.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e941703a-0f30-4f4c-a997-bc3b4295f289-2018-12-12T170000.000Z,1975,PubMed:27161151 +Improved Mouse Model,Model Systems Non-human model organism,"Drapeau E, et al., 2018, PMID: 30302388","Mice showed increased anxiety and hyper-reactivity to novel stimuli, +increased escape behaviors, and increased repetitive behaviors. +Together with the increased freezing behavior in the cued fear conditioning, this suggest a dysregulation of amygdala circuitry that will require further investigation. In +addition, our mice displayed impairments in several hippocampal-dependent learning and memory tests as well as cognitive inflexibility, thus recapitulating ID and +insistence on sameness observed in autism and in the majority of patients with PMS. Although PMS patients are heterozygous for Shank3 mutations/deletions, most of the +previous models have failed to demonstrate any relevant phenotype in heterozygous animals. Here, we were able to observe an intermediate phenotype for heterozygous mice in several of the parameters tested, notably in the open field, rotarod, startle response, escape behavior, +reversal probe test, and elevated zero-maze. Our findings are consistent with recent results from an independent model also generated by disrupting all Shank3 isoforms (Wang et al., 2016).",Score,1.5 (2),"Downgraded as only ID/Autism phenotypes were reported for mouse model, but scored higher than earlier independent mouse model since heterozygotes were more rigorously phenotyped.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e941703a-0f30-4f4c-a997-bc3b4295f289-2018-12-12T170000.000Z,1975,PubMed:30302388 +Behavioral study,Model Systems Non-human model organism,"Zapata J, et al., 2017, PMID: 28262662","Human patients had seizures, delayed or no speech, hyperactivity, and intellectual disability. Knowndown of Shrm4 in rat hippocampus led to anxiety-like behavior, reduced sociability, and susceptibility of seizures. Learning and memory was not assessed in this rat model.",Score,0 (2),"Learning and memory were not assessed in the rat model, which is key to the patient phenotypes. Additionally, because there is no convincing human evidence, the ID/Autism GCEP decided not to score this evidence on 1/6/2021.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a94d20f8-9909-48b2-9860-d17c6dc73ec3-2021-01-13T170000.000Z,1976,PubMed:28262662 +Rescue of mouse cortical migration defect with hSIL1,Rescue Non-human model organism,"Inaguma Y, et al., 2014, PMID: 24473200","In the first part of this study, Sil1 was knocked down using RNAi electroported into the ventricular zone of mouse brain at E13. This was shown to delay cortical migration of neurons. Rescue experiments were performed using human SIL1 as it was shown to be resistant to the RNAi vector pSUPER-mSIL1#1. pCAG-EGFP and RNAi vector pSUPER-mSIL1#1 were co-electroporated along with pCAG-Flag-hSIL1 to investigate whether the impact on cortical migration could be rescued. +The positional defects caused by SIL1-knockdown were rescued at P0 (Fig 5Aa–c). In contrast, expression of the SIL1 variants identified in patients (Flag-SIL1-7G, -SIL1-L457P or -SIL1-15del) was unable to rescue the migration defects (Fig 5Ac–f).",Score,0.5 (2),"The score is reduced because this study focusses on only one aspect of the MSS phenotype. However, it does provide support of the role of Sil1 in cortical neuron migration, and hence may explain the intellectual disability phenotype in MSS.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3511d4dd-48bc-4d93-9b86-16bf46fabc5d-2023-12-05T170000.000Z,1977,PubMed:24473200 +SIL1 RNAi knock down and cortical neuron migration defect,Model Systems Non-human model organism,"Inaguma Y, et al., 2014, PMID: 24473200","SIL1 knockdown in the cerebral ventricular zone of mice on embryonic day 13, using RNAi, was shown to delay postnatal migration of cortical neurons, which reached the appropriate locations 7 days later than controls. At postnatal day 7, some of these neurons were noted to be multipolar and to form fewer connections than normal, resulting in reduced interhemispheric axonal projections beyond the corpus callosum. However, a typical network between the two hemispheres established at p30. The authors suggest that the delayed neuronal migration and inter-hemispheric axon development noted here may contribute to intellectual disability in MSS (PMID: 31701543).",Score,0.5 (2),"Score is reduced because the study focuses on only one aspect of the MSS phenotype, but it does show a possible mechanistic link between Sil1 function in cortical migration and MSS phenotype.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3511d4dd-48bc-4d93-9b86-16bf46fabc5d-2023-12-05T170000.000Z,1977,PubMed:24473200 +BOR Mouse,Model Systems Non-human model organism,"Bosman EA, et al., 2009, PMID: 19389353","The mouse model exhibited head-bobbing behavior, vestibular dysfuntion, and hearing loss. Mice also displayed unilateral hypoplastic kidney and a lack of hair cells in the cristae ampulari and cochlea.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e2587f3b-52e1-4765-a9ac-82d8cc5ae45b-2017-06-22T160000.000Z,1979,PubMed:19389353 +Eckard_Functional Alteration,Functional Alteration Patient cells,"Eckard SC, et al., 2014, PMID: 25064072","They found that SKIV2L-deficient THES patients had a type I IFN signature that was even more robust than the mean ISG scores in AGS patients, while there was no evidence for an IFN signature in the three THES patients with TTC37 mutations",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_53d69181-61b3-4393-ae46-bd68307a98f1-2024-04-23T160000.000Z,1981,PubMed:25064072 +Cryo-EM of human SKI complex,Protein Interaction,"Kögel A, et al., 2022, PMID: 35120588","Ski3 (encoded by SKIC3) together with Ski2 (encoded by SKIC2), and Ski8 proteins assemble with a 1:1:2 stoichiometry to form a stable tetrameric assembly both in vivo and in vitro (Brown et al., 2000; Halbach et al., 2013; Synowsky and Heck, 2008). +Cryo-EM structural analysis of the purified human SKI (hSKI) showed that the hSKI3C arm wraps around the hSKI2N domain (Figure 2B, left panel). The hSKI2N domain is an extended region that can be subdivided into individual segments (Figure 2C). +The first (‘‘inner’’) segment of hSKI2 (hSKI2 residues 1–121) binds inside the superhelical axis of hSKI3C with sparse secondary structure elements, spanning almost the entire length of the solenoid and forming an integral part of its hydrophobic core (Figure 2B). +Variants in SKIC2 (SKIV2L) gene have been reported to cause syndromic diarrhoea, or trichohepatoenteric syndrome (Fabre et al 2012; PMID: 22444670; GenCC classifications: 1 definitive, 2 strong, 1 moderate, 1 supportive (as of 9 Apr 2024)",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0e528747-17dd-4c07-95cb-de05ad840740-2024-04-23T160000.000Z,1982,PubMed:35120588 +Double-knockout of zebrafish KCC2a and KCC2b,Model Systems Non-human model organism,"Stödberg T, et al., 2015, PMID: 26333769",The motor deficit is observed in both zebrafish and humans.,Review,0 (2),It is not clear whether the jerky spasms noted in the zebrafish were a result of seizures or not.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_768a3318-a75d-412a-91e6-78d51609ac3e-2023-03-07T170000.000Z,1983,PubMed:26333769 +Electrophysiology of KCC2 variants in HEK293 cells,Functional Alteration Non-patient cells,"Stödberg T, et al., 2015, PMID: 26333769","Pressure application of glycine evoked large inward currents (IGly) in eGFP-positive cells held at –80 mV. The IGly amplitude varied linearly with the holding potential and reversed in polarity. Fitting the I–V relationship, cells transfected with both GlyR a2 and wild-type KCC2 yielded a more hyperpolarising ECl than cells solely expressing GlyR a2, consistent with Cl extrusion by KCC2. KCC2 mutants, however, exhibited a depolarized ECl relative to wildtype KCC2. The estimated ECl for all three mutants was similar and did not differ significantly from that in cells solely expressing GlyR a2 and eGFP (Fig. 3c), consistent with passive equilibration of Cl ions as predicted from the pipette and extracellular solutions. To further explore impaired mutant KCC2 +activity, we measured the rate at which ECl recovers to a starting value after a period of chloride load, as described previously. Glycine was applied every 30 s while holding cells at 80 mV +then at þ 40 mV to load them with Cl. When the holding potential was reset to 80 mV, glycine-evoked currents were larger due to the increased driving force. In cells transduced with wild-type KCC2, glycine-evoked currents IGly returned to the initial amplitude consistent with transporter-mediated extrusion of chloride. The rate at which IGly amplitude recovered for the +three KCC2 mutants was much slower. The recovery rate in cells expressing L426P and G551D mutants was not significantly different from cells expressing only GlyR a2 and eGFP, consistent with near complete loss of KCC2 function. The recovery rate for the L311H mutant was intermediate, suggesting some residual KCC2 activity.",Review,0 (0.5),This is variant-level functional evidence.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_768a3318-a75d-412a-91e6-78d51609ac3e-2023-03-07T170000.000Z,1983,PubMed:26333769 +Glycosylation and expression changes of KCC2 variants,Functional Alteration Non-patient cells,"Stödberg T, et al., 2015, PMID: 26333769","When compared with wild-type, the mutants L311H, L426P and G551D showed significantly reduced KCC2 expression at the cell surface versus total (whole-cell lysate) expressed transporter. The proportion of wild-type KCC2 existing in the glycosylated state was 50% at the surface and 43% in whole-cell lysate; significantly lower proportions were observed for all three mutants at both the cell surface and in total cell lysates. +Immunostaining of permeabilised cells revealed that all three mutants were overall +expressed at similar levels to wild-type KCC2. However, while wild-type KCC2 was robustly detected at the surface of intact cells, much less KCC2 was detected in cells +expressing KCC2-L311H, -L426P and -G551D.",Review,0 (0.5),This is a variant-level functional study.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_768a3318-a75d-412a-91e6-78d51609ac3e-2023-03-07T170000.000Z,1983,PubMed:26333769 +Electrophysiology of KCC2 variants in HEK293 cells,Functional Alteration Non-patient cells,"Saitsu H, et al., 2016, PMID: 27436767","To determine whether individual KCC2 mutants contributed equally to the reduction, we also measured and compared ECls in cells only transfected with one type of KCC2 mutant. We found that the ECls in cells expressing the E50_Q93del mutant in individuals 1 and 2 (−36.5±3.1 mV, n=12) and in the cells expressing the M415V mutant in individual 3 (−26.5 ± 3.2 mV, n = 10) were much more positive than that in WT-expressing cells (−53.6±3.8mV, n=11). The ECls in cells expressing the A191V mutant in individuals 1 and 2 (−45.2±3.7mV, n=10) and in the cells expressing the S323P mutant in individual 3 (−47.8±3.5mV, n=10) also seemed to be +more positive than that in WT-expresing cells, but did not reach statistical significance.",Review,0 (0.5),"This is a variant-level functional study. In addition to the above variants, p.E50_Q93del was also tested, because the RNA study showed that c.279+1G>C results in p.E50_Q93del.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_768a3318-a75d-412a-91e6-78d51609ac3e-2023-03-07T170000.000Z,1983,PubMed:27436767 +Vernau 2013 Paper,Model Systems Non-human model organism,"Vernau KM, et al., 2013, PMID: 23469184",Leigh syndrome,Score,4 (2),"Neuropathological, MRI, biochemical, and neurocognitive differences consistent with Leigh syndrome spectrum",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e3907183-4cb2-4df7-bace-ecc1821b3acc-2019-01-14T170000.000Z,1988,PubMed:23469184 +SLC1A3 Knock-In Mice,Model Systems Non-human model organism,"Kovermann P, et al., 2020, PMID: 32954283","The first set of mutant knock-in mice were subject to generalized seizures and death before the weaning period, requiring a backcross onto the 129/SvJ strain in order to reduce lethal seizure activity and delay the onset. Even so, mutant mice demonstrated significant phenotypes indicative of human Episodic Ataxia including epilepsy, ataxia, and reduced motor/gait coordination. In order to determine the pathogenc mechanism, cerebellar Bergmann glia cells were examined to find a pronounced age-dependent reduction of cell numbers between P10 and P20. Immunostaining showed decreased numbers of somata and expression, demonstrating that the EAAT1 mutants were subject to cell death. Granule cell migration was also impaired during development, coupled with invasion of reactive astrocytes into the molecular layer demonstrating attempted repair. Following from this change, Purkinje neurons were examined and found to have been reduced and the morphology altered in mutant mice. As the P290R variant is known to increase EAAT1 anion currents in heterologous expression systems, measurement of these currents in mouse Bergmann glia cells showed significantly increased current, decreased Cl- concentration, and a resulting higher TUNEL expression in these cells, indicating earlier apoptosis events of these cell types. Spiking activities and developmental acceleration is absent in these cell types, likely due to progressive deterioration. This was verified by an observation of cerebellar size, where mutant cerebellar tissue showed generalized degeneration compared to the WT mice.",Score,3 (2),"This knock-in of a known pathogenic human variant model clearly recapitulates the important phenotypes of the Episodic Ataxia Type 6, with seizures, ataxia, and migraine neurological signs all being observed in these organisms. The authors also provide further investigation into the pathogenic mechansim, supporting a gain-of-function with increased anion currents leading to Bergmann glia cell degeneration and apoptosis. As this model recapitulates both the phenotypes and likely mechanism of the human disorder, it receives increased points.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3bcae41b-3438-4e82-8f29-83cca7f142f0-2020-10-09T160000.000Z,1990,PubMed:32954283 +EAAT1 mRNA and Protein Expression,Expression A,"Kovermann P, et al., 2020, PMID: 32954283","Northern blot analysis of RNAs from a variety of human tissues was performed to characterize the expression of each glutamate transporter. Hybridization with an EAAT1 probe revealed RNA expression in all five surveyed areas of the brain tissue, but also in some other unrelated tissues such as the heart and muscle. Human Protein Atlas agrees that there is minimal expression of RNA in several human tissues, however there is no recorded expression of EAAT1 protein itself anywhere except all areas of the brain (specifically the cerebral cortex and cerebellum).",Score,0.5 (0.5),"As there is unique expression of the EAAT1 transporter localized to all areas of the brain, specifically supporting the neurological function, this evidence earns default points.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3bcae41b-3438-4e82-8f29-83cca7f142f0-2020-10-09T160000.000Z,1990,PubMed:32954283 +Rasmussen2014,Functional Alteration Patient cells,"Rasmussen J, et al., 2014, PMID: 27896095","A significant positive correlation was found between free carnitine levels and residual OCTN2 transporter activities in cultured skin fibroblasts from patients with four different PCD genotypes (R2 = 0.430, p < 0.01).",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_2beee8a9-193c-41ca-92c4-484c8e034b02-2018-04-24T160000.000Z,1992,PubMed:27896095 +Chaouch_Zebrafish,Model Systems Non-human model organism,"Chaouch A, et al., 2014, PMID: 26870663","Knockdown of neuromuscular junction proteins usually affects motility and swimming behaviour of injected embryos. Indeed, MO-injected embryos displayed altered tail morphology, and swimming and touch-evoked escape responses at 48 hpf were impaired. +Histologically, we observed normal muscle morphology while NMJ development was abnormal. Motor axon terminal showed short and erratic outgrowth toward the muscle fibre with no evidence of complete synapse formation, pointing towards an underlying presynaptic defect. NMJ morphology and function were normal in embryos injected with a standard control MO and in noninjected wild type embryos. In addition, knockdown embryos often showed oedema of the hindbrain, heart, yolk sac and tail. Abnormal heart development was observed with increased severity of phenotype with reduced blood flow to the tail. Knockdown embryos displayed these characteristics in both the presence and absence of the apoptotic suppressing anti-p53 MO",Score,2 (2),2 (phenotype recapitulation),https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_efd22051-13dc-49ed-b8cd-ded1d67f2bf1-2023-12-18T170000.000Z,1995,PubMed:26870663 +Pop_Rescue,Rescue Patient cells,"Pop A, et al., 2018, PMID: 29238895","Transfection of SLC25A1−/− fibroblasts (Patient 9 from Nota et al., 2013) with wild-type SLC25A1 not only restored SLC25A1 levels, as detected by immunoblotting but also resulted in the expected increase of citrate efflux (by > 3-fold compared with cells transfected with an empty vector), accompanied by decreased intracellular D-2-HG and L2-HG levels.",Score,0.5 (1),Biochemical rescue,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_efd22051-13dc-49ed-b8cd-ded1d67f2bf1-2023-12-18T170000.000Z,1995,PubMed:29238895 +Li_Drosophila,Model Systems Non-human model organism,"Li H, et al., 2018, PMID: 30108060",biochemical phenotype recapitulated,Score,0.5 (2),0.5 (biochemical phenotype recapitulation),https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_efd22051-13dc-49ed-b8cd-ded1d67f2bf1-2023-12-18T170000.000Z,1995,PubMed:30108060 +Inflammatory Myopathy in German Shepherd Dogs,Model Systems Non-human model organism,"Shelton GD, et al., 2019, PMID: 31594244","he transport activity of the p.L349P AGC1 mutant was measured upon reconstitution of purified recombinant protein into liposomes. As shown in Fig. 4C, the substitution of L349 with proline causes a strong impairment of transport activity compared to WT AGC, as the mutant form of AGC1 was unable to transport aspartate or glutamate in exchange with internal glutamate.",Score,0 (2),GCEP elected to exclude for current curation given deviation from phenotype reported in patients to date,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_47bba424-b4e3-4216-aae0-2a4602bc2e92-2023-08-21T160000.000Z,1997,PubMed:31594244 +Malate: Aspartate shuttle Genes Functions,Biochemical Function A,"Pardo B, et al., 2022, PMID: 35008954","GOT2, MDH2 are both on the mitochondrial side of the malate aspartate shuttle +Both conditions are associated with developmental epileptic encephalopathies in OMIM (not yet curated by Mito GCEP)",Score,1 (0.5),Score 1 point for 2 genes in the same pathway implicated in similar phenotypes,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_47bba424-b4e3-4216-aae0-2a4602bc2e92-2023-08-21T160000.000Z,1997,PubMed:35008954 +Testing +5 splice variant,Functional Alteration Patient cells,"Zhang ZH, et al., 2014, PMID: 24586645","Isolated and reverse transcribed mRNA from peripheral blood lymphocytes from the proband and his parents. Performed PCR of resulting cDNA with primers that anneal to sequences in exons 5 and 8 followed by agarose gel electrophoresis and sequencing of the amplification products. +The patient and his mother both had two bands of 503 bp and 2292 bp, while his father just one band of 503 bp. The 503 bp product had expected normal sequence, while the entire intron 6 (1789 bp) of SLC25A13 gene, along with the mutation c.615+5G.A, was retained in the 2292 bp product. The aberrant mRNA molecule with intron 6 retention, r.[615+1_615+ 1789ins; 615+5g.a] caused a frame shift from codon 206, added 6 amino acids, and produced a premature termination (TAA from the inserted sequence) at codon 212, thus forming a truncated citrin molecule p.Ala206Valfs212X.",Score,0.5 (1),The variant tested was not deposited in ClinVar,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_bc373b9e-ec5e-4471-92a1-bbdd9aa3378c-2021-07-23T220742.579Z,1998,PubMed:24586645 +Inhibition of SLC25A22 in Rat Astrocytes,Model Systems Cell culture model,"Goubert E, et al., 2017, PMID: 28620281","GC1 was silenced in rat C6 glioma cells using short hairpin RNA (shRNA). Silencing GC1 in C6 resulted in a reduction of the GC1 mRNA combined with a decrease of the mitochondrial glutamate carrier activity, similar to what is observed in human fibroblasts of affected patients. Primary astrocyte cultures from rat cortical cortices were used to study the biochemical consequences of GC1 inhibition. It abolishes NAD(P)H production upon glutamate stimulation, the mitochondrial respiratory chain (MRC) is fully activated by glucose but not by glutamate resulting in a decrease of the cytosolic ATP level, and results in intracellular glutamate accumulation.",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e9a7ba06-6ddf-4a94-a0df-0b6c164f72b9-2020-05-19T160000.000Z,2001,PubMed:28620281 +Drosophila variant models x3,Model Systems Non-human model organism,"Rosenberger FA, et al., 2021, PMID: 33608280","Each mutation impaired SAM flux into mitochondria and lowered mitoSAM levels (Fig. 1A and fig. S1E) with null having the lowest mitoSAM level +Only the null and p223l mutations caused larval lethality (Fig. 1B) where we observed respiratory chain dysfunction (Fig. 1C and fig. S1F), markedly reduced CoQ9 steady-state levels (Fig. 1D), and impaired lipoic acid metabolism (Fig. 1E) - the null and the P223L show virtually no lipoylated PDC",Score,2 (2),0.5x3 (three variants all with decreased mitoSAM similar to null) + 0.5 (p.P223L with larval lethality similar to null),https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5e91c575-34b9-4142-8492-5fbbdb95066f-2023-07-31T160000.000Z,2002,PubMed:33608280 +Conditional knock out of Slc25a26 in mice,Model Systems Non-human model organism,"Rosenberger FA, et al., 2021, PMID: 33608280","Hemizygous KO mice (Slc25A26+/−) were viable and fertile, while homozygous disruption (Slc25A26−/−) was embryonically lethal (Fig. 2A). Imaging of mitochondrial ultrastructure revealed swollen organelles with highly irregular cristae and large intramitochondrial vacuoles in SAMC KO cells (fig. S2D). +Proteomics showed a profound mitochondrial defect affecting both mitochondrial translation and OXPHOS (fig. S2, E and F) with both nuclear and mitochondrial encoded subunits of complexes I, III, and IV severely decreased (fig. S2, G and H). Complex I, III, and V assembly (Fig. 2B and fig. S2I) and isolated respiratory chain enzyme activities were markedly affected +Consistent with fly and human data (9), protein lipoylation on pyruvate dehydrogenase and α-ketoglutarate dehydrogenase was not detectable in SAMC KO cells",Score,2 (2),0.5 (embryonic lethality in KO) + 0.5 (combined OXPHOS defect by BN PAGE) + 0.5 (combined OXPHOS defect by RC analysis) + 0.5 (decreased protein lipoylation of pdh and akgdh),https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5e91c575-34b9-4142-8492-5fbbdb95066f-2023-07-31T160000.000Z,2002,PubMed:33608280 +Patient Cell Studies,Functional Alteration Patient cells,"Thompson K, et al., 2016, PMID: 27693233","Mitochondrial respiratory chain activities in subjects 1, 2, and 5 showed decreased complexes I, III, and IV with a compensatory increase in Complex II. Subject 3 showed decreased complex I and IV with normal combined Complex II+III. Subject 6 had decreased Complex IV and decreased combined Complex II+III. qPCR revealed mtDNA depletion in all patients: Patients 1, 2 (<5% of controls) and Patients 3,5,7 (11-34% of controls)",Score,1.5 (1),More than one patient cell/tissue demonstrating mitochondrial alterations. (Score 1.5 pts),https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0a6890a4-e2d5-4895-956d-3f3103ec6a2b-2021-06-14T151738.675Z,2004,PubMed:27693233 +Lactococcus lactis Transport activity,Model Systems Non-human model organism,"Thompson K, et al., 2016, PMID: 27693233","Both the p.Arg80His and p.Arg235Gly alterations had severe effects on transport activity with residual transport rates of 24% and 3%, respectively (Figure 4B).",Score,0.5 (2),abnormal mito transport in bacterium studies,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0a6890a4-e2d5-4895-956d-3f3103ec6a2b-2021-06-14T151738.675Z,2004,PubMed:27693233 +Yeast Complementation Studies,Model Systems Non-human model organism,"Thompson K, et al., 2016, PMID: 27693233",Neither of the mutant strains were able to on ethanol or glycerol indicating that the mutant alleles were not able to complement thee OXPHOS defect of the aac-null mutants.,Score,0.5 (2),Reduced points as model system was yeast. Complementation studies support pathogenicity.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0a6890a4-e2d5-4895-956d-3f3103ec6a2b-2021-06-14T151738.675Z,2004,PubMed:27693233 +Mitochondrial DNA maintenance gene,Biochemical Function A,"Rahman J, et al., 2017, PMID: 27977873","Per Leigh map, POLG, SUCLA2, SUCLG1, FBXL4 associated with mtDNA maintenance. Also RNASEH1",Score,1 (0.5),5 other genes associated with LSS = 1 point,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0a6890a4-e2d5-4895-956d-3f3103ec6a2b-2021-06-14T151738.675Z,2004,PubMed:27977873 +SLC25A46 function,Biochemical Function A,"Abrams AJ, et al., 2015, PMID: 26168012","SLC25A46 plays a role in mitochondrial dynamics (PMID: ). According to Leigh map, one other protein involved in mitochondrial dynamics has been implicated in causing Leigh Syndrome (DNM1L) (Rahman 2017 PMID: 27977873). Therefore, the function of SLC25A46 is shared with one other known gene in the disease of interest.",Score,0.5 (0.5),The SLC25A46 encoded protein shares a biochemical relationship or function with 1 gene product whose dysfunction is known to cause Leigh syndrome (Awarded 0.5 pt),https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6e456b6d-7a9b-42d2-ab51-0531f5184b41-2020-08-27T163757.565Z,2005,PubMed:26168012 +SLC25A46 Zebrafish model,Model Systems Non-human model organism,"Abrams AJ, et al., 2015, PMID: 26168012",The SLC25A46 knockdown zebrafish model demonstrates a neurodevelopmental phenotype including alterations in swimming indicative of neuronal circuit dysfunction which recapitulates some of the neurological/neurodevelopmental symptoms seen in Leigh syndrome.,Score,0.5 (2),The SLC25A46 knockdown zebrafish model demonstrates a neurodevelopmental phenotype including alterations in swimming indicative of neuronal circuit dysfunction which recapitulates some of the neurological/neurodevelopmental symptoms seen in Leigh syndrome. Scored 0.5 for a neurodevelopmental phenotype as per scoring rubric.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6e456b6d-7a9b-42d2-ab51-0531f5184b41-2020-08-27T163757.565Z,2005,PubMed:26168012 +SLC25A46 Bovine model,Model Systems Non-human model organism,"Duchesne A, et al., 2017, PMID: 28376083","The bovine model recapitulates a neurological phenotype (swaying of the hindquarters during standing or walking, which regularly led to losing balance, spinning on forelimbs, and falling) and neuropathological phenotype (Microscopic lesions were consistently observed in the spinal cord and in the peripheral nerves of all 9 affected calves. Lesions also were found in the brainstem and in thoracic nuclei in 6 calves) that can be correlated to Leigh syndrome.",Score,1.5 (2),Scored 0.5 pts for the neurological abnormalities and the 1 pt for the neuropathological changes identified for a total of 1.5 pts. Scoring rubric was used for guidance.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6e456b6d-7a9b-42d2-ab51-0531f5184b41-2020-08-27T163757.565Z,2005,PubMed:28376083 +atc/atc SLC25A46 mouse model,Model Systems Non-human model organism,"Terzenidou ME, et al., 2017, PMID: 28376086",This mouse model recapitulates some of the neurodevelopmental features seen in Leigh syndrome as well as premature mortality.,Score,1 (2),"The mouse model demonstrated a pronounced neurological and neurodevelopmental phenotype including ataxia, unsteady locomotion, tonic-clonic seizures, limb-clasping during tail suspension, reduced muscle strength, and growth retardation with premature lethality (Score 1 pt).",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6e456b6d-7a9b-42d2-ab51-0531f5184b41-2020-08-27T163757.565Z,2005,PubMed:28376086 +Zebrafish SLC25A46 knockdown,Model Systems Non-human model organism,"Abrams AJ, et al., 2015, PMID: 26168012",Embryos had fewer retinal ganglion cell axons that reached the tectum by 72 hpf. Motor neurons had significantly shorter axons tracts. Axonal blebbing and degeneration was observed at the morphant motor neuron terminals,Score,1.5 (2),Morpholino model and not stable knockdown.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9852fb40-0df1-4668-ba57-38a4971cb244-2020-05-26T160000.000Z,2006,PubMed:26168012 +Mitochondrial fusion/fission dynamics,Biochemical Function A,"Abrams AJ, et al., 2015, PMID: 26168012",MFN2 plays a major role in mitochondrial fusion. MFN2 deficient cells have abnormal fragmented mitochondria.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9852fb40-0df1-4668-ba57-38a4971cb244-2020-05-26T160000.000Z,2006,PubMed:26168012 +Drosophila dSLC25A46a knockdown,Model Systems Non-human model organism,"Ali MS, et al., 2020, PMID: 32140609","Pan-neuron-specific dSLC25A46a knockdown resulted in impaired motility in both larvae and adults. At neuromuscular junctions, it was found an aberrant morphology, mitochondrial hyperfusion, together with the accumulation of reactive oxygen species and reductions in ATP.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9852fb40-0df1-4668-ba57-38a4971cb244-2020-05-26T160000.000Z,2006,PubMed:32140609 +shRNA knockdown,Functional Alteration Non-patient cells,"Park JH, et al., 2014, PMID: 25373420","ShRNA knockdown of Slc26a2 caused decreased proliferation of chondrocytes (differentiated from mouse progenitor mesenchymal cells) and reduced basal proteoglycan synthesis, possibly by inhibiting the effect of IGF-1 on synthesis.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_311c9799-169e-4409-98bd-74b6d414904c-2020-06-01T160000.000Z,2007,PubMed:25373420 +Expression in mouse articular cartilage,Expression A,"Park JH, et al., 2014, PMID: 25373420",Immunohistochemistry showed that Slc26a2 was expressed in the chondrocytes of freshly isolated mouse articular cartilage explants.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_311c9799-169e-4409-98bd-74b6d414904c-2020-06-01T160000.000Z,2007,PubMed:25373420 +Expression in mouse articular cartilage,Expression A,"Park JH, et al., 2014, PMID: 25373420",Immunohistochemistry showed that Slc26a2 was expressed in the chondrocytes of freshly isolated mouse articular cartilage explants.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_392a7ac1-7ef5-45c7-97e0-2c1c1bd7884d-2020-08-03T160000.000Z,2008,PubMed:25373420 +Knockout mouse,Model Systems Non-human model organism,"Zheng C, et al., 2019, PMID: 30685387","Features such as short and thick neck, small chest, short limbs, protuberant abdomen, hypoplasia of the long bones, and short ribs are consistent with the presentation of ACG1B in humans.",Score,1 (2),"The EP decided to downgrade this model to 1 point because while it was a complete knockout, it did not completely recapitulate the human phenotype (for example, accelerated ossification of vertebral bodies was inconsistent with ACG1B).",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_392a7ac1-7ef5-45c7-97e0-2c1c1bd7884d-2020-08-03T160000.000Z,2008,PubMed:30685387 +Expression in mouse articular cartilage,Expression A,"Park JH, et al., 2014, PMID: 25373420",Immunohistochemistry showed that Slc26a2 was expressed in the chondrocytes of freshly isolated mouse articular cartilage explants.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_da79a651-9fc7-453e-a1c1-145771baa2f9-2020-07-14T160000.000Z,2009,PubMed:25373420 +Mouse c.919-A>G model,Model Systems Non-human model organism,"Lu YC, et al., 2011, PMID: 21811566","This mutation leads to the loss of exon 8 and a prematurely truncated protein. The mouse had similar phenotype to the model in Everett 2001, including profound hearing loss, vestibular disfunction, enlarged vestibular aqueduct, and hair cell degeneration.",Score,1.5 (2),Downgraded to 1.5 points for the same reason as Everett 2001- the mouse model had no abnormal thyroidal phenotype.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_49e794f4-8725-4499-a0a2-82591b42cab5-2017-06-07T040000.000Z,2010,PubMed:21811566 +SLC29A3 KO mouse model,Model Systems Non-human model organism,"Nair S, et al., 2019, PMID: 31270333","Many phenotypes at the organ/organismal level including stunted growth, hypertrichosis, skeletal deformities, hypogonadism, hepatosplenomegaly, and lymphadenopathy and also at the cellular level including hystiocytosis were similar to disease in humans and this model is consistent mode of inheritance.",Score,3 (2),Many phenotypes consistent with human disease both at the organ and cellular levels. PMID: 22174130 is another KO model that supports the phenotype at the organ and cellular levels showing severe histiocytosis.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_cdde7d77-09cc-4ef2-99eb-f9acd8c8df04-2024-05-07T160000.000Z,2011,PubMed:31270333 +Nakamura_Rescue,Rescue Non-human model organism,"Nakamura S, et al., 2017, PMID: 28119822","Heterozygous Glut1-deficient mice perform poorly on Rotarod tests. Rotarod tests of mice injected with AAV-hSLC2A1 showed that motor function improved, irrespective of administration route, compared to untreated Glut+/- mice. At 4 weeks post ICVI, motor function was significantly improved to the level of wild-type mice. Footprint tests showed no difference between treated and untreated mice. +Measurement of CSF and blood glucose levels showed that CSF glucose levels were partially restored and CSF/blood glucose ratio was significantly elevated in treated mice (87.5 ± 12.1 mg/dL, 0.495) compared to untreated mice (71.3 ± 4.3 mg/dL, 0.42). Levels in wild-type = 92.4 ± 7.9 mg/dl, 0.69 ± 0.05.",Score,1.5 (2),"The evidence is scored reduced points since the human wild type (96% homology to mouse Slc2a1) is shown to rescue the model phenotype. Also, the paper does not discuss rescue of the seizure phenotype in mice. +Note: PMID: 29624790 by the same group uses the AAV vector using the human endogenous SLC2A1 promoter instead of synapsin-I.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a20a0bc0-49d5-41fc-9507-cec19a43bd81-2019-04-18T123454.696Z,2012,PubMed:28119822 +SLC38A9 regulates lysosomal metabolism,Biochemical Function B,"Rebsamen M, et al., 2015, PMID: 25561175","Activation of the mTORC1 pathway by SLC38A9 regulation of amino acid transport mediates mTORC1 activity, and thereby lysosomal metabolism",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_34c72694-90be-4ba1-a876-4f77562e7e72-2022-08-02T160000.000Z,2018,PubMed:25561175 +SLC38A9 knockout zebrafish,Model Systems Non-human model organism,"Wu X, et al., 2022, PMID: 35457018","Knockout zebrafish showed abnormal lysosomal amino acid metabolism, as evinced by elevated levels of multiple free amino acids",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_34c72694-90be-4ba1-a876-4f77562e7e72-2022-08-02T160000.000Z,2018,PubMed:35457018 +Hypomorphic SLC39A8 mouse,Model Systems Non-human model organism,"Gálvez-Peralta M, et al., 2012, PMID: 22563477",This mouse recapitulates the FTT and early mortality (die between GD18.5 and 48h postnatally) seen in many individuals with Leigh syndrome.,Score,0.5 (2),This mouse recapitulates the FTT and early mortality (die between GD18.5 and 48h postnatally) seen in many individuals with Leigh syndrome. Scored based on U24 model rubric.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5fddaae4-d982-49e7-9e83-b84d15f3cf2c-2020-11-23T195104.867Z,2020,PubMed:22563477 +Functional analysis of SLC39A8 mutations,Functional Alteration Non-patient cells,"Choi EK, et al., 2018, PMID: 29453449","Cells lines demonstrated reduced Mn SOD activity concurrent with increased ROS levels. Mutant cells also demonstrated altered gene expression of oxidative phosphorylation enzymes, which are accompanied by mitochondrial dysfunction.",Score,1 (0.5),Multiple non-patient cell lines demonstrating mitochondrial dysfunction.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5fddaae4-d982-49e7-9e83-b84d15f3cf2c-2020-11-23T195104.867Z,2020,PubMed:29453449 +Whole-cell patch-clamp,Functional Alteration Non-patient cells,"Thorsen K, et al., 2017, PMID: 29167417",Abbreviation of APD,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b5f6fcca-f8a9-47c2-bae9-a72df92f3bd1-2020-08-03T160000.000Z,2022,PubMed:29167417 +Zebrafish knockdown and WT/mutated mRNA micorinjection,Rescue Non-human model organism,"Thorsen K, et al., 2017, PMID: 29167417",,Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b5f6fcca-f8a9-47c2-bae9-a72df92f3bd1-2020-08-03T160000.000Z,2022,PubMed:29167417 +Zebrafish knockdown,Model Systems Non-human model organism,"Thorsen K, et al., 2017, PMID: 29167417",Abbreviation of APD leads to abbreviation of the systolic contraction in zebrafish,Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b5f6fcca-f8a9-47c2-bae9-a72df92f3bd1-2020-08-03T160000.000Z,2022,PubMed:29167417 +pHi measurements in HEK-293 transfected cells,Biochemical Function B,"Thorsen K, et al., 2017, PMID: 29167417",An abbreviated QT interval is the hallmark of SQTS,Score,1 (0.5),Robust methodology demonstrating how change in protein function leads to phenotype.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b5f6fcca-f8a9-47c2-bae9-a72df92f3bd1-2020-08-03T160000.000Z,2022,PubMed:29167417 +Fly model,Model Systems Non-human model organism,"Asjad HMM, et al., 2017, PMID: 28972153","The authors mention a previous publication (PMID:21187381) which shows that in flies, dopaminergic neurons are involved in both locomotion and the sleep cycle. Also, the authors mention another publication (PMID:16093388) in which the DAT null fly phenotype is characterized as fumin (""sleepless"" in Japanese). Therefore, the hyperlocomotion and sleeplessness could be connected to human hyperkinetic movements and irritability also caused by dopaminergic neuron dysfunction. Seeking expert opinions on if we will be scoring this model.",Score,1.5 (2),"Mutant flies were not tested for DA uptake levels (-1.0 pt). Missing key neuromuscular phenotypes such as rigidity, tremor, etc (-1.0). +Human variant (+0.5). Knock-in (+0.5). +The variant protein stayed in the cell bodies of dopaminergic neurons instead of entering the axons in the brain of the fly (+0.5).",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_bb7a8001-1bc9-4cdf-bb99-1979737bda79-2023-01-09T170000.000Z,2025,PubMed:28972153 +mouse expression,Expression A,"Strømme P, et al., 2011, PMID: 21964919","Abundant full-length Slc9a6 messenger RNA was detected in cerebral cortex from wild-type mice. Intense positive X-GAL staining, indicating the presence of targeted Slc9a6, was observed not only in the molecular layer of the cerebellum and hippocampus, but also in the cortical and subcortical regions, including the amygdala",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1d97fc8d-e744-449a-939c-386895c121cd-2018-05-02T160000.000Z,2029,PubMed:21964919 +Null mouse 2,Model Systems Non-human model organism,"Xu M, et al., 2017, PMID: 29349289","A novel null mouse model as well as the mouse previously reported in Ouyang 2013 were studied for longitudinal neurodevelopmental and neurodegenerative phenotypes. They found a mixed pathology of impaired neurodevelopment as well as neurodegeneration, revealed by prominent brain undergrowth as well as progressive brain volume loss, most profound in the cerebellum, which is strongly in line with human condition (On autopsy Christianson et al 1999 noted loss of Purkinje cells in cerebellum with age). A strong astrocytic and microglial response was also noted in aging mutant male mouse brain, extending beyond cerebellum alone.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1d97fc8d-e744-449a-939c-386895c121cd-2018-05-02T160000.000Z,2029,PubMed:29349289 +Microarray,Expression B,"Schwede M, et al., 2014, PMID: 23508127",NHE9 is upregulated in microarray data from postmortem brains of individuals with autism,Score,0 (0.5),"No valid evidence to support variants in this gene cause autism in human. +Variants found in this gene were presumably loss of function variants (deletion, nonsense variant). However, the gene expression was reported to be upregulated in autism cortex in this paper.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_463ee005-1264-45da-bd85-3776a6637c68-2020-10-08T160000.000Z,2030,PubMed:23508127 +Subcellular localization and pH homeostasis,Functional Alteration Non-patient cells,"Prasad H, et al., 2017, PMID: 28815171",No subcellular localization or expression change was observed. No loss-of-function was observed with respect to endosomal pH homeostasis and transferrin endocytosis.,Score,0 (0.5),No functional alteration observed for these variants.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_463ee005-1264-45da-bd85-3776a6637c68-2020-10-08T160000.000Z,2030,PubMed:28815171 +Fletcher - Expression/Degradation,Expression B,"Fletcher SJ, et al., 2018, PMID: 29678925",Transiently transfected HEK293T cells were co expressed with SLFN14 WT - GFP and either SLFN14 WT or Mutant - myc vectors. Both varaints K218E and K219N co expression (WT/mutant) was 37% and 54% that of WT/WT. An E. coli expression vector was used to investigate degradation and folding of mutant K218E by fluorescence microscopy. The mutant exhibited differences in emission energy at 340 nm demonstrating different conformation of the WT and mutant protein.,Score,0.5 (0.5),"As previously demonstrated by Fletcher et al, PMID: 26280575, SLFN14 missense variants K218E and K219N both demonstrate decreased protein expression. Fluorescence microscopy demonstrated dissimilar tertiary structures of WT and K218E mutant SLFN14, supporting the hypothesis of post translational degradation caused by protein misfolding.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_f31ec838-fc84-47a2-9341-1fe494788a09-2022-05-25T160000.000Z,2031,PubMed:29678925 +Katayama Expression,Expression A,"Katayama K, et al., 2009, PMID: 19936227","In situ hybridization and immunofluorescent staining of Slitrk6 in mouse inner ear at different developmental ages revealed dense expression prenatally at the lumenal surface of the sensory epithelium where hair cells localize. Also prenatally, in the ventromedial and laterodorsal regions. Postnatal day 1, transcripts detected in supporting cells of cochlea, and weak expression in OHCs and IHCs",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e9b9e41c-1b12-4159-9729-8de648e747b0-2020-04-21T211522.429Z,2032,PubMed:19936227 +Katayama Animal Model,Model Systems Non-human model organism,"Katayama K, et al., 2009, PMID: 19936227",No obvious external abnormalities and normal fertility. Gross abnormality of cochlear innervation. ABR indicated mid-frequency hearing loss and reduced startle response,Score,2 (2),Supported by Matsumoto et al. 2011 (21298075) mouse model,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e9b9e41c-1b12-4159-9729-8de648e747b0-2020-04-21T211522.429Z,2032,PubMed:19936227 +SLX4 Rescue 1,Rescue Cell culture model,"Shah S, et al., 2013, PMID: 23840564","WT SLX4 rescues MMC and PARP inhibitor sensitivity of Patient Fanconi Anemia fibroblasts. However, p.W823* nonsense variant does not rescue the sensitivity",Score,0 (1),"Authors noted that ""Sequencing of the SLX4 gene in the tumor from the patient with the truncating mutation revealed loss of the mutant allele. This might mean that SLX4 is not a breast cancer predisposition gene.""",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_4acc26ec-2174-4b21-bb02-965ae3539062-2023-12-21T180000.000Z,2033,PubMed:23840564 +Biochemical Function 1,Biochemical Function B,"Hodskinson MR, et al., 2014, PMID: 24726326",breast cancer is an epithelial cancer,Score,0.25 (0.5),The mouse model if for Fanconi anemia and is a homozygous knockout inconsistent with AD breast cancer. There is no way to determine if the phenotype would be seen as a dominant disorder in the mouse line.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_4acc26ec-2174-4b21-bb02-965ae3539062-2023-12-21T180000.000Z,2033,PubMed:24726326 +Transfection of SLX4 wild type in patient´s cell lines,Rescue Cell culture model,"Kim Y, et al., 2011, PMID: 21240275","The introduction of the mutant proteins did not rescue the FA phenotypes of the patients’ cells. However, a slight improvement was noted in the various assays possibly due to overexpression of the mutant proteins, which might have residual function. These experiments demonstrate that biallelic SLX4 mutations cause a new subtype of Fanconi anemia, FA-P and FANCP becomes an alias for the SLX4 gene.",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ab56e51d-64d2-49ba-a927-ab04e4a1e254-2023-10-27T170000.000Z,2034,PubMed:21240275 +"Mouse knockout of Btbd12, the mouse ortholog of SLX4",Model Systems Non-human model organism,"Crossan GP, et al., 2011, PMID: 21240276","The Btbd12 knockout mouse, the mouse ortholog ofSLX4, which recapitulates many key features of the human Fanconi anemia. Btbd12-deficient animals are born at sub-Mendelian ratios, have greatly reduced fertility, are developmentally compromised and are prone to blood cytopenias. Btbd12−/− cells prematurely senesce, spontaneously accumulate damaged chromosomes and are +particularly sensitive to DNA crosslinking agents. Genetic complementation reveals a crucial requirement for Btbd12 (also known as Slx4) to interact with the structure-specific +endonuclease Xpf-Ercc1 to promote crosslink repair. The Btbd12 knockout mouse therefore establishes a disease model for Fanconi anemia and genetically links a regulator of nuclease incision complexes to the Fanconi anemia DNA crosslink repair pathway.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ab56e51d-64d2-49ba-a927-ab04e4a1e254-2023-10-27T170000.000Z,2034,PubMed:21240276 +NCBI Fetal expression (not from this PMID),Expression A,"Wang Z, et al., 2022, PMID: 35281600",Fetal expression is pretty high between 10-20 weeks gestation.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_44a6fa0b-b6e7-422e-9d01-b74aad2a8b29-2024-05-13T160000.000Z,2035,PubMed:35281600 +Crim1 null mice,Expression A,"Iyer S, et al., 2016, PMID: 26821812",Immunohistochemistry,Score,0.25 (0.5),Antibody recognizes phosph-Smad2/3,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5e0055af-46d4-42c2-93fa-f3c4d238b3d4-2023-11-06T170000.000Z,2037,PubMed:26821812 +Tgfbr2 conditional null mice,Expression A,"Bhattacharya A, et al., 2021, PMID: 33801433",Immunohistochemistry,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5e0055af-46d4-42c2-93fa-f3c4d238b3d4-2023-11-06T170000.000Z,2037,PubMed:33801433 +Smad4 inducible KO mice,Model Systems Non-human model organism,"Crist AM, et al., 2018, PMID: 29460088","Postnatal ablation of Smad4 caused various vascular defects, including the formation of distinct arteriovenous malformations in the neonate retina, and arteriovenous malformations are typical of the juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome",Score,2 (2),This mouse model shows arteriovenous malformations that are typical of the juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b9b79d0f-4259-49d7-882d-4ca23bb7e8cf-2023-04-18T160000.000Z,2040,PubMed:29460088 +smad4 KO mice,Model Systems Non-human model organism,"Kim YH, et al., 2018, PMID: 30571376","Mice with global Smad4 deletion in neonatal and adult +stages reproduce phenotypes observed in patients with +juvenile polyposis–HHT, including anemia and arteriovenous +malformations in the brain, gastrointestinal tract, and skin",Score,2 (2),This mouse model recapitulates most of the juvenile polyposis–HHT phenotypes,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b9b79d0f-4259-49d7-882d-4ca23bb7e8cf-2023-04-18T160000.000Z,2040,PubMed:30571376 +Fly Model,Model Systems Non-human model organism,"Li D, et al., 2021, PMID: 33980485","LoF of the SMARCA5 Drosophila ortholog Iswi (orthologous to human SMARCA1 or SMARCA5) led to smaller body size, reduced sensory dendrite complexity, and tiling defects in larvae. In adult flies, Iswi neural knockdown caused decreased brain size, aberrant mushroom body morphology, dendrite and axon mispatterning, and abnormal locomotor function. Iswi LoF was rescued by wild-type but not mutant SMARCA5.",Score,0 (2),The drosophila gene is orthologous to both human SMARCA1 and human SMARCA5.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ce97120a-5094-4768-b305-941353791584-2022-08-03T160000.000Z,2043,PubMed:33980485 +SMARCA4 encodes a catalytic subunit of the BAF complex,Biochemical Function B,"Dykhuizen EC, et al., 2013, PMID: 23698369","SMARCA4 encodes a catalytic subunit of the BAF (SWI/SNF) chromatin remodeling complex. SMARCA4 missense mutations within ATP domain cause Coffin-Siris syndrome. Germline mutations associated with Coffin-Siris syndrome have also been reported in other SWI/SNF subunit genes, including SMARCB1, SMARCC2, SMARCD1, SMARCE1, ARID1A, ARID1B, ARID2, and DPF2, while mutations in the SMARCA2 gene cause a similar phenotype, Nicolaides-Baraitser syndrome. Mutations in other genes encoding transcription factors involved in the BAF complex have also been associated with ID/ASD/epilepsy, including ADNP, ACTL6B, and ACTB. More generally, chromatin remodeling is well known mechanism of dozens of ID genes.",Score,1 (0.5),Upgrade score due to strength of evidence: It is known that germline mutations disrupting functions of several other BAF complex subunits cause Coffin-Siris syndrome,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_61d29c73-9a30-4664-9df2-2f5831219221-2020-06-17T160000.000Z,2045,PubMed:23698369 +S302A/S304A mice,Model Systems Non-human model organism,"Ochoa D, et al., 2020, PMID: 31819260","Delayed neuronal differentiation has been implicated in many forms of intellectual disability and ASD, including CSS.",Score,0.5 (2),Not well-established phenotype.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_aa645aa6-3a03-4ab7-9d09-b17be3184259-2022-02-02T170000.000Z,2050,PubMed:31819260 +Heterozygous knockout mouse,Model Systems Non-human model organism,"Fujita Y, et al., 2017, PMID: 28408410","Growth retardation, craniofacial anomalies (including cleft palate), anxiety, and immune problems are all features of CdLs.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9467eaad-a86a-4b24-8cd4-98ebb57121c1-2020-04-07T160000.000Z,2052,PubMed:28408410 +Carballo_Protein Interactions,Protein Interaction,"Carballo GB, et al., 2018, PMID: 29558958","When Shh binds to Ptch and activates Smo, Smo converts Gli3R into an activated form (Gli3A). Gli3 has been shown to regulate digit number and identity (feature of Pallister-Hall-like syndrome) (Litingtung et al. 2002; PMID: 12198547).",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_33566da0-0f61-4dc5-b629-affb4e68e9c7-2023-10-20T160000.000Z,2055,PubMed:29558958 +Carballo_Biochemical Function,Biochemical Function B,"Carballo GB, et al., 2018, PMID: 29558958","These phenotypes are all consistent with the disease of interest, Pallister-Hall-like syndrome.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_33566da0-0f61-4dc5-b629-affb4e68e9c7-2023-10-20T160000.000Z,2055,PubMed:29558958 +Genes expressed concordantly with Atoh1 during inner ear dev,Expression A,"Yoon H, et al., 2011, PMID: 21519551",Used RT-PCR and in situ hybridization to investigate expression patterns of some of the newly identified genes in the inner ear. Compared relative levels of expression of each gene for during and not during inner ear development. Found that SMPX had 41 fold higher expression during inner ear development. It is speculated that SMPX is therefore involved in the development of the inner ear as a critical regulator of cytoskeletal dynamics and/or maturation and maintenance of hair cells,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_29773bee-1f13-43f6-bda0-c5a646efccd7-2017-09-12T160000.000Z,2056,PubMed:21519551 +HEK Cell SMS site-directed mutagenesis,Functional Alteration Non-patient cells,"Zhang Z, et al., 2011, PMID: 21647366","computational predictions showing impacts on the pKa's and hydrogen bond networks of the crystal structure of the protein as well as entropy effects led to the testing of several different substitutions at the 3 residues tested. using western blots to identify stabilized dimers, they iedntified that the G56S (clinically observed) was predicted to destabilize the dimer but did notinstead lowered dimer affinity...other p.G56 variants destabilized the dimer, however. The p.V132 site served almost as a positive control, because it did not alter dimer stabilization even with several substitutions. The p.I150 site was found to be highly susceptible to dimer destabilization",Score,0.5 (0.5),"This study showed that several different variants, at 3 different sites can impact the dimerization of the protein. Therein impacting protein function. Some of them were clinically observed variants in patients with SRS.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_8f1ca85b-ad57-4c64-9abf-9ae5d915703f-2018-05-16T195543.428Z,2057,PubMed:21647366 +Spermidine to Sperimine catalysis assays,Biochemical Function B,"Zhang Z, et al., 2013, PMID: 23468611","Spermine deficiency is the marker of Snyder Robinson syndrome. The enzyme's ability to convert spermidine to sperimine is highly contingent on the structural integrity of the dimer among other factors. The variants tested here, and the proof of the enzyme's function support that variation in this protein is involved in the spermine deficiency seen in humans with SRS",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_8f1ca85b-ad57-4c64-9abf-9ae5d915703f-2018-05-16T195543.428Z,2057,PubMed:23468611 +Western Blots of 5 different SRS patient variants,Functional Alteration Patient cells,"Peng Y, et al., 2016, PMID: 26761001","Western blots showed that the stability of the monomers was compromised by the variants and that there was recduced levels of spermine synthase protein for all the patients either by native or denatured western blot analysis. They also showed that the G56S, F58L, G67E, and P112L variants decreased dimer affinity.",Score,1 (1),Gave default score for characterization of 5 variants.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_8f1ca85b-ad57-4c64-9abf-9ae5d915703f-2018-05-16T195543.428Z,2057,PubMed:26761001 +Drosophila SMS KO model,Model Systems Non-human model organism,"Li C, et al., 2018, PMID: 29348635",The model recapitulates the pathological polyamine imbalance of SRS and causes survival defects and synaptic degeneration. The model also provides underlying mechanisms of the pathology of Snyder-Robinson.,Score,1 (2),"Since this is a fly model and ID was not assessed, it was downgraded. There is good evidence showing the neurodegeneration via immunolabeling and other enzymatic assays, but these enzymatic assays should be counted towards the similarity between humans and the flies.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_8f1ca85b-ad57-4c64-9abf-9ae5d915703f-2018-05-16T195543.428Z,2057,PubMed:29348635 +Mitochondrial mobility,Functional Alteration Non-patient cells,"Li L, et al., 2013, PMID: 24392030",In both young (7DIV) and mature (14DIV) A53T neurons mitochondria mobility was impaired.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d21593ae-ed10-4442-8167-24f96f917302-2022-05-03T134931.425Z,2060,PubMed:24392030 +aS multimer:monomer ratio,Functional Alteration Non-patient cells,"Dettmer U, et al., 2015, PMID: 26076669","highly significant decreases (details in Fig. 3 legend +and Methods) in the tetramer:monomer ratio for A30P (77.5±15.5% of WT, +that is, a 22.5% decrease), E46K (61.7±10.1% of WT, a 38.3% +decrease), G51D (47.8±10.0% of WT, a 52.2% decrease) and +A53T (66.5±10.4% of WT, a 33.5% decrease). H50Q caused a +smaller (83.7±14.4% of WT, 16.3% decrease) but still significant. +(Po0.05) reduction",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d21593ae-ed10-4442-8167-24f96f917302-2022-05-03T134931.425Z,2060,PubMed:26076669 +iPSC-derived dopaminergic neurons,Model Systems Cell culture model,"Diao X, et al., 2021, PMID: 34572052",Both show aggreggation of the mutated protein,Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d21593ae-ed10-4442-8167-24f96f917302-2022-05-03T134931.425Z,2060,PubMed:34572052 +RNA expression in human cadaver eyes,Expression A,"Zhang T, et al., 2021, PMID: 33553197","RNA expression analysis in human cadaver eyes confirmed wide expression of SNRNP200 in multiple eye tissues including cornea, iris, lens, vitreous body, sclera, retina, and optic nerve.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_41acb15c-18a0-412b-a308-66a7f4e2837a-2022-05-24T160000.000Z,2061,PubMed:33553197 +Whole mount in situ hybridization in zebra fish.,Expression A,"Zhang T, et al., 2021, PMID: 33553197","Whole mount in situ hybridization in zebra fish revealed a generalized expression of SNRNP200 at two-cell stage, 50%-epiboly, 8-somite stage, 1pdf, and 2pdf. Retinal cryosections showed high expression at the ciliary marginal zone at 3dpf and 5dpf.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_41acb15c-18a0-412b-a308-66a7f4e2837a-2022-05-24T160000.000Z,2061,PubMed:33553197 +Overexpression of mutant SNRNP200 in kockout zebra fish.,Model Systems Non-human model organism,"Zhang T, et al., 2021, PMID: 33553197","Overexpression of mutant caused generalized body defects and retinal defects in zebrafish through dominant negative effect. In humans with SNRNP200 mutations, no systemic defects have been observed so far. However, still retinal defects were observed in mutants and this is a satisfactory evidence that SNRNP200 is required for normal retinal structure and function.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_41acb15c-18a0-412b-a308-66a7f4e2837a-2022-05-24T160000.000Z,2061,PubMed:33553197 +Sodium currents - rat cardiomyocytes,Functional Alteration Non-patient cells,"Choi JI, et al., 2016, PMID: 27028743","Compared to WT-STNA1, INa-L (% of peak current) was significantly increased with E409Q mutant, but not the A390V mutant (0.49±0.14 in WT-SNTA1 vs. 0.94±0.23 in A390V-SNTA1, +p = 0.099; vs. 1.12±0.24 in E409Q-SNTA1, p = 0.019).",Review,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_03c758a6-9290-4e14-9501-0ffb0fbfe8ce-2020-04-24T160000.000Z,2062,PubMed:27028743 +Sodium current,Functional Alteration Non-patient cells,"Choi JI, et al., 2016, PMID: 27028743","Rate of slow recovery was significantly prolonged in A390V-SNTA1 compared to WT-SNTA1. +INa-L (% of peak current) was significantly increased with both mutants compared to WT-SNTA1 (0.58±0.10 in WT vs. 0.90±0.11 in A390V-SNTA1, p = 0.048; vs. 0.88±0.07 in E409Q-SNTA1, p = 0.023). There was no significant difference in INa-L between A390V-SNTA1 and E409Q-SNTA1 (p = 0.903).",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_03c758a6-9290-4e14-9501-0ffb0fbfe8ce-2020-04-24T160000.000Z,2062,PubMed:27028743 +Ye knockout mouse,Model Systems Non-human model organism,"Ye L, et al., 2015, PMID: 25811986","Global Snx10-deficiency in mice results in a combined phenotype of osteopetrosis (due to osteoclast defect) and rickets (due to high stomach pH and low calcium availability, resulting in impaired bone mineralization). Snx10 knockdown (KD) mice exhibited severe growth retardation with failed tooth eruption compared to WT or heterozygous controls. Snx10 KD mice die between 3 and 4 weeks post-partum with impaired gastric acidification and are severely hypocalcemic compared to wild type littermates. The overall skeletal development was impaired, with higher radio-density in the 3-week-old Snx10 KD mice (unresorbed trabecular bone, lacked marrow spaces, radiograph and by micro-CT of transverse sections of long bones (femur, tibia, humerus) revealed an inner ring of cortex-like (denser) bone within the trabecular consistent with a severely osteopetrotic human phenotype). Osteoclast-specific Snx10 knockout had no effect on calcium balance, and therefore led to severe osteopetrosis without rickets. Supplementation with calcium gluconate rescued mice from the rachitic phenotype and dramatically extended life span in global Snx10-deficient mice, suggesting that this may be a life-saving component of the clinical approach to Snx10-dependent human osteopetrosis that has previously gone unrecognized.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_4c6f3ffa-405b-4b64-b29d-b4dc157ef586-2024-06-24T160000.000Z,2063,PubMed:25811986 +Stattin functional alteration in patients,Functional Alteration Patient cells,"Stattin EL, et al., 2017, PMID: 28592808",Stimulation with RANKL resulted in a robust formation of larger osteoclasts than control. Electron microscopy showed that these osteoclasts had defective ruffled borders and were unable to resorb bone in vitro evidenced by both an absence of resorption pits and lack of CTX in the culture supernatant.,Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_4c6f3ffa-405b-4b64-b29d-b4dc157ef586-2024-06-24T160000.000Z,2063,PubMed:28592808 +Aggregation,Functional Alteration Non-patient cells,"Prudencio M, et al., 2009, PMID: 19483195",33 ALS-associated variant SOD1 proteins were found to be insoluble in non-ionic detergents and SDS. All ALS-associated mutations in SOD1 increased the inherent aggregation propensity of the protein. In the majority of pedigrees in which patients exhibit reproducibly short disease durations are associated with mutations that show a high inherent propensity to induce aggregation of SOD1.,Score,1 (0.5),Used a large set of data from SOD1-associated ALS pedigrees to identify correlations between disease features and biochemical/biophysical properties of more than 30 different variants of mutant SOD1 (8 of which were not included in the patients found in this curation).,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_97d17778-d21e-441f-b4b7-49eccaa8cbab-2021-07-13T192226.690Z,2066,PubMed:19483195 +Hao Expression,Expression A,"Hao X, et al., 2014, PMID: 24887110","Sox10 expression was detected in the cochlear lateral wall of young adult mice and in the human cochlea, including the lateral wall, organ of Corti, and auditory nerve. Detected by immunohistochemical imaging and TEM (in mice only)",Score,1 (0.5),Upgraded for human expression information,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_00a5b707-a265-4af0-a7e1-f15734ea42b9-2018-06-19T160000.000Z,2068,PubMed:24887110 +SOX17 expression in mice,Expression A,"Corada M, et al., 2013, PMID: 24153254",SOX17 is exclusively expressed in the endothelial cells of mouse arteries (not expressed in endothelial cells of mouse veins).,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_8d47cc1b-9fe0-4f2f-9415-1490d81a5ca3-2023-04-24T160000.000Z,2069,PubMed:24153254 +SOX17 expression in human,Expression B,"Gräf S, et al., 2018, PMID: 29650961",SOX17 is predominantly localized to the endothelial cells within plexiform lesions in the lungs of IPAH patients.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_8d47cc1b-9fe0-4f2f-9415-1490d81a5ca3-2023-04-24T160000.000Z,2069,PubMed:29650961 +Drosophila CG18472/Spag1 RNAi knockdown,Model Systems Non-human model organism,"Zur Lage P, et al., 2018, PMID: 29743191","Male infertility, immotile sperm, the loss of auditory/vibration mechanotransduction in Ch neurons (impaired larval hearing), and defective adult proprioception in SPAG1 depleted Drosophila mutants are phenotypes consistent with the human SPAG1 mutations that result in ciliary immotility in respiratory cells resulting in respiratory symptoms and immotile nodal cilia that lead to laterality defects. This study concludes that CG18472/Spag1 likely conserves the dynein assembly function of human SPAG1.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c0d43e40-0aa3-41cf-9e3a-8311e685c7be-2022-06-22T190000.000Z,2077,PubMed:29743191 +Knockout of he Caenorhabditis elegans SPG20 orthologue,Rescue Non-human model organism,"Truong T, et al., 2015, PMID: 26114733","Worms with spartin knockout ortholog (F57B10) exhibited a marked degree of pathology, represented by slower crawling speed and thrashing frequency, significantly shorter lifespan, and a reduced capacity to cope with oxidative stress when compared to WT worms. +In the presence of oxidative stress by exposure to paraquat or sodium azide, animals overexpressing spartin showed a rescued phenotype, as they did for their lifespan.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5f0c5bcd-68a3-46f2-b632-82feb28381d4-2022-12-19T170000.000Z,2078,PubMed:26114733 +Waseem_Expression_Experiment,Expression A,"Waseem NH, et al., 2020, PMID: 32339198","Researchers investigated expression levels of two transcripts of SPATA13 +NM_001166271;NP_001159743 (1277 amino acids) and NM_153023;NP_694568 (652 amino acids) in seventeen different human cell lines derived from the eye. They found expression of both SPATA13 transcripts in the human iris, ciliary epithelium, retinal pigment epithelium, retina and lens",Score,0 (0.5),Ubiquitous expression (not just eye),https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5ef1d5a1-5a5b-425b-998d-0c6e23d3bd40-2023-03-16T190000.000Z,2079,PubMed:32339198 +Lysosomal abnormalities,Functional Alteration Patient cells,"Renvoisé B, et al., 2014, PMID: 24999486",Fibroblasts prepared from patients with SPG11 have selective enlargement of LAMP1-positive structures.,Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d32f521e-3d88-4b35-94e6-5fc4124c159c-2023-06-07T160000.000Z,2083,PubMed:24999486 +Spg11 knockout mouse,Model Systems Non-human model organism,"Branchu J, et al., 2017, PMID: 28237315","The Spg11 knockout mouse developed early-onset motor impairment and cognitive deficits as well as signs of peripheral neuropathy. The behavioral deficits were associated with progressive brain atrophy with the loss of neurons in the primary motor cortex, cerebellum and hippocampus, as well as with accumulation of dystrophic axons in the corticospinal tract. Spinal motor neurons also degenerated and this was accompanied by fragmentation of neuromuscular junctions and muscle atrophy. At 16 months, most of the knockout mice had an abnormal posture with spread hind limbs, lower pelvic elevation and pronounced kyphosis of the thoracic spine. +This degeneration was accompanied by an accumulation of lipid material in lysosomal structures, similar to the observations made in human SPG11 brains (Denora et al., 2016).",Score,3 (2),"This knockout mouse recapitulates the full range of symptoms associated with SPG11 mutations observed in HSP, ALS and CMT patients.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d32f521e-3d88-4b35-94e6-5fc4124c159c-2023-06-07T160000.000Z,2083,PubMed:28237315 +cerebral organoids,Model Systems Cell culture model,"Pérez-Brangulí F, et al., 2019, PMID: 30476097","For the delineation of potential defect in SPG11 brain development the authors employed 2D culture systems and 3D human brain organoids derived from SPG11 patients’ iPSC and controls. They revealed that an increased rate of asymmetric divisions of neural progenitor cells (NPCs) leads to proliferation defect, causing premature neurogenesis. Correspondingly, SPG11 organoids appeared smaller than controls and had larger ventricles as well as thinner germinal wall. Premature neurogenesis and organoid size were rescued by GSK3 inhibititors including tideglusib. These findings shed light on the neurodevelopmental mechanisms underlying disease pathology. The finding that dysfunction of SPG11 interferes with the development of iPSC-derived brain organoids is in line with early finding that dysfunction of SPG11 interferes with the development of iPSC-derived brain organoids is in line with early cortical atrophy diagnosed in the patients diagnosed in the patients.",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d32f521e-3d88-4b35-94e6-5fc4124c159c-2023-06-07T160000.000Z,2083,PubMed:30476097 +Silkworm lemon mutant,Model Systems Non-human model organism,"Jiang G, et al., 2020, PMID: 32269807","This work builds upon an older study (PMID) which showed that variants in the silkworm spr gene result in sepiapterin reductase deficiency, and accumulation of sepiapterin and other compounds in thes silkworms leading to an abnormal yellow color. In the current study, nine strains of silkworm lemon mutant had a nonsense variant resulting in a C-terminal deletion of 5 amino acid (homozygous in the yellow worms). The homozygous worms had reduced motor ability to move towards mulberry leaves, normal phenylalanine level, decreased dopamine and serotonin levels, and increased neopterin level. Treatment with L-dopa and carbidopa increased the dopamine level of the lemon mutant. These characteristics of the lemon mutant resemble the findings of SR deficiency in humans.",Score,1 (2),"The score is decreased because, while the biochemical abnormalities recapitulate the findings in human SR deficiency, the nature of the model (silkworm) does not allow for comparison of clinical features. Note that an older paper on silkworm mutants (PMID 19246455) was also scored.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1c9f2ff6-39f1-4abc-9fdf-de4c0e23120d-2021-06-04T221815.205Z,2084,PubMed:32269807 +Northern blot for SPTBN4 in human tissues/IHC rat brain,Expression A,"Berghs S, et al., 2000, PMID: 11086001","Expression was detected in human brain and at lower level in muscle by NB. In rat, particular highly expressed in large myelinated neurons in brain, colocalizes with ankyrin(G) and is enriched at axon initial segments and nodes of Ranvier. In addition, in rat embryo, betaIVSigma1 spectrin (larger isoform) is detectable from embryonic day 19 in hippocampus, concomitantly with immunoreactivity at the axon initial segments.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ff8934be-15d6-474e-b5fa-30328f633170-2022-06-22T160000.000Z,2087,PubMed:11086001 +Pig SPTBN4 spontaneous model phenotyping,Model Systems Non-human model organism,"Derks MFL, et al., 2019, PMID: 31850074","see overalpping human phenotypes above. Not described are ABR and electrophysiological responses, no equivalent to ID in humans",Score,1 (2),"Phenotype is limited to clinical description and muscle investigation consistent with reported neuromuscular pathology in humans and mice. However, nerve conduction velocities, or other pathologic features of the disorder (e.g. hearing loss, MRI) have not been performed. Thus, reduced points are given.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ff8934be-15d6-474e-b5fa-30328f633170-2022-06-22T160000.000Z,2087,PubMed:31850074 +Enzymatic assay,Biochemical Function B,"Ernst D, et al., 2015, PMID: 25567748",Elevated deoxysphingolipids in cells carrying SPTLC2 mutations similar to the elevation of these in neurotoxic sphingolipids in patient's plasma,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_2294e1cf-3aad-471e-a360-9f6f8c3b4d8f-2023-01-10T170000.000Z,2088,PubMed:25567748 +Lipid MS,Biochemical Function B,"Ernst D, et al., 2015, PMID: 25567748",Decreased sensation due to neuronal damage caused by neurotoxic deoxysphingolipids,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_2294e1cf-3aad-471e-a360-9f6f8c3b4d8f-2023-01-10T170000.000Z,2088,PubMed:25567748 +NMJ studies in Drosophila,Model Systems Non-human model organism,"West RJH, et al., 2018, PMID: 29761896","Sphingolipids are essential for synaptic structure and function; SPTLC2 mutations leads to defects in neuromuscular synapse structure and synapses depleted for sphingolipids were capable of greater growth when combined with the synaptic overgrowth mutation highwire (hiw). +One obvious ultrastructural defect that is present in sphingolipid depleted synapses is enlarged mitochondria.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_2294e1cf-3aad-471e-a360-9f6f8c3b4d8f-2023-01-10T170000.000Z,2088,PubMed:29761896 +hydrogen sulfide oxidation,Biochemical Function A,"Rahman J, et al., 2017, PMID: 27977873","SQOR- sulfide:quinone oxidoreductase plays a role as the first step in the oxidation pathway of sulfide (hydrogen sulfide, H2S).",Score,0.5 (0.5),"Variants in ETHE1, the next step in the oxidation pathway of sulphides. Variants in ETHE1 have been associated with an accumulation of H2S and with Leigh syndrome spectrum.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_09ea3b0c-cc3a-44d1-a702-9f1674c33040-2021-01-21T005124.845Z,2090,PubMed:27977873 +L341V mutation disrupts LIR to LC3B binding,Functional Alteration Non-patient cells,"Goode A, et al., 2016, PMID: 27158844","Protein affinity isolation assays in which interaction partners LC3B or ubiquitin covalently immobilized on beads were used to capture recombinant GST-SQSTM1 fusion proteins, followed by detection of bound protein by western blotting. L341V mutant selectively reduced capture of GST-SQSTM1 by LC3B, relative to the wild type, whereas binding to ubiquitin was unaffected. As a control the previously characterized PDB-linked UBA domain SQSTM1 mutation, G425R (SQSTM1G425R), also now reported in cases of ALS, was found to selectively impact only on ubiquitin-binding, with no evidence of this mutation affecting LC3B recognition. Using a native ESI-MS approach, found the abundance ratio of LC3B bound to WT LIR compared to LIR (L341V) was 3:1, entirely consistent with a reduced binding affinity of the mutant LIR. They then confirmed the MS data using isothermal titration calorimetry, finding the LIR (L341V) peptide was associated with a ∼3-fold reduction in LC3B binding affinity (10.9 ± 1.1 μM) and a substantially reduced enthalpy of interaction. Using NMR they looked at the structural differences between WT SQSTM1 and the mutant and found 8 residues that were substantially different between the 2 complexes, with the largest effects involving V33, F52, L53, V54 and R70. Finally, in the NSC-34 cell line with the mCherry-EGFP-SQSTM1 mutant construct there were visibly fewer red acidic vesicles in the absence of the autophagy inhibitor, BafA1, than the WT. The number was further reduced following BafA1 treatment, indicating that the cells were still functional with respect to autophagy, consistent with reversal of the mutant phenotype (reduction in PCC values) observed following treatment of mutant-expressing cells with the autophagy-enhancer rapamycin.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_dae3327f-6381-44cc-8baa-8fa1fc0d31d5-2022-12-13T170000.000Z,2091,PubMed:27158844 +Keap1 binding and NF-κB and Nrf2 reporter assays,Functional Alteration Non-patient cells,"Goode A, et al., 2016, PMID: 27554286","Interactions with endogenous Keap1 were determined by capture with anti-FLAG, and western blotting precipitates for Keap1. Consistent with previous reports using MBP pull-down assays, the G351A KIR mutant was largely unable to capture endogenous Keap1; further, we found that the P348L KIR mutant was also defective in Keap1 binding. The K344E mutation did not affect Keap1 binding of SQSTM1/p62 and likewise the more distant L341V mutant, located within the LIR, bound Keap1 normally. +Effects of expression of L341V, K344E, P348L and G351A mutant SQSTM1/p62 on activation of basal NF-κB signaling were determined using luciferase reporter assays. All four of the ALS-FTLD mutants failed to activate NF-κB activity, relative to wild-type SQSTM1/p62, whereas the E396X positive control produced strong activation. Thus, this defective NF-κB signaling phenotype does not appear to be a feature of LIR/KIR mutants of SQSTM1/p62. +Given the selective effects of the two KIR mutations (P348L, G351A) on the SQSTM1/p62-Keap1 interaction, they assessed the effects of mutant protein expression on activation of Nrf2 signaling in reporter assays. Expression of wild-type SQSTM1/p62 activated Nrf2 signaling relative to empty vector. Nrf2 activity associated with expression of L341V and K344E mutants was not significantly different to wild-type SQSTM1/p62. However, both the P348L and G351A KIR mutants showed significantly reduced activation of Nrf2 compared to wild-type SQSTM1/p62. Thus, the Keap1 interaction code accurately translates to functional differences in the abilities of different SQSTM1/p62 mutants to regulate Nrf2 signaling. +The results suggest that SQSTM1 mutations within the KIR of SQSTM1/p62 contribute to aetiology of some cases of ALS-FTLD through a mechanism involving aberrant expression or regulation of oxidative response genes.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_dae3327f-6381-44cc-8baa-8fa1fc0d31d5-2022-12-13T170000.000Z,2091,PubMed:27554286 +Effect of p62 mutants on mitochondrial dysfunction,Functional Alteration Patient cells,"Bartolome F, et al., 2017, PMID: 28490746","Mitochondrial health and function are reflected in the mitochondrial membrane potential (ΔΨm). A significant decrease in ΔΨm was observed in p62 KD SH-SY5Y cells compared to either untransfected or cells transfected with scrambled (SCR) siRNA control. Equivalent effects on the ΔΨm were observed in the mutant fibroblasts when compared to age-matched controls. Both, p62 KD SH-SY5Y cells and p62 mutant fibroblasts showed a depolarization in response to the F0-F1-ATP synthase (ATPase or complex V) inhibitor oligomycin, suggesting ΔΨm in p62 KD cells is partially maintained by ATP hydrolysis by the ATPase. +The activity of the mitochondrial electron transport chain (ETC) and the rate of substrate supply can be estimated by measurement of mitochondrial NADH and FAD autofluorescence. The analysis of the FAD autofluorescence was used to generate the FAD redox index, which was higher in the p62 KD SH-SY5Y cells compared to untransfected and SCR cells. Increased NADH and FAD redox indexes in p62 deficient cells reflects inhibition of complex I-driven respiration and suggest more activated complex II dependent respiration as a compensatory mechanism. Mitochondrial NADH pool obtained was found to be reduced in the p62 KD cells and in the p62 mutant fibroblasts indicating a lack of substrates. Lower FAD pool levels were also found in the p62 KD cells confirming an inhibition in complex I and reduced substrate availability. Further analysis of complex I activity using an activity microplate assay confirmed the inhibition of complex I in the p62 mutant fibroblasts compared to controls. +Altered mitochondrial function could be linked to an overproduction of cytosolic reactive oxygen species (ROS). The p62 KD cells and p62 mutant fibroblasts showed higher Het rates (representative of cytosolic ROS production) than controls. +Nrf2 directly regulates cellular energy metabolism by modulating the availability of substrates for mitochondrial respiration through a p62 and Nrf2 positive feed-forward regulatory loop. So they evaluated the role of Nrf2 activation on mitochondrial function in p62-deficient cells. The NADH redox index was significantly reduced in p62 mutant fibroblasts treated with Nrf2 activators compared to the same fibroblasts without treatment and the NADH pool was restored reaching equivalent values to the control fibroblasts. Results suggest that Nrf2 activation restores cellular metabolism in the p62-deficient cells by increasing the availability of substrates for mitochondrial respiration. +During an oxidative insult, neurons divert part of their glucose pool towards the pentose phosphate pathway (PPP), thereby increasing the production of NAD(P)H. The NAD(P)H levels in the p62 KD SH-SY5Y cells and p62 mutant fibroblasts were significantly increased compared to controls.",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_dae3327f-6381-44cc-8baa-8fa1fc0d31d5-2022-12-13T170000.000Z,2091,PubMed:28490746 +C9orf72 associates with p62 (SQSTM1),Protein Interaction,"Chitiprolu M, et al., 2018, PMID: 30022074","To identify new functions of C9ORF72 during oxidative stress, researchers immunoprecipitated endogenous C9ORF72 from cells exposed to arsenite-induced oxidative stress (+As) and untreated counterparts. C9ORF72 immunoprecipitated p62, and HA-p62 reciprocally immunoprecipitated C9ORF72 both in the absence and presence of oxidative stress. Proximity ligation assays (PLA) confirmed that in intact cells p62 and C9ORF72 closely associate. Finally, more recombinant p62 was pulled down with recombinant purified GST-C9ORF72 than with beads containing GST alone. +Further, to test if C9ORF72 and p62 control elimination of stress granules, p62 or C9ORF72 were depleted with siRNA. Depletion of C9ORF72 had minimal effect on p62 levels. During recovery from stress (1 h recovery after 30 min arsenite), 88 or 84% of cells, respectively, treated with siRNA targeting p62 or C9ORF72 failed to eliminate stress granules. p62 knockdown had no effect on stress granule numbers in ATG5−/− cells suggesting that p62 operates in a ATG5-dependent autophagy pathway to clear stress granules.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_dae3327f-6381-44cc-8baa-8fa1fc0d31d5-2022-12-13T170000.000Z,2091,PubMed:30022074 +"Inhibition of Ref(2)P, the Drosophila homologue of the p62",Model Systems Non-human model organism,"Hurley EP, et al., 2021, PMID: 33557921","Inhibiting Ref(2)P in the motor neuron was conducted as ALS is known to result in a loss of motor function, being classified as a motor-neuron disease.",Score,0.5 (2),"Although the model system was able to recapitulate the motor dysfunction observed in ALS, in some of the model, specifically the ddc-Gal4HL4.3D-expressing neurons, there was a significant increase in median lifespan, suggesting an imperfect model of ALS. +Did not score based on suggestion from the ALS GCEP on December 13, 2022 for the reasons above, and because Drosophila were previously determined by the GCEP to be an imperfect model of ALS",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_dae3327f-6381-44cc-8baa-8fa1fc0d31d5-2022-12-13T170000.000Z,2091,PubMed:33557921 +Conditional cerebellar Srd5a3 mouse knockout,Model Systems Non-human model organism,"Medina-Cano D, et al., 2018, PMID: 30311906","In a previous study, SRD5A3 KO mice were shown not to survive beyond E12. Therefore, in this study, the authors generated a cerebellum conditional knock out. This mouse develops cerebellar hypoplasia, as observed in humans with biallelic loss of function variants in SRD5A3. In addition, the mice have memory and motor coordination deficits, correlating with features noted in human cases including intellectual disability, motor delay, and ataxia (in some patients). Furthermore, the authors clearly demonstrate hypo-N-glycosylation of proteins, as has been noted in human patients.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_f8336b45-245d-4309-8451-e99acb568663-2024-01-17T170000.000Z,2093,PubMed:30311906 +FUS and CREST associattion in mouse cortical neurons,Protein Interaction,"Chesi A, et al., 2013, PMID: 23708140","FUS and CREST were able to physically associate in mouse cortical neurons. As a positive control, the nBAF complex core subunit Brg was co-immunoprecipitated by CREST (d). The antibody to CREST also co-immunoprecipitated FUS. Antibodies to several other nBAF subunits weakly co-immunoprecipitated FUS (e)",Score,0.5 (0.5),FUS and CREST interaction was als proved in the paper (PMID:23708140),https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6e148a06-50fc-45f3-90ea-023dc8687577-2023-05-25T160000.000Z,2095,PubMed:23708140 +CREST co-aggregates with FUS,Protein Interaction,"Kukharsky MS, et al., 2015, PMID: 25888396","CREST co-aggregates with FUS but not with TDP-43 or TAF15. (A) Endogenous FUS co-immunoprecipitates with CREST-GFP. Pull-down of GFP-tagged CREST from transfected cells was performed with GFP-Trap beads as described in Material and methods, endogenous FUS was detected in the immunoprecipitate (IP) by Western blotting (WB).",Review,0 (0.5),"In the paper (PMID:23708140), the author had proved that FUS and CREST could associated in mouse cortical neurons. This experiment reproduce the association between FUS and CREST. +So the defaule score should not be caculated.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6e148a06-50fc-45f3-90ea-023dc8687577-2023-05-25T160000.000Z,2095,PubMed:25888396 +Loss of CREST leads ALS-like motor defects in mice,Model Systems Non-human model organism,"Cheng C, et al., 2019, PMID: 30976389","Both CREST haploinsufficiency and Q394X mice displayed deficits in +motor coordination",Score,1 (2),Cheng et al constructed CREST knockout (Crest +/− )and Q394X knock-in mice through CRISPR/Cas9 system. Both of the two models displayed deficits in motor coordination only partially mimic ALS phenotype. So we downgrade default score to 1 point .,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6e148a06-50fc-45f3-90ea-023dc8687577-2023-05-25T160000.000Z,2095,PubMed:30976389 +Wang_mitochondrial dysfunction,Biochemical Function B,"Wang Y, et al., 2017, PMID: 28638454",Fibroblasts from patients with SSBP1 variants show mtDNA deletion and depletion as well as reduced protein levels of TFAM and POLG1 and reduced area and volume of nucleoids.,Score,0.5 (0.5),Default points are scored based on expert review.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_51701b05-3956-4d7b-adc7-7ba4192e8283-2021-05-20T160000.000Z,2096,PubMed:28638454 +SSBP1 mitochondrial maintenance,Biochemical Function A,"Rahman J, et al., 2017, PMID: 27977873","SSBP1 is a housekeeping gene involved in mitochondrial biogenesis, including mtDNA replication and maintenance (summary by Tiranti et al., 1995; Jurkute et al., 2019). It is also a subunit of a single-stranded DNA (ssDNA)-binding complex involved in the maintenance of genome stability (Huang et al., 2009). Four other mitochondrial maintenance genes (POLG, SUCLA2, SUCLG1, and FBXL4) have been implicated in causing Leigh syndrome.",Score,1 (0.5),SSBP1 shares a similar function to 2-5 genes associated with Leigh syndrome (Awarded 1 pt),https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6ef6f4e7-6e59-4eaf-b303-7f975542d1b9-2021-06-14T144803.625Z,2097,PubMed:27977873 +th17 in Stat3 GOF patients,Biochemical Function B,"Wienke J, et al., 2015, PMID: 26343524","Groups have shown that Stat3 is important for the development of the T helper 17 subset of CD4 T cells. TH17 cells are commonly associated with autoimmunity. Thus, this relationship between Stat3 and increased Th17 in patients with autoimmunity may be causal.",Score,0.25 (0.5),"The evidence for autoimmunity is correlative with Th17 production and is not actually shown in the paper, thus, I am downgrading the score.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_47daba8d-d94b-4efc-ac42-28d9dd81e891-2022-02-16T181712.967Z,2103,PubMed:26343524 +Stat3-K392R mouse,Model Systems Non-human model organism,"Warshauer JT, et al., 2021, PMID: 34115115","In humans, this STAT3 GOF variant is associated with early incidence of type I diabetes. In the NOD mouse model, mice start to become diabetic between 10-15 weeks of age. With the addition of the human STAT3 variant, the mice start became diabetic at 5-10 weeks of age.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_47daba8d-d94b-4efc-ac42-28d9dd81e891-2022-02-16T181712.967Z,2103,PubMed:34115115 +STAT3 DNA binding,Functional Alteration Non-patient cells,"Asano T, et al., 2021, PMID: 34137790","Transfection of variants into HEK293 cells resulted in the reduction of STAT3 DNA binding for the majority of variants. For those variants without decreased DNA binding, alternative splicing was investigated, and it was found that alternative transcripts or translation reinitiating were being generated that resulted in variants with dominant negative effects.",Score,1 (0.5),"This is an extensive work that demonstrates the vast majority of STAT3 LOF variants are dominant negative and not loss of heterozygosity. I have upgraded the score due to the vast number of variants tested, as well as the quality of the data generated.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_beb3aa5b-240e-45d7-969a-9de3e5564457-2021-12-24T160548.234Z,2104,PubMed:34137790 +Knock-In STIM1 I115F Mouse Model,Model Systems Non-human model organism,"Cordero-Sanchez C, et al., 2019, PMID: 31666234","Characterization of wt mice compared to I115F mice shows no signs of early mortality. The mutant mice do appear smaller and have a larger heart/spleen when comparing to WT sizes. Myotubes from I115F mice show significantly altered and increased SOCE as compared to wt mice as early as 1 month and consistently elevated throughout the mouse lifetime. Histological and functional alterations are present in the mutant I115F mice as well with reduced muscle mass, myopathic muscle fibers, and pseudo-aggregates resembling the tubular aggregates of human TAM. Motor and strength performance also decreased in mutant mice, with the reduced ability becoming evident at 3 months until the end of their lifetime. Significant hematological defects were observed as well, with pronounced thrombocytopenia and increased bleeding observed similar to human probands on the more severe end of the TAM spectrum.",Score,3 (2),"This model recpitulates most of the significant phenotypes that are characteristic of the human STIM1 probands, including thrombocytopenia, muscle weakness, necrosis, muscle fiber myopathic signs, and pseudo-tubular inclusions. Additionally, these mice displayed the same pathogenic mechanism as humans in the increased Calcium influx and disruption of SOCE. Therefore, since this is a human pathogenic variant expressed and the quality of the phenotypes, this model is upgraded to 3.0 points.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9419adda-b3fb-4c2d-8562-6a0318260bbd-2021-04-01T160000.000Z,2107,PubMed:31666234 +STRC Null Mouse,Model Systems Non-human model organism,"Verpy E, et al., 2008, PMID: 18849963","The knockout of the STRC gene in mice causes progressive deafness, where variation in the gene causes prelingual hearing loss in humans. Additionally, they found that low magnification scanning electron micrographs could show that the stereocilia of STRC -/- mice were less aligned than STRC +/+ mice. Immunolabeling confirmed absence of STRC in null mouse. Used Cochleaer microphonics and compound action potentials as well as distortion-product otoacoustic emissions (DPOAE) to measure hearing loss.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_977b98b7-00f4-4200-9b17-f37303889ab4-2017-12-19T050000.000Z,2110,PubMed:18849963 +SUCLG1 interaction,Protein Interaction,"Madej T, et al., 2014, PMID: 24319143","SUCLA2 encodes the beta subunit of mitochondrial succinyl CoA synthetase which forms a heterodimer with SUCLG1 resulting in an ATP/ADP specific. Their interaction and formation of ADP-forming succinyl-CoA ligase complex SUCLG1-SUCLA is demonstrated via x-ray crystallography experiments on NIH NCBI Molecular Modeling Database. SUCLG1 has been curated and determined to have a moderate associated with Leigh syndrome spectrum. Therefore, this interaction provides further evidence in support of SUCLA2 and its association with Leigh syndrome spectrum.",Score,0.5 (0.5),The encoded protein interacts with one gene product whose dysfunction is known to cause Leigh syndrome. (Awarded 0.5 pts),https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_eedc8c99-a02a-4a34-ba72-1b0fc975e63f-2019-04-18T180100.762Z,2114,PubMed:24319143 +SUCLA2 knockdown in murine neuronal cells,Functional Alteration Non-patient cells,"Zhao Y, et al., 2017, PMID: 28769029","ShRNA targeting SUCLA2 in mouse neuronal cells, leading to a significant reduction in SCS A-B activity, was studied. Cells demonstrated reduced mitochondrial membrane potential, reduced ATP content, increased oxidative stress demonstrated by Mitosox fluorescence, mitochondrial depletion, suppression of both mitochondrial fusion and fission proteins, and reduced synaptic density.",Score,1 (0.5),Cell culture model with SUCLA2 knockdown was performed in a neuronal cell type providing increased evidence of its pathological relationship with Leigh syndrome. (Awarded 1 pt),https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_eedc8c99-a02a-4a34-ba72-1b0fc975e63f-2019-04-18T180100.762Z,2114,PubMed:28769029 +Sufu p.T396I mutant mice have dysregulated Gli3 activity,Model Systems Non-human model organism,"Makino S, et al., 2015, PMID: 25760946","Sufu T396I/T396I embryos exhibited severe polydactyly and demonstrated a spectrum of developmental anomalies including cranio-facial defects, collectively indicative of compromised Gli3 activity. The clinical and functional anomalies of this knock-in model closely resemble those of the affected children described in De Mori et al. 2017.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_59700c43-cff6-454e-895f-623c8cd68f8e-2023-03-22T160000.000Z,2117,PubMed:25760946 +Knock down (post-transcriptional silencing of CG9943),Model Systems Non-human model organism,"Da-Rè C, et al., 2014, PMID: 25164807",Decreased oxidative phosphorylation is included in Leigh syndrome spectrum definition,Score,1 (2),"Per Mito GCEP guidance: 0/3 points for neuropath evidence; 0/2 points for MRI evidence, 1/1 points for biochem or mito dysfunction; 0/1 point for neurocognitive/developmental difference = 1",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_2ed17d9b-e746-4f1f-9c39-26f46bb2eadc-2019-04-08T160338.698Z,2119,PubMed:25164807 +Knockout cloned pigs,Model Systems Non-human model organism,"Quadalti C, et al., 2018, PMID: 29601977","neuropathological evidence somewhat consistent with Leigh syndrome spectrum diagnosis, biochemical/mito evidence somewhat consistent with Leigh syndrome spectrum diagnosis; neurocognitive/developmental differences somewhat consistent with Leigh syndrome spectrum",Score,2 (2),Per MitoGCEP guidance: 1/3 for neuropathological evidence; 0/2 for MRI evidence; 0.5/1 for biochem/mito dysfunction; 0.5/1 for neurocognitive/developmental differences = 2,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_2ed17d9b-e746-4f1f-9c39-26f46bb2eadc-2019-04-08T160338.698Z,2119,PubMed:29601977 +drosophila transgenic model,Model Systems Non-human model organism,"Montes-Chinea NI, et al., 2018, PMID: 30533528",Both animal model and patients developed presynaptic NMJ dysfunction.,Score,0 (2),Same KO drosophila model from another paper was already curated and received points,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ff8871e1-5eed-4414-8137-432d57f328d1-2023-07-12T160000.000Z,2124,PubMed:30533528 +Richman function,Biochemical Function B,"Richman TR, et al., 2016, PMID: 27319982",TACO1 is an RNA-binding protein that specifically binds the cytochrome c oxidase (COX) subunit I (MT-CO1) mRNA and is required for COXI translation; MT-COI is a component of complex IV of the mitochondrial respiratory complex. MT-COI associated with clinically heterogeneous mitochondrial disorders.,Score,2 (0.5),"LeighMap paper 19 other translational proteins related to LS, increase points to maximum per Mito GCEP biocuration review meeting.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ae2fd0e4-db4e-4e17-bfc8-c43719066f97-2019-10-16T150433.004Z,2126,PubMed:27319982 +Knockout mouse model,Model Systems Non-human model organism,"Richman TR, et al., 2016, PMID: 27319982","Neuropathological evidence (Purkinje cell loss in cerebellum, atypical finding), mitochondrial dysfunction (demonstrated complex IV deficiency), motor dysfunction (progressive motor decline and incoordination)",Score,2.5 (2),"Scored neuropathological evidence 0.5 points (Purkinje cell loss in cerebellum, atypical finding), mitochondrial dysfunction 1 point (demonstrated complex IV deficiency), and motor dysfunction 1 point (progressive motor decline and incoordination), per Mito GCEP review meeting",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ae2fd0e4-db4e-4e17-bfc8-c43719066f97-2019-10-16T150433.004Z,2126,PubMed:27319982 +Identification of a FUS/TLS protein interaction network,Protein Interaction,"Sun S, et al., 2015, PMID: 25625564","FUS/TLS was triply tagged, including a localization-affinity purification (LAP)-tag. Tandem affinity purification was used to elute FUS/TLS-associated proteins and quantitative mass spectrometry was used to identify the proteins. The criteria for protein identification included 1) a calculated False Discovery Rate (FDR) below 1%, 2) all the proteins must have been identified with more than two unique peptides, and 3) all peptide signals for each protein must have at least 4-fold enrichment in FUS/TLS immunoprecipitates compared to the control. The FUS/TLS interactome was found to be comprised of 35 proteins, one of which was TAF15.",Score,0.25 (0.5),"Known ALS-associated protein, FUS, was found to directly interact with other ALS-linked RNA binding proteins, including TAF15, through affinity chromatography followed by quantitative mass spectrometry. +The score was reduced as the mass spectrometry results for TAF15 were not validated with Western blot and many RNA binding proteins were pulled down in the affinity chromatography.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_605446ae-fd1f-4451-bd49-643c24cd652e-2021-11-03T020945.214Z,2127,PubMed:25625564 +RNASeq of TAF15 and FUS Downregulated Motor Neuron,Biochemical Function A,"Kapeli K, et al., 2016, PMID: 27378374","∼76 and 85% of the genes in the FUS-only and TAF15-only knockdown experiments were also downregulated in the double knockdown. However, we found that a subset of genes (n=144) were downregulated only upon combined loss of TAF15 and FUS in human MNs (Fig. 6f), indicating a potential redundancy between TAF15 and FUS in controlling gene expression. These genes that were downregulated upon combined TAF15 and FUS loss were enriched for GO terms, reflecting extracellular cellular matrix composition, cell proliferation, wound healing and cytokine activity. +Upon comparison to the RNASeq results from iPSC generated motor neurons from fibroblasts of two ALS patients with causative R521G mutation in FUS, in addition to the overlap between the genes downregulated and those downregulated by loss of TAF15, there was also overlap with the genes downregulated by loss of FUS and to a greater extent when compared the genes affected by simultaneous depletion of both FUS and TAF15.",Score,0 (0.5),"The results of this experiment are very similar to those reported by Ibrahim et al (PMID: 23416048), in the experiment entitled TAF15 Targets Genes with Synaptic Activities",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_605446ae-fd1f-4451-bd49-643c24cd652e-2021-11-03T020945.214Z,2127,PubMed:27378374 +TANC2 disease mutations affecting KIF1A interaction,Functional Alteration Non-patient cells,"Stucchi R, et al., 2018, PMID: 30021165","Unlike WT TANC2, TANC2-R1066X failed to accumulate at the dendritic spines seen by dendritic protrusions of neurons expressing GFP-TANC2_WT, GFP-TANC2_R760C or GFP-TANC2_R1066X. These results are in agreement with the important role of the C-terminal PDZ binding domain for TANC2 synaptic localization. The missense mutation did not impair localization, but it was enough to be detrimental to KIF1A binding and thus impair the recruitment of KIF1A-transported vesicles. This was verified by quantifications of average run length, speed and run duration of anterograde/retrograde transport of vesicles in the axon initial segment of neurons co-expressing wild-type or R760C mutant TANC2.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b3d3d067-5a78-44b4-9c57-25cc784123bf-2022-09-07T160000.000Z,2129,PubMed:30021165 +AP-MS of TANC2 in rat brain extracts,Protein Interaction,"Stucchi R, et al., 2018, PMID: 30021165","bioGFP-TANC2 was expressed in HEK293 cells, purified using streptavidin-pulldowns and then incubated with rat brain extracts. Co-purified proteins have been identified by AP-MS and classified as TANC2 interactors. Postsynaptic density proteins, such as PSD-95(DLG4), SAP-97(DLG1), CASK, Scribble, Centaurin gamma2 and 3 (AGAP1 and AGAP3), and various subunits of the NMDA receptor (Grin1 and Grin2B) were identified as the main interactors of TANC2. Grin1 and Grin2B have been curated by the ClinGen Epilepsy GCEP and found to be definitively linked to autosomal dominant Complex NDD. TANC2 was also found to be interacting with KIF1A also through BioID and AP-MS. KIF1A is a gene previously curated by the ClinGen ID/ASD GCEP and found to be definitively associated with autosomal dominant syndromic ID. CASK has also been curated by the ClinGen ID/ASD GCEP as definitively associated with X-linked syndromic intellectual disability.",Score,1 (0.5),Score was upgraded by Expert Panel from 0.5 to 1 due to the number of physical interaction partners of TANC2 that have been associated with neurodevelopmental disorders.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b3d3d067-5a78-44b4-9c57-25cc784123bf-2022-09-07T160000.000Z,2129,PubMed:30021165 +Heterozygous TANC2 mice models,Model Systems Non-human model organism,"Kim SG, et al., 2021, PMID: 33976205","The synaptic and behavioral phenotypes of Tanc2+/− mice implicate Tanc2 in the regulation of synaptic plasticity and behaviors, including long term potentiation, learning and memory, hyperactivity, and anxiety-like behavior, which are phenotypes consistent with the disease of interest.",Score,1 (2),Downgraded by the expert panel from 2 points to 1 point since the mouse behavior is non-specific.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b3d3d067-5a78-44b4-9c57-25cc784123bf-2022-09-07T160000.000Z,2129,PubMed:33976205 +Mouse hippocampal neurons with Taok1 knock-down,Model Systems Cell culture model,"van Woerden GM, et al., 2021, PMID: 33565190",Cultured mouse hippocampal neurons with Taok1 knock-down showed neuronal migration deficit. proper neuronal migration is important for normal brain development.,Score,0.5 (1),Downgraded because shRNA off-target effects were not ruled out. Rescue experiment were not performed.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_79c712d0-ac0e-4bf0-8e68-bd598b3bca42-2021-08-04T160000.000Z,2130,PubMed:33565190 +Taok1 knock-down embryonic mouse brain,Model Systems Non-human model organism,"van Woerden GM, et al., 2021, PMID: 33565190","Reduced Taok1 expression levels in the embryonic mouse brain affect neural migration in vivo, a process that is critical for normal brain development.",Score,1.5 (2),"Because TAOK1 role in neuronal migration was scored in other experimental evidences included in this curation, evidence from this model system was lowered to prevent scoring the same evidence twice.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_79c712d0-ac0e-4bf0-8e68-bd598b3bca42-2021-08-04T160000.000Z,2130,PubMed:33565190 +Proteasome inhibition increases proteolytic cleavage of TDP,Functional Alteration Non-patient cells,"Rutherford NJ, et al., 2008, PMID: 18802454","In the presence of proteasome inhibitor PSI, TDP-43 was cleaved into ∼35 and ∼25 kDa fragments, which also led to a marked increase in cleaved (active) capase-3 levels, which promotes apoptotic cell death and accumulates upon such inhibition. Furthermore, when we co-treated the cells with PSI and the caspase inhibitor, Z-VAD (OMe)-FMK, the generation of proteolytic TDP-43 fragments was inhibited. HSP70 immunoblot analysis was used to verify the inhibition of the proteasomal machinery. As expected, HSP70 levels were increased after PSI treatment and the levels persisted in the presence of caspase inhibitor Z-VAD (OMe)-FMK.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_bf8bf781-25c9-4f16-b8cc-b0533390e4e2-2021-07-27T160623.437Z,2134,PubMed:18802454 +TDP-43 (N390D/+) knock-in mice,Model Systems Non-human model organism,"Huang SL, et al., 2020, PMID: 31964415","Concentrated on the use of the N390D/+ male mice as around 30% of the N390D/+ female mice were indistinguishable from the +/+ female mice suggesting that estrogen might exert a protective effect - this could be related to the increased prevalence of ALS in males compared with females. +Physical phenotypes +ALS patients experience declines in various motor functions across disease course, and these mice showed a similar age-dependent decline in various motor functions including performance of rotarod and abnormal hind limb-clasping and kyphosis as well as spastic and trembled gait later in life. They also showed paralysis in the hindlimb, and patients do experience paralysis later in disease course. (figure 2, Additional file 9: Movie S1 and Additional file 10: Movie S2, Additional file 11: Movie S3). +ALS patients experience muscle atrophy, which was also exhibited by the mice in the calf muscles and shown by loss of soleus muscle mass (Fig. 2d and e). +Furthermore, while the innervation of neuromuscular junctions (NMJ) in the soleus muscle of 3-month old N390D/+ mice appeared to be normal as the +/+ mice (yellow color, Fig. 2f), denervation of the NMJ of soleus muscle was detected in N390D/+ mice at the age of 6 months, as exemplified in the representative images of the bottom panel in Fig. 2f, by approximately 23% in comparison to the +/+ male mice (Fig. 2g). The extent of NMJ denervation progressively increased with further aging of the N390D/+ mice (data not shown). +Various molecular cellular changes seen in humans was also recapitulated in this mouse model. This includes: +Accumulation, enhanced cleavage, elevated phosphorylation and increased insolubility of spinal cord TDP-43 +Age-dependent mislocalization of TDP-43 and pTDP-43, accumulation of ubiquitinated proteins in spinal cord MN, and loss of spinal cord MN +Alteration of autophagy and proteasome activity +Increase of spinal cord Bcl-2 protein as a consequence of mis-regulation of Bcl-2 pre-mRNA splicing",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_bf8bf781-25c9-4f16-b8cc-b0533390e4e2-2021-07-27T160623.437Z,2134,PubMed:31964415 +Mitochondrial translation Leigh Map,Biochemical Function A,"Rahman J, et al., 2017, PMID: 27977873","The TARS2 gene encodes mitochondrial threonyl-tRNA (Thr-tRNA) synthetase, which is involved in mitochondrial translation (summary by Diodato et al., 2014). More than 10 other nuclear and mitochondrial genes with a similar function have been implicated in causing Leigh syndrome (GFM1, GFM2, TSFM, TRMU, MTFMT, GTPBP3, TACO1, MTRFR, LRPPRC, EARS2, FARS2, IARS2, NARS2, MT‐TI, MT‐TK, MT‐TL1, MT‐TL2, MT‐TV, MT‐TW)",Score,2 (0.5),TARS2 shares similar function more than 10 genes known to cause Leigh syndrome (Score 2 pt per scoring rubric),https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_475a994f-8420-45bb-8f14-9fe85cdcdbbc-2021-06-14T144425.888Z,2135,PubMed:27977873 +Drosophila model lacking TBC1D24,Model Systems Non-human model organism,"Fernandes AC, et al., 2014, PMID: 25422373","Drosophila model lacking gene, called Sky. Authors claim that mechanism for neurodegradation is at endosome-to-lysosome trafficking stage. They found that synaptic vesicle-associated proteins were ""younger"", suggesting older proteins are more efficiently degraded, and that synaptic transmission is facilitated by efficient protein turnover at lysosomes.",Score,0.5 (2),Potential molecular mechanism,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0fcb9839-6798-4195-8959-08d45bc63339-2020-03-11T132031.642Z,2136,PubMed:25422373 +TBC Domain,Biochemical Function B,"Finelli MJ, et al., 2016, PMID: 26668325",Also tested p.A515V and p.C156X. These were shown to reduce ability of gene to confer neuroprotection compared to WT TBC1D24,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0fcb9839-6798-4195-8959-08d45bc63339-2020-03-11T132031.642Z,2136,PubMed:26668325 +Mitophagy and mitochondrial function in TBCK−/− fibroblasts,Functional Alteration Patient cells,"Tintos-Hernández JA, et al., 2021, PMID: 34816123","TBCK-/- fibroblasts from 4 patients homozygous for p.Arg126* show impaired mitochondrial control, including accumulation of mitophagosomes, reduced mitochondrial respiratory capacity and mitochondrial DNA content. Lysosomal proteolytic function is also significantly reduced in these cells. Acidifying lysosomal nanoparticles rescues the mitochondrial respiratory defects in fibroblasts, suggesting impaired mitochondrial quality control secondary to lysosomal dysfunction. In addition, the degree of mitochondrial dysfunction was correlated with a neurodegenerative clinical course (observed in patients with the recurrent p.Arg126* variant compared to patients with a milder phenotype, without evidence of disease progression).",Score,1 (1),"Mitochondrial and lysosomal defects observed in fibroblasts from patients from Puerto Rico with the p.Arg126* founder variant (Boricua mutation) who exhibit a severe neurodegenerative phenotype with prominent motor neuron degeneration, but not in patients with other LoF variants with a milder phenotype. The reason for this is unclear at present. Note that the autopsy report of 2 sisters with a p.Gln102* variant and a similar neurodegenerative phenotype also showed signs of a lysosomal storage disease (Beck-Wödl et al. 2018, PMID: 30591081).",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1df2bd2a-9170-401b-b680-5f8613043b33-2024-02-07T200000.000Z,2138,PubMed:34816123 +Alterations in neuroprogenitor cells from patient iPSCs,Functional Alteration Patient cells,"Moreira DP, et al., 2022, PMID: 35095425","Neuroprogenitor cells (iNPC) derived from induced pluripotent stem cells (iPSC) from two siblings with biallelic LoF variants showed impaired autophagosome biogenesis, cell cycle progression, and migration. iNPC of patients also showed decreased mTOR signaling.",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1df2bd2a-9170-401b-b680-5f8613043b33-2024-02-07T200000.000Z,2138,PubMed:35095425 +TBK1 mutant transfected HEK293T cells functional alterations,Functional Alteration Non-patient cells,"de Majo M, et al., 2018, PMID: 30033073","Decreased phosphorylation of the substrate IRF3. +Western blot showing reduced levels of phosphorylated IRF3 for the mutants compared to WT, confirmed using immunocytochemistry. + + +Decreased binding to, and phosphorylation of, OPTN. +Co-IP with HA-tag pull down of TBK1 showing no binding of OPTN for mutants compared to WT. transiently cotransfected HEK293T treated with alkaline phosphatase and analyzed by Western blot showed a lack of OPTN phosphorylation in mutated samples. + + +Decrease the phosphorylation of TBK1 itself. +Western blot showing reduced levels of phosphorylated TBK1 for the mutants compared to WT, confirmed using immunocytochemistry. + + +Disruption of TBK1 homodimerization. +Native gel analysis of transiently cotransfected HEK293T cells showed weaker dimer and monomer for G217R.",Score,1 (0.5),"Four distinct functional alterations have been demonstrated for two different mutations, thus have increased to a maximum score of 1.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_509b9e29-d354-4974-96e9-e819c3fee579-2022-11-03T160000.000Z,2139,PubMed:30033073 +TBK1 mutant lymphoblastoids show reduced TBK1phosphorylation,Functional Alteration Patient cells,"de Majo M, et al., 2018, PMID: 30033073",Western blot analysis of 5 patient lymphoblastoid cell lines carrying 5 different TBK1 mutations showed lower levels of phosphorylated TBK1 compared to 7 controls lymphoblastoid cell lines. This difference was quantitated using an unpaired 2 tailed t-test (p=0.0229).,Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_509b9e29-d354-4974-96e9-e819c3fee579-2022-11-03T160000.000Z,2139,PubMed:30033073 +Conditional neuron-specific Tbk1 knockout mouse model,Model Systems Non-human model organism,"Duan W, et al., 2019, PMID: 31039129","Reduced (barely detectable) expression of TBK1 in TBK1-NKO mice neuronal tissues (cortex and cerebellum), mimicking the haploinsuffieceincy of TBK1 observed in ALS patient TBK1 mutation carriers. +Impaired motor function, demonstrated by reduced swimming distance of TBK1-NKO mice, recapitulating motor impairments experienced by ALS patients, loss of the ability/reduced capacity to walk. +ALS patients display numerous neuropathological changes, including the loss/death of motor neurons, abnormally shaped neurons, presence of ubiquitinated protein inclusions in affected motor neurons, etc. Many similar features were observed in TBK1-NKO mice, namely: A) abnormally shaped neurons in the cortex Fig. 4A and Fig S1, B) decreased density of dendritic spines in the cortex and hippocampus (Fig. 4B, C and Fig. S2), C) reduced number of synapses in the cortex (Fig. 4D, E), D) Presence of protein aggregates containing ubiquitin and p62 (Fig. 5), E) increased astrocyte activation (Fig. 6A), F) glial degeneration (Fig. 6B), G) p62 aggregates in abnormal cerebellar astrocytes (Fig. 6C), H) elevated p62 expression in cerebellum and cortex (only significant in the cortex) (Fig. 7A) and I) dendritic swelling in the Purkinje cell layer +and neurofibrillary tangles in the cortex (Fig. 8).",Score,0 (2),Homozygous deletion does not TBK1 in this mouse model does not mirror the effects of homozygous deletion of TBK1 in humans (lethality).,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_509b9e29-d354-4974-96e9-e819c3fee579-2022-11-03T160000.000Z,2139,PubMed:31039129 +TBK1 interacts with the ALS protein UBQLN2,Protein Interaction,"Chen T, et al., 2020, PMID: 32413959","Numerous mutations in UBQLN2 have been implicated a cause of ALS, this disease-gene relationship has been curated and classed as ""definitive"" by the ClinGen ALS GCEP. +TBK1 and OPTN have been demonstrated as protein interacting partners through both 1) immunoprecipitation of TBK1-myc and UBLN2-Flag, in both directions and 2) GST pull-down where His-UBQLN2 was effectively pulled down with GST-TBK1.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_509b9e29-d354-4974-96e9-e819c3fee579-2022-11-03T160000.000Z,2139,PubMed:32413959 +Kennedy 2017,Model Systems Non-human model organism,"Kennedy L, et al., 2017, PMID: 28945738",A reduced EF and dilation of the LV would correlate to a human DCM phenotype.,Score,0 (2),DCM phenotype was only present with tbx20; casz1 compount heterozygous mice. Mice heterozygous for one of the two loss of function proteins did not display a DCM phenotype.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_58a014d9-2d97-4041-961d-cfd09fa11adf-2020-08-12T160000.000Z,2142,PubMed:28945738 +Kennedy Protein Interaction,Protein Interaction,"Kennedy L, et al., 2017, PMID: 28945738",F2561 variant recognized to greatly decrease interaction with CASZ1. This mutation has been identified in DCM family to result in LOF mutation and have a dominant negative effect.,Score,0 (0.5),CASZ1 does not have a known association with DCM. Cannot be scored.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_58a014d9-2d97-4041-961d-cfd09fa11adf-2020-08-12T160000.000Z,2142,PubMed:28945738 +Figure 1. Expression of Tbx4 and Tbx5 in the developing lung,Expression A,"Arora R, et al., 2012, PMID: 22876201","Strong expression of Tbx4 in the developing mouse lung and trachea. TBX4 plays an important tole in branching morphogenesis during lung development. Elsewhere, expression has also been confirmed in human lung tissues.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1b8cc228-67d2-4530-8129-ebafee7fafa1-2021-03-10T214611.990Z,2144,PubMed:22876201 +In vitro protein-protein interaction,Protein Interaction,"Gregorio CC, et al., 1998, PMID: 9817758","Using yeast two-hybrid studies, interaction between NH2-terminal titin domains (Z1-Z2) and TCAP was demonstrated. An immunoelectron microscope showed co-localization of these two domains.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_4c8ab9d8-919a-443f-b027-5aec92b273d1-2020-08-12T160000.000Z,2148,PubMed:9817758 +Zebrafish model,Model Systems Non-human model organism,"Teng CS, et al., 2018, PMID: 30375332",Both zebrafish and humans experience coronal synostosis.,Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_11e46ed0-dbfb-4151-ba1c-cc56214d6ca6-2021-01-28T170000.000Z,2150,PubMed:30375332 +In situ hybridization,Expression A,"Teng CS, et al., 2018, PMID: 30375332",Tcf12 expression was observed within the mesenchyme of not only the coronal but also the metopic and sagittal sutures. Tcf12 expression was also observed more broadly in the suture mesenchyme and cells surrounding the skull bone,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_11e46ed0-dbfb-4151-ba1c-cc56214d6ca6-2021-01-28T170000.000Z,2150,PubMed:30375332 +RAI1 similarity,Biochemical Function A,"Vetrini F, et al., 2019, PMID: 30819258","RAI1 is transcriptional regulator like TCF20, and the two are structurally related. RAI1 is the dosage-sensitive gene responsible for Smith–Magenis syndrome (deletion/haploinsufficiency), a complex disorder characterized by ID, sleep disturbance, multiple congenital anomalies, obesity, and neurobehavioral problems [ref 17–21 in this paper]. BabySeq has classified the RAI1:SMS association as Definitive.",Review,0 (0.5),"Could consider awarding a reduced score of 0.25 since related gene is associated with a similar, but not the same, phenotype. However, syndromic neurodevelopmental disorders are a large class as are transcriptional regulators, and no demonstration of shared target genes.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_619ae2be-5ab6-418d-8824-373369337faa-2020-10-07T172001.182Z,2151,PubMed:30819258 +Arrest in B cell development in E47−/− mice,Model Systems Non-human model organism,"Beck K, et al., 2009, PMID: 19752184",Arrest in B cell development with resultant agammaglobulinemia and early onset infections is well observed in patients carrying TCF3 mutations. The model system showed that E47 is essential for developmental progression at the prepro–B cell stage.,Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_402ff7db-2e09-4e76-9284-1e7c4ae84fb3-2023-01-07T120000.000Z,2153,PubMed:19752184 +mouse conditional knock out,Model Systems Non-human model organism,"Chodelkova O, et al., 2018, PMID: 29751817","Conditional knock-out analysis showed that Tcf7L2, but not Tcf7L1, is the principal Wnt mediator important for maintenance of progenitor cell identity in the ventricular zone. In the absence of Tcf7L2, the Wnt activity is reduced, ventricular zone markers Pax6 and Sox2 are downregulated and the neuroepithelial structure is severed due to the loss of apical adherens junctions. This results in decreased proliferation of radial glial cells, the reduced number of intermediate progenitors in the subventricular zone and hypoplastic forebrain.",Score,1 (2),two mouse model show similar neurology phenotype,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b11a5317-868b-49a9-b051-721940fb5936-2021-12-15T170000.000Z,2155,PubMed:29751817 +RT-PCR of TCOF1 in TCS Patients,Expression B,"Masotti C, et al., 2009, PMID: 20003452",RT-PCR showed decreased transcription of TCOF-1 in leukocytes and mesenchymal cell samples from patients with Treacher Collins syndrome.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3f91c5fe-8e58-4c98-9878-e428e2e41dd7-2019-09-17T160000.000Z,2158,PubMed:20003452 +Garcia-Gonzalo_Protein Interaction,Protein Interaction,"Garcia-Gonzalo FR, et al., 2011, PMID: 21725307","Demonstrated that Tctn2 and Tctn1 interact with other proteins in a large complex localized to the transition zone between the ciliary axoneme and the basal body.  +Generated NIH-3T3 cells stably expressing Tctn1 fused to a localization and affinity purification (LAP) tag +Identified 154 proteins specifically in the Tctn1-LAP purification. Among the proteins with the highest number of mass spectra, the two strongest Tctn1 interactors were Tctn2 and Tctn3 +Coimmunoprecipitation assays using tagged proteins expressed in COS1 cells showed Tctn1 interacted with Tctn2 (and Tctn3, Mks1, Cc2d2a and B9d1).",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_82bc1eb0-882b-48a2-a29f-23bec8d75def-2023-07-27T160000.000Z,2159,PubMed:21725307 +Garcia-Gonzalo_Mouse,Model Systems Non-human model organism,"Garcia-Gonzalo FR, et al., 2011, PMID: 21725307",showed that Tctn2 affects Ciliogenesis in a tissue-specific manner.,Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_82bc1eb0-882b-48a2-a29f-23bec8d75def-2023-07-27T160000.000Z,2159,PubMed:21725307 +TECRL expression,Expression A,"Devalla HD, et al., 2016, PMID: 27861123","In adult mice, reverse transcription quantitative polymerase chain reaction (RT–qPCR) analyses showed that Tecrl expression was highest in the heart with very low to almost undetectable levels in brain, skeletal muscle, stomach, pancreas, liver, kidney, small intestine, and uterus (Appendix Fig S1E). Expression analysis of TECRL across a panel of human tissues clearly demonstrates that TECRL is predominantly expressed in the heart and skeletal muscle (Fig 2I).",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6889dc44-eef0-4a4d-8fdb-aef2dc570f29-2021-01-20T170000.000Z,2161,PubMed:27861123 +TECRLc.331+1G>A characterisation,Functional Alteration Patient cells,"Devalla HD, et al., 2016, PMID: 27861123","Analysis of intracellular calcium ([Ca2+]i) dynamics revealed smaller [Ca2+]i transient amplitudes as well as elevated diastolic [Ca2+]i in TECRL-homozygous-hiPSC-CMs with the TECRLc.331+1G>A mutation compared with Control-hiPSC-CMs. The [Ca2+]i transient also rose markedly slower and contained lower sarcoplasmic reticulum (SR) calcium stores, evidenced by the decreased magnitude of caffeine-induced [Ca2+]i transients. +TECRL-homozygous-hiPSC-CMs with the TECRLc.331+1G>A mutation showed prolonged action potentials (APs) compared with Control-hiPSC-CMs. Moreover, stimulation by noradrenaline significantly increased the propensity for triggered activity based on delayed afterdepolarizations (DADs).",Score,2 (1),In-depth characterisation of variant effect with numerous assays and multiple effects demonstrated.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6889dc44-eef0-4a4d-8fdb-aef2dc570f29-2021-01-20T170000.000Z,2161,PubMed:27861123 +Stooke-Vaughan Animal Model,Model Systems Non-human model organism,"Stooke-Vaughan GA, et al., 2015, PMID: 25758224","Zebrafish model rolling stones (rst) arose in mutagenesis study. Rst mutatns have ""otoliths that are loose within the ear"". Embryos 3-5 dpf showed misplaced saccular otolith that was untethered or stuck on ventral floor of the otic vesicle. Nonsense variant found in Tecta ortholog.",Score,1 (2),Downgraded for animal model type,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0c7395aa-89bb-40e2-a226-0500fef478bb-2018-01-02T170000.000Z,2162,PubMed:25758224 +Stooke-Vaughan Expression,Expression A,"Stooke-Vaughan GA, et al., 2015, PMID: 25758224",Expression of tecta in the zebrafish was specific to sensory maculae in zebrafish ear. Also wasn't expressed in the cristae.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0c7395aa-89bb-40e2-a226-0500fef478bb-2018-01-02T170000.000Z,2162,PubMed:25758224 +Legan Animal Model,Model Systems Non-human model organism,"Legan PK, et al., 2014, PMID: 24363064","Supported genotype-phenotype correlation of mutations in zona adhesion and zona pellucida domains with progressive, HF HL and stable, mid-freq HL respectively. Mutations were also semi-dominant, with homozygotes having more severe phenotype, but says unlikely that het phenotype is caused by haploinsufficiency.",Score,4 (2),Upgraded because this paper has three mouse models with variants seen in humans that are well characterized.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_95b38b73-f807-4401-9600-fe1f319b9dd9-2018-01-02T170000.000Z,2163,PubMed:24363064 +Stooke-Vaughan Expression,Expression A,"Stooke-Vaughan GA, et al., 2015, PMID: 25758224",Expression of tecta in the zebrafish was specific to sensory maculae in zebrafish ear. Also wasn't expressed in the cristae.,Review,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_95b38b73-f807-4401-9600-fe1f319b9dd9-2018-01-02T170000.000Z,2163,PubMed:25758224 +TERT reactivation reverses tissue degeneration in aged mice,Rescue Non-human model organism,"Jaskelioff M, et al., 2011, PMID: 21113150","Homozygous TERT-ER mice had short dysfunctional telomeres and sustained increased DNA damage signaling and classical degenerative phenotypes upon successive generational matings and advancing age. Telomerase reactivation in such late generation TERT-ER mice extended telomeres, reduced DNA damage signaling and associated cellular checkpoint responses, allowed resumption of proliferation in quiescent cultures, and eliminated degenerative phenotypes across multiple organs including testes, spleen, and intestine.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_afb6ea76-e8ac-4a38-b42c-23fc18a9623b-2020-07-30T205843.081Z,2167,PubMed:21113150 +CKO TERT Mesenchymal Cells Impairs Mouse Pulmonary Fibrosis.,Model Systems Non-human model organism,"Liu T, et al., 2015, PMID: 26555817","TERT-specific deficiency in mesenchymal cells caused attenuation of pulmonary fibrosis as manifested by reduced lung hydroxyproline content, type I collagen and α-smooth muscle actin mRNA levels. The TERT-deficient mouse lung fibroblasts displayed decreased cell proliferative capacity and higher susceptibility to induced apoptosis compared with control cells.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_afb6ea76-e8ac-4a38-b42c-23fc18a9623b-2020-07-30T205843.081Z,2167,PubMed:26555817 +DNA methylation profiling,Functional Alteration Patient cells,"Levy MA, et al., 2021, PMID: 34750377","Genome-wide DNA methylation profiling of whole blood identified a unique TET3 episignature that provides a quantitative and functional readout of TET activity. The results stratified affected individuals into three distinct groups based on molecular subtype—bi-allelic, mono-allelic, and control. The bi-allelic group produced the highest methylation variant pathogenicity (MVP) prediction score (>0.95), controls all had scores near zero, and the mono-allelic samples had more moderate scores from approximately 0.5–0.8.",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_fbafb28e-a0b7-4e60-813a-6f12ddcd2bd2-2023-11-17T170000.000Z,2169,PubMed:34750377 +Tfe3 KO Mice,Model Systems Non-human model organism,"Pastore N, et al., 2017, PMID: 28283651","TFE3 deficiency resulted in altered mitochondrial morphology and function both in vitro and in vivo due to compromised mitochondrial dynamics. These mice showed significant abnormalities in energy balance and alterations in systemic glucose and lipid metabolism, resulting in enhanced diet‐induced obesity and diabetes. Viral‐mediated TFE3 overexpression improved the metabolic abnormalities induced by high‐fat diet. Metabolic anomalies such as obesity and neonatal transient hypoglycemia and hyperlactatemia are observed in patients affected by this disease.",Score,0 (2),Lack of construct validity (the difference in mechanism of pathogenicity between mice and humans) suggested that this mouse model is unscorable.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_4d36998f-4d2a-4485-bf51-ce5275fb86d7-2024-03-19T060000.000Z,2170,PubMed:28283651 +Deletion of Tgfbr1 leads to skin tumorigenesis in mice,Model Systems Non-human model organism,"Cammareri P, et al., 2016, PMID: 27558455",MAPK pathway hyperactivation (through BrafV600E or KrasG12D knockin) and TGFb signalling ablation (through Tgfbr1 deletion) in LGR5+ve stem cells enables rapid cSCC development in the mouse. Mutation of Tp53 (which is commonly mutated in sporadic cSCC) coupled with Tgfbr1 deletion in LGR5+ve cells also results in cSCC development.,Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_570947a0-3e45-419c-bc22-0fdc60ca6009-2019-12-20T212550.834Z,2173,PubMed:27558455 +Frequent TGFBR1 mutations in cSCC with TGFb signalling LOF,Functional Alteration Patient cells,"Cammareri P, et al., 2016, PMID: 27558455","Frequent TGFBR1 mutations are identified in human vemurafenib-induced skin lesions and in sporadic cSCC. Functional analysis reveals these mutations ablate canonical TGFb Smad signalling, which is localized to bulge stem cells in both normal human and murine skin.",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_570947a0-3e45-419c-bc22-0fdc60ca6009-2019-12-20T212550.834Z,2173,PubMed:27558455 +HCF-1 interaction,Protein Interaction,"Dehaene H, et al., 2020, PMID: 31905202",Coimmunoprecipitation found association of THAP11 and HCF-1.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6976fdb2-7650-46b7-887c-454666f23bc8-2024-02-09T170000.000Z,2176,PubMed:31905202 +MMACHC transcription factor,Biochemical Function B,"Dehaene H, et al., 2020, PMID: 31905202","The Chip-seq observation suggests that THAP11 activates MMACHC gene transcription and that the THAP11F80L mutation impairs this activation, consistent with the cobalamin-disorder phenotype of the patient from whom the mutation was identified.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6976fdb2-7650-46b7-887c-454666f23bc8-2024-02-09T170000.000Z,2176,PubMed:31905202 +Ronin mouse model,Model Systems Non-human model organism,"Chern T, et al., 2022, PMID: 35013307","A CRISPR/Cas9 mouse model carrying the same point mutation as the human patient (F80L) had CNS, hematological, and cardiac defects consistent with cblC patients. +ChIP-PCR showed that the RONIN F80L protein was no longer able to bind the Mmachc promoter and the mice exhibited dramatic reductions in Mmachc RNA and protein expression. RoninF80L/F80L MEFs also displayed the consequential reduction in the functional activity of MTR and MUT.",Score,2 (2),"Only a single mouse survived for phenotyping, and MMA and Hcy levels were not reported. +They also observed additional unexpected phenotypes such as craniofacial dysmorphia, homeotic transformations, and white belly spotting.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6976fdb2-7650-46b7-887c-454666f23bc8-2024-02-09T170000.000Z,2176,PubMed:35013307 +HeLa Cell functional alteration,Functional Alteration Non-patient cells,"Beaulieu CL, et al., 2013, PMID: 23621916",Knockdown of THOC6 triggered a greater percentage of cells exhibiting apoptosis in comparison to the cells transfected with control siRNA.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_db4039ce-b9e7-40ba-ac45-a622bb75b803-2024-03-15T160000.000Z,2178,PubMed:23621916 +Expression-level evidence: zebrafish,Expression A,"Beaulieu CL, et al., 2013, PMID: 23621916","Whole mount in-situ hybridization demonstrates zebrafish expression 24, 48, and 72 hpf (hours post-fertilization). The protein has high expression in optic tectum and eyes at 24 hpf. The expression is reduced at 48 and 72 hpf but there is a bit of expression at the midbrain-hindbrain boundary.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_db4039ce-b9e7-40ba-ac45-a622bb75b803-2024-03-15T160000.000Z,2178,PubMed:23621916 +Mouse Model,Model Systems Non-human model organism,"Werren EA, et al., 2024, PMID: 38388531",The delayed development and reduced body size seen in the mice recapitulate the phenotype seen in humans.,Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_db4039ce-b9e7-40ba-ac45-a622bb75b803-2024-03-15T160000.000Z,2178,PubMed:38388531 +Mouse models of Tim50 deletion and cardiac overexpression,Model Systems Non-human model organism,"Tang K, et al., 2017, PMID: 28432072","The Tim50 gene (the M. musculus ortholog of human TIMM50) was knocked out using CRISPR/Cas9 gene editing. The model was then subjected to aortic banding to constrict blood flow out of the heart. The model recapitulates the human phenotype in that loss of Tim50 exacerbated the cardiac hypertrophy and increased heart weight (Figure 3A), cardiomyocyte cross-sectional area (Figure 3B), left ventricular dysfunction (Figure 3C), and cardiac fibrosis (Figure 3D). On the other hand, transgenic Tim50 had a protective effect against these phenotypes induced in the model (Figure 4). This is reminiscent of one patient's dilated cardiomyopathy (PMID: 31058414) and another's death in childhood due to cardiorespiratory arrest (PMID: 30190335). At the molecular level, the Tim50 knockout mice exhibited abnormalities in mitochondrial metabolism (Figures 5A, 5B, 5D, and 5E) similar to those observed in affected human patients. These respiratory chain defects were also consistent with the human phenotype of lactic acidosis. While lactic acidosis can be triggered by multiple causes, one of them is a defect in oxygen utilization by the mitochondria.",Score,2 (2),"Default scoring was used because the knockout model recapitulates many of the features of the human patients, both at the organismal level (exacerbating hypertrophy cardiomyopathy) and molecular level (respiratory chain defects). The knockout model was complemented by an overexpression model with protective effects. On the other hand, further up-scoring of this close phenotypic match was not performed due to the need for aortic banding in the model to trigger cardiac phenotypes, which were then exacerbated rather than primarily caused by Tim50 knockout.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_92bd34f9-b744-4246-b50f-cfa8ab95597b-2021-10-25T202158.414Z,2181,PubMed:28432072 +Cellular mitochondrial defects rescued by exogenous TIMM50,Rescue Patient cells,"Reyes A, et al., 2018, PMID: 30190335","Patient immortalized skin fibroblasts exhibit reduced mitochondrial membrane potential, indicating organelle dysfunction (Figure 2C). Lentiviral infection resulting in wild-type TIMM50 expression rescued this phenotype by restoring membrane potential to levels similar to control cells, while the empty vector lentiviral particles did not (Figure 2C). Patient immortalized skin fibroblasts also exhibit defective accumulation of mitochondrial imported TFAM signal, reflecting deficient activity of the TIM23 complex responsible for mitochondrial import of TFAM (Figures 3A, 3B). Lentiviral infection resulting in wild-type TIMM50 expression rescued this phenotype by restoring TFAM import into the mitochondria, while the empty vector control did not (Figures 3C,3D). Patient immortalized skin fibroblasts also exhibit defective oxygen consumption relative to control cells (Figure 4C). Lentiviral infection resulting in wild-type TIMM50 expression rescued this phenotype in patient cells by restoring oxygen consumption levels equivalent to the control cells, while lentiviral particles harboring the empty vector did not (Figure 4D). Finally, patient-derived immortalized fibroblasts exhibit smaller size, slow growth, and increased apoptosis, particularly when grown on galactose rather than glucose (Figure 6). Lentiviral infection resulting in wild-type TIMM50 expression rescued this phenotype in patient cells by restoring cell size (Figure 6A), growth rate (Figure 6B), and percentage of apoptotic cells (Figure 6D).",Score,1.5 (1),"This rescue experiment was up-scored because exogenous expression of wild-type TIMM50 in patient cells rescued six different cellular defects (reduced mitochondrial membrane potential, deficient activity of the TIM23 complex / TFAM import, defective oxygen consumption smaller cell size, slow growth, and increased apoptosis). These defects collectively modeled not only the mitochondrial metabolic defects but also the failure to thrive / growth defects characteristic of human patients.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_92bd34f9-b744-4246-b50f-cfa8ab95597b-2021-10-25T202158.414Z,2181,PubMed:30190335 +Kremer 2015 rescue in patient cells,Rescue Patient cells,"Kremer LS, et al., 2017, PMID: 28604674","Blue native PAGE blot of patient fibroblasts (#96687-T) demonstrated impaired complex I assembly, which was restored after re-expression of TIMMDC1 (Fig. 2g, Supplementary Fig. 10).",Score,1 (1),"rescue of impaired complex I assembly in patient cells, which fits with reduced complex I activity in patient tissue NOTE: the patient from whom the cells were derived does not meet inclusion criteria for Leigh syndrome",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_83d26d62-2863-46d9-ad7d-96c086e65e8e-2021-06-30T220013.257Z,2183,PubMed:28604674 +TIMP3 C-terminus can block VEGF-induced angiogenesis,Biochemical Function B,"Qi JH, et al., 2013, PMID: 23469166","Choroidal neovascularization is a recognized driver of vision loss in many patients that tends to occur late in the progression of Sorsby fundus dystrophy. It is not yet clear whether the mechanism(s) by which TIMP3 variants contribute to this phenomenon are direct or indirect. However, infusion of the VEGF inhibitor bevacizumab has emerged as a promising intervention that can help preserve vision in affected individuals (PMID:17433023). The findings of this study open up the possibility that the anti-angiogenic function of TIMP3 may be defective in some or all disease-associated variants.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_8594a02c-c0f3-4542-b6d3-f089ba94417e-2021-07-02T174320.328Z,2184,PubMed:23469166 +Oxidative stress sensitivity in the Timp3 S179C mouse,Model Systems Non-human model organism,"Wolk A, et al., 2020, PMID: 32828705","The phenotypes of this model system recapitulate some of the degenerative features of the human model, particularly in the retinal pigment epithelium (RPE). Sensitivity to oxidative stress was revealed when low-dose sodium iodate triggered RPE degeneration and disorganization in the Timp3 S179C/S179C mice but not the wild-type controls (Figure 4). Rhodamine-phalloidin staining also revealed an increased area of degeneration within the central region of the RPE in Timp3 S179C/S179C mice but not in the wild-type controls (Figure 5). It is important to point out the caveat that the mice were homozygous for the mutant allele encoding Timp3 Ser179Cys, whereas human patients were heterozygous. This difference in genotype introduces the possibility of loss-of-function effects that are specific to the mouse but absent from the human patients.",Score,0.5 (2),"The trigger of oxidative stress helps the mice recapitulate one of the phenotypes of human SFD. However, one caveat is that the mice are homozygous rather than heterozygous for the variant of interest, making it possible that they show some loss-of-function effects or dosage effects that would be absent from the human patients who harbor a single variant alongside a wild-type allele.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_8594a02c-c0f3-4542-b6d3-f089ba94417e-2021-07-02T174320.328Z,2184,PubMed:32828705 +Alston rescue,Rescue Patient cells,"Alston CL, et al., 2016, PMID: 27374774","Retroviral-mediated expression of TMEM126B in subject 2 fibroblasts largely restored the levels of assembled complex I (Figure 3A). In addition, after lentiviral-mediated expression +of TMEM126B, enzyme activities were significantly increased in fibroblasts re-expressing TMEM126B from subjects 2 and 3, whereas fibroblasts from a healthy control or subject with recessively inherited, pathogenic FOXRED1 variants (described previously ref28) showed no increased activity (Figure 3B).",Score,0.5 (1),partial rescue of mitochondrial dysfunction in cells from 1 patient and affected sibling,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_f9df6705-7638-45c1-b3ec-db19fe0d39b9-2022-03-07T170000.000Z,2189,PubMed:27374774 +Leigh map,Biochemical Function A,"Rahman J, et al., 2017, PMID: 27977873","Chaperone protein involved in the assembly of complex I. There are at least 7 other genes involved in complex I assembly (NDUFAF2, NDUFAF4, NDUFAF5, NDUFAF6, C17ORF89, FOXRED1, NUBPL). Additional assembly factors may not be specifically associated with Leigh syndrome. The mitochondrial complex I intermediate assembly (MCIA) complex, containing assembly factors NDUFAF1, ECSIT, ACAD9, and TMEM126B, is required for building the intermediate ND2-module.",Score,2 (0.5),"complex I assembly factor, a function shared with ~6-9 gene products",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_f9df6705-7638-45c1-b3ec-db19fe0d39b9-2022-03-07T170000.000Z,2189,PubMed:27977873 +Theunissen 2017 rescue,Rescue Patient cells,"Theunissen TEJ, et al., 2017, PMID: 29093663","Patient fibroblasts were rescued by lentiviral transduction with wild-type TMEM126B (isoform A, NM_018480.4). Blue-Native PAGE and immunoblotting with anti-NDUFA5 indicated that the amount of fully assembled complex I in patient fibroblasts was largely restored upon complementation (Figure 1C).",Score,0.5 (1),partial rescue of mitochondrial dysfunction in cells from 1 patient (same genotype as 1 previously investigated patient),https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_f9df6705-7638-45c1-b3ec-db19fe0d39b9-2022-03-07T170000.000Z,2189,PubMed:29093663 +Proliferation assay,Rescue Cell culture model,"Qin Y, et al., 2010, PMID: 20154675",Larger cells with increased proliferation rates in TMEM127 depleted cells were rescued by enforced expression of TMEM127. This enforced expression using independent constructs lead to reduced mTORC1 signaling. Cell proliferation was reduced in cells overexpressing TMEM127.,Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9b965b4e-c909-41da-995b-cdc2af9b3183-2021-06-16T143347.758Z,2190,PubMed:20154675 +Forward scatter FACS analysis,Model Systems Cell culture model,"Qin Y, et al., 2010, PMID: 20154675",TMEM127 is a tumor suppressor gene associated with Pheochromocytoma development. Normal TMEM127 limits mTORC1 activation. LoF variants disrupt TMEM127 gene expression could lead to cell overgrowth in Hereditary Pheochromocytoma.,Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9b965b4e-c909-41da-995b-cdc2af9b3183-2021-06-16T143347.758Z,2190,PubMed:20154675 +RT-PCR,Expression B,"Qin Y, et al., 2010, PMID: 20154675","A 4-fold decrease in TMEM127 transcription expression levels of TMEM127-mutant samples (n=7) in pheochromocytomas compared to 16 non-mutated pheochromocytomas of various genetic backgrounds. +LOH from 19 TMEM127 mutant tumors (multiple affected cases from the same family or bilateral tumors) was confirmed.",Score,2 (0.5),"7 TMEM127 mutant Pheo tumor samples (6 different variants, two tumors from 2 different families had the same variant, IVS3-2A>C/(p.Leu138fs). LOH from 19 TMEM127 mutant tumors (multiple affected cases from the same family or bilateral tumors) was confirmed.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9b965b4e-c909-41da-995b-cdc2af9b3183-2021-06-16T143347.758Z,2190,PubMed:20154675 +35394880 - Targeted Inactivation of Tmem138,Model Systems Non-human model organism,"Guo D, et al., 2022, PMID: 35394880",Central nervous system & retinal anomalies,Score,1 (2),Decided as that on the curation,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c7ebf874-24b0-4566-bc51-8e4dad4b0fb9-2023-04-26T160000.000Z,2192,PubMed:35394880 +Guo TMEM138 - TMEM231/AHI1/RHODOPSIN,Protein Interaction,"Guo D, et al., 2022, PMID: 35394880","Fig. 12.Tmem138 interacts with Ahi1, Tmem231, and rhodopsin. A hypothetical model for the CC membrane complex involved in rhodopsin trafficking.(A) Tmem138 interacts with rhodopsin revealed by protein pulldown assay in HEK293 cells in both forward and reverse directions. (B) Tmem138 coimmuno-precipitated with rhodopsin from P21 retinal extracts. The retinal extracts were prepared from rhodopsin–Cre-drivenTmem138b/c(conditional knockout) andTmem138c/+(control) retinas. (C) Tmem138 interacts with Ahi1. (D) Tmem138 interacts with Tmem231. (E) Tmem231 interacts with rhodopsin. (F) Tmem231does not interact with Ahi1. (G) A hypothetical model. Tmem138 localized at the base of the CC membrane is crucial for molecular organization of the CC byformation of the Tmem138/Tmem231/Ahi1 complex. This complex transiently interacts with rhodopsin to facilitate IFT powered by different types of motorsalong actin and/or microtubule tracks. Disruption of Tmem138 results in a defective CC complex (mislocalization of Ahi1 and Tmem231), impeding rhodop-sin (possibly some other OS proteins as well) entering and/or traveling across the CC. Eventually, rhodopsin is mislocalized, and the photoreceptors degener-ate, releasing extracellular vesicles.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c7ebf874-24b0-4566-bc51-8e4dad4b0fb9-2023-04-26T160000.000Z,2192,PubMed:35394880 +TMEM231 interaction,Protein Interaction,"Roberson EC, et al., 2015, PMID: 25869670",same complex at ciliary transition zone,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_52100cfc-22b6-47c5-9b9c-512a1a4f1cfc-2022-01-12T170000.000Z,2194,PubMed:25869670 +MEF rescue,Rescue Cell culture model,"Roberson EC, et al., 2015, PMID: 25869670",Patient variant show non-rescue,Score,0 (1),Not scored as evidence used to upgrade missense variant scores,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_52100cfc-22b6-47c5-9b9c-512a1a4f1cfc-2022-01-12T170000.000Z,2194,PubMed:25869670 +C. elegans,Model Systems Non-human model organism,"Roberson EC, et al., 2015, PMID: 25869670",Model system matched disturbed ciliary gate function upon TMEM231 LOF.,Score,0 (2),Not scored as lower organism model,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_52100cfc-22b6-47c5-9b9c-512a1a4f1cfc-2022-01-12T170000.000Z,2194,PubMed:25869670 +TMEM231 mutant mouse,Model Systems Non-human model organism,"Roberson EC, et al., 2015, PMID: 25869670",Recapitulation of human MKS phenotypes,Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_52100cfc-22b6-47c5-9b9c-512a1a4f1cfc-2022-01-12T170000.000Z,2194,PubMed:25869670 +HL-1 atrial cardiomyocytes,Model Systems Cell culture model,"Siragam V, et al., 2014, PMID: 25343256","Electrograms and conduction velocities were recorded from control, TMEM43-WT, and TEMEM43-S358L cell cultures. Control and wild type cells beat with regular, synchronous rhythms, while the mutant cells showed a slower, irregular rhythm.",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_675dc788-9749-413f-93ce-8c1fc3adbe84-2018-10-26T160000.000Z,2196,PubMed:25343256 +S358L Mouse Model,Model Systems Non-human model organism,"Zheng G, et al., 2019, PMID: 29980933","S358L heterozygous adult male mice showed higher level of LVEDD (p-value 0.0435) and lower level of posterior wall thickness in systole (p-value 0.0125) indicating enlarged cardiac chambers and thinner ventricular walls. After tense running, 1/4 KI mice had ECG abnormality and 1/8 had sudden cardiac death after tense exercise on running wheel (0 wild type). Ratio of heart weight to body weight increased in KI group compared to control. Fibrosis and fat accumulation were elevated in KI mouse hearts. RNA-seq showed that KI mice had higher expression of markers of fibrosis and adipogenesis.",Score,3 (2),TMEM43 S358L-KI mice showed classic features of ARVC: structural abnormalities and cardiac fibrosis.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_675dc788-9749-413f-93ce-8c1fc3adbe84-2018-10-26T160000.000Z,2196,PubMed:29980933 +TMEM70 KO rat rescue,Rescue Non-human model organism,"Marković A, et al., 2022, PMID: 35203486","Transgenic rescue resulted in viable animals that showed the variable expression of the Tmem70 transgene across the range of tissues and only minor differences in terms of the growth parameters. TMEM70 protein was restored to 16–49% of the controls in the liver and heart, which was sufficient for the full biochemical complementation of ATP synthase biogenesis as well as for mitochondrial energetic function in the liver. In the heart, there was partial biochemical complementation that led to a minor impairment in left ventricle function.",Score,2 (2),"Transgenic rescue resulted in viable animals that showed the variable expression of the Tmem70 transgene across the range of tissues and only minor differences in terms of the growth parameters. TMEM70 protein was restored to 16–49% of the controls in the liver and heart, which was sufficient for the full biochemical complementation of ATP synthase biogenesis as well as for mitochondrial energetic function in the liver. In the heart, there was partial biochemical complementation that led to a minor impairment in left ventricle function.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5be60130-254d-4af4-aca0-eb8cd88a143c-2022-06-16T160000.000Z,2198,PubMed:35203486 +C57BL/6J Cochlear Expression,Expression A,"Karuppasamy S, et al., 2012, PMID: 22787490",Used western blotting analysis to determine the expression of the TMIE protein in the cochlea. They used C57BL/6J mice and found that Tmie protein expression is increased in postnatal develpmental stages. Relative to its expression in other tissues.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b025a472-0a48-469c-a5f3-70df12ade334-2017-09-29T040000.000Z,2200,PubMed:22787490 +CSR,Biochemical Function B,"Castigli E, et al., 2005, PMID: 15630136","Analyzed the ability of BAFF and APRIL to induce class switch recombination (CSR) in murine B cells to IgG1, IgA, and IgE using B cells from mice deficient in CD40 or TACI. First established that BAFF and APRIL activate CSR independent of CD40L–CD40 interaction, using B cells from CD40−/− mice. Next examined TACI deficient B cells which virtually failed to synthesize IgG1, IgA, and IgE in response to APRIL, suggesting that APRIL induction of CSR is mediated by TACI. B cells stimulated with BAFF consistently failed to secrete IgA, but BAFF may use both TACI and BAFF-R to induce CSR.",Score,0.5 (0.5),TACI is a receptor for BAFF and APRIL (PMID: 10973284; found that APRIL binds with high affinity in 293T cells transiently expressing TACI). Here it was demonstrated that binding of BAFF or APRIL to TACI mediates class switch recombination in B cells. This is consistent with the hypogammaglobulinemia seen in patients with TACI deficiency.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3049236b-8132-4dfa-8cda-2a328962a0a4-2021-01-20T170000.000Z,2203,PubMed:15630136 +Byun et al. Rescue in patient cells,Rescue Patient cells,"Byun M, et al., 2013, PMID: 23897980","Despite expressing low levels of OX40 on the cell surface, the patient had completely abolished OX40 ligand binding on PHA activated T cells. Lentiviral transfection of OX40-WT rescued this phenotype, restoring OX40 ligand binding in patient T cells. Meanwhile, lentiviral transfection of the patient variant OX40-R65C, failed to rescue this phenotype. This result is also in line with severely impaired OX40 ligand binding in Jurkat cells expressing the OX40-R65C variant.",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_4759ec3f-6876-41c4-a6eb-fdceedccbc60-2023-06-15T170000.000Z,2205,PubMed:23897980 +Neulen 2009 FunctAlt1,Functional Alteration Non-patient cells,"Neulen A, et al., 2009, PMID: 19506933",Effect of L29Q on isometric force and unloaded shortening velocity in triton-skinned myocardium. Results showed no statistical significance.,Score,0 (0.5),"Triton-skinned myocardium preparations have no functional cell membranes or sarcoplasmic reticulum, but myofilamint lattice is intact.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5d832673-8acb-4a02-ae34-35e0d9981b70-2023-09-13T160000.000Z,2208,PubMed:19506933 +Gallopudi 2012 FunctAlt1,Functional Alteration Non-patient cells,"Gollapudi SK, et al., 2012, PMID: 23008774",pCA-tension relationship and contractile dynamics in detergent-skinned rat cardiac papillary muscle fibers reconstituted with L29Q mutant showed decrease in calcium sensitivity and an increase in the rate of crossbridge (XB) recruitment dynamics.,Score,0 (0.5),Conflicting data again? This paper addresses more of a global change in myofilament dynamics.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5d832673-8acb-4a02-ae34-35e0d9981b70-2023-09-13T160000.000Z,2208,PubMed:23008774 +Li 2013 FunctAlt1,Functional Alteration Non-patient cells,"Li AY, et al., 2013, PMID: 24260207","""The L29Q cTnC mutation decreased the Ca2+ binding affinity and enhanced the effects of pseudo-phosphorylation of cTnI in thin filament preparations but caused a small yet significant increase in Ca2+sensitivity of force and reduced the effects of pseudo-phosphorylation of cTnI in single SCM. More importantly, the effect of the L29Q cTnC mutation on Ca2+ sensitivity of force generation is extremely SL-dependent with the impact being maximal at the shorter SL (1.9 µm) and is virtually abolished at longer SL (2.3 µm).""",Score,0.5 (0.5),Consistent with Dweck's hypothesis that the calcium sensitizing effect of cTnC mutation is more pronounced in the presence of PKA-mediated phosphorylation of cTnI but is sarcomere length dependent.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5d832673-8acb-4a02-ae34-35e0d9981b70-2023-09-13T160000.000Z,2208,PubMed:24260207 +Robertson FunctAlt1,Functional Alteration Non-patient cells,"Robertson IM, et al., 2015, PMID: 26341255",NMR showed that the structure of cTnC was unchanged by L29Q but there was possibly a slight decrease in protein stability. In situ fluoresence from heart muscle cells showed that L29Q did not affect overall calcium sensitivity but decrease cooperativity. It also abolished the effect of force-generating cross-bridges on the calcium sensitivity of structural changes.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5d832673-8acb-4a02-ae34-35e0d9981b70-2023-09-13T160000.000Z,2208,PubMed:26341255 +Marques mouse model,Model Systems Non-human model organism,"Marques MA, et al., 2021, PMID: 34163821","Myocardial fibrosis, left ventricular hypertrophy, diastolic dysfunction all similar to HCM phenotype in humans",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5d832673-8acb-4a02-ae34-35e0d9981b70-2023-09-13T160000.000Z,2208,PubMed:34163821 +Knock-in mouse model of p.Asp73Asn,Model Systems Non-human model organism,"McConnell BK, et al., 2015, PMID: 26379556","All the phenotypes observed in the mouse model recapitulate severe (mean decrease in LVEF = 28%), early-onset DCM in humans, apart from the very high incidence of SCD (83% of the mice died between weeks 6 and 19), and the commonly observed atrial thrombosis (25% of the mice).",Score,1.5 (2),"Mice possess all characteristics of early-onset DCM but also atrial thrombosis (25% of mice), abnormal EGC (prolonged QRS and QT intervals) and very high incidence of SCD.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6ad71467-74c0-4a7c-932d-c5ca5747e59e-2020-10-09T160000.000Z,2209,PubMed:26379556 +CRISPR/Cas9 TNNC1 knock-out tadpole,Model Systems Non-human model organism,"Landim-Vieira M, et al., 2020, PMID: 32038292",DCM in humans is characterised by left-ventricular dilation and thinned left-ventricular wall.,Score,0.5 (2),"TNNC1 in human DCM is an autosomal dominant gene. The only report of potential bi-allelic inheritance is in this paper, but one of the two variants has been implicated in HCM previously and shares functional characteristics with other HCM variants. This model is a KO, and the total inactivation of the gene does not really represent the mechanism of human DCM given by TNNC1 variants.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6ad71467-74c0-4a7c-932d-c5ca5747e59e-2020-10-09T160000.000Z,2209,PubMed:32038292 +Rescue of cTnI in human TNNI3.p.98trunc sample,Rescue Patient cells,"Bollen IAE, et al., 2017, PMID: 28436080",Exchange with WT troponin complex restored cTnI levels in the TNNI3p.98trunc sample to 83% of that of controls exchanged with WT troponin complex.,Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_668087ea-0d2f-42c2-a291-f73400d34023-2020-10-09T160000.000Z,2214,PubMed:28436080 +assessment of Ca2+-sensitivity and length-dependent activ.,Functional Alteration Patient cells,"Bollen IAE, et al., 2017, PMID: 28436080",The TNNI3:p.98trunc mutation from a 46-year-old male with DCM did not result in a truncated protein and instead caused haploinsufficiency leading to increased Ca2+-sensitivity and impaired length-dependent activation,Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_668087ea-0d2f-42c2-a291-f73400d34023-2020-10-09T160000.000Z,2214,PubMed:28436080 +single membrane-permeabilized cardiomyocytes in human LV,Expression B,"Bollen IAE, et al., 2017, PMID: 28436080","The TNNI3p.98trunc patient showed reduced expression of troponin I to 39% (Figure 3D), troponin T to 64%, and troponin C to 73%, and altered stoichiometry between the three cardiac troponin subunits.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_668087ea-0d2f-42c2-a291-f73400d34023-2020-10-09T160000.000Z,2214,PubMed:28436080 +Cardiac myofibrils from TNNI3-Lys36Gln patients,Functional Alteration Patient cells,"Vikhorev PG, et al., 2017, PMID: 29093449","TNNI3-Lys36Gln had faster relaxation kinetics. Passive stiffness was reduced. However, there was no change in maximum force (Figure 2B, D2 indicates TNNI3-Lys36Gln). +The decrease in myofibril passive stiffness was a common feature in all hearts with DCM-associated mutations and may be causative of DCM.",Score,0.5 (1),"Already assigned this variant a functional evidence score based on Carballo et al. Since this study provides additional functional data, we score it for the evidence points, but to avoid overscoring of single variants/gene alterations in many functional studies, we reduced the score from the default 1.0 for functional alteration to 0.5",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_668087ea-0d2f-42c2-a291-f73400d34023-2020-10-09T160000.000Z,2214,PubMed:29093449 +Csq transgenic mouse develops DCM,Model Systems Non-human model organism,"Wheeler FC, et al., 2009, PMID: 19763165","Mutant Csq/TNNI3K mice had decreased survival and their hearts exhibited enlargement, impaired systolic function, and bradycardia",Score,1 (2),The TNNI3K mutation alone was not sufficient to lead to premature death or cardiomyopathy. This phenotype was seen in conjunction with Csq transgenic mice or in conjunction with transverse aortic constriction.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_f5ce5790-8940-4d7a-a85c-8682be86939d-2020-08-12T160000.000Z,2215,PubMed:19763165 +TNNT2 encodes troponin complex subunit,Biochemical Function B,"Marques MA, et al., 2016, PMID: 27721798",Defective sarcomeric proteins,Score,1 (0.5),Structural and cellular alterations triggered by HCM-causing mutations in troponin and tropomyosin proteins - a review,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ef922dc4-4e41-422b-ac3d-605fea375005-2021-02-04T170000.000Z,2219,PubMed:27721798 +B cell expression,Expression A,"Broderick L, et al., 2019, PMID: 31409799","In mice, B cells have greater expression of Top2b mRNA and protein compared to T cells, which is consistent with previous reports in humans (PMID: 24053356).",Score,0.5 (0.5),Consistent with B-cell immunodeficiency found in patients.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_677a64c1-b005-44f6-9846-a7f371222667-2021-10-19T125736.122Z,2221,PubMed:31409799 +B-cell specific Top2b−/− mice,Model Systems Non-human model organism,"Broderick L, et al., 2019, PMID: 31409799","Immunophenotyping demonstrated that the bone marrow of Top2b−/−mb1-cre mice have fewer PrePro B cells, Pre B, and immature B cells compared to control mice. To test the role of Top2b in humoral immunodeficiency and antigen-specific responses, Top2b−/−mb1-cre and littermate control mice were immunized with ovalbumin (OVA). Fourteen days after immunization, serum samples from control mice demonstrated increased OVA-specific IgG, which was not observed in Top2b−/−mb1-cre mice. The immunization responses in the Top2b−/−mb1-cre mice are consistent with the failure to mount a vaccine response observed in patients.",Score,1 (2),"The B-cell specific Top2b−/− mice recapitulate features of human disease including reduced B cells numbers and failure to mount a vaccine response, however these mice are homozygous for loss of top2b in B cells in contrast to the heterozygous genotype of human patients.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_677a64c1-b005-44f6-9846-a7f371222667-2021-10-19T125736.122Z,2221,PubMed:31409799 +Top2b+/EE587E knockin mice,Model Systems Non-human model organism,"Broderick L, et al., 2019, PMID: 31409799",Several observations indicated the presence of B cell defects in the Top2b+/EE587E mice relative to wild-type controls: (1) the spleen-to-body ratio was reduced; (2) total serum IgG was reduced; (3) immunization with ovalbumin or Pneumovax-23 generated significantly lower titers of antigen-specific antibody; and (4) flow cytometric immunophenotyping of the bone marrow and spleen demonstrated reduced numbers of B cells at most stages of B-cell development.,Score,3 (2),"Using the patient identified allele, Top2b+/EE587E heterozygous mice recapitulated the Hoffman syndrome patient defects in peripheral blood B cells without an effect on peripheral blood T cells. Mice recapitulated features of human disease including reduced B cells numbers and failure to mount a vaccine response, however dysmorphic features were not addressed.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_677a64c1-b005-44f6-9846-a7f371222667-2021-10-19T125736.122Z,2221,PubMed:31409799 +Long gene transcription defect,Functional Alteration Non-patient cells,"Broderick L, et al., 2019, PMID: 31409799","Since defects in TOP2B give rise to reduced transcription of long genes, the authors investigated the expression of transcription factors involved in establishing and/or maintaining B- and T-cell fate. Rag1 and E2A, genes required for both B- and T-cell development, were similarly expressed in bone marrow derived lineage-negative CD117-negative progenitor cells between mutant and wild-type mice. However, pre-B cells from Top2b+/EE587E mice demonstrated reduced expression of the B cell-specific transcription factors Pax5 and Foxo1. Unlike the B cell-specific transcription factors, expression of the T cell-specific transcription factors Notch1 and Tcf1 in the spleen was similar to littermate controls.",Score,0.5 (0.5),"TOP2B makes transient double-stranded DNA breaks that alleviate negative supercoils. Failure to relax topological stress can reduce the production of multiple gene products, even in the absence of a genetic mutation. These defects preferentially cause loss of function of large genes, which are most vulnerable to topologic stress. Many B-cell-specific transcription factor genes are relatively long and require TOP2B for efficient transcription, suggesting a pathogenesis mechanism for the TOP2B mutations and the role of TOP2B in B-cell development.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_677a64c1-b005-44f6-9846-a7f371222667-2021-10-19T125736.122Z,2221,PubMed:31409799 +Heterozygous Trp73+/− mice,Model Systems Non-human model organism,"Gonzalez-Cano L, et al., 2016, PMID: 26482843","Trp73 +/− mice had multiple basal bodies but lacked motile cilia, exhibited aberrant clusters of cilia of varying lengths, and possessed angled, disorganized, and truncated cilia.",Score,0.5 (2),not all human phenotypes were found and the alteration of ciliary motility in the CNS (brain),https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_96b17463-2bd0-431c-a8df-0c1ac28a97ab-2023-09-14T160000.000Z,2224,PubMed:26482843 +TAp73 /p73 regulator of airway multiciliogenesis,Model Systems Non-human model organism,"Nemajerova A, et al., 2016, PMID: 27257214","Animal model exhibited chronic upper and lower respiratory tract infections, severe rhinitis, and purulent otitis media. Neutrophils and mucosecretions resemble the clinical phenotypes of PCD patients. Also, the model displayed profound ciliogenesis defects in airway ciliated cells",Score,0.5 (2),"not all clinical phenotypes of PCD were displayed +Reported previously in Yang et al., 2000 [PMID 10716451]. However, more phenotypes were characterized",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_96b17463-2bd0-431c-a8df-0c1ac28a97ab-2023-09-14T160000.000Z,2224,PubMed:27257214 +IMPC mouse KO model,Model Systems Non-human model organism,"Cacheiro P, et al., 2019, PMID: 31127358","KO mouse, homozygous embryonic lethal prior to organogenesis +Heterozygous: abnormal neural closure at E9.5; Early adult:increased body fat, cateract, Late adult: impaired righting response, abnormal limb grasping, increased grip strength",Score,0.5 (2),0.5 score fro embryonic lethality (according to Mito disease ClinGen scoring rubric),https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_74e89426-cb27-4474-b892-dc303a9de644-2021-01-14T212800.773Z,2225,PubMed:31127358 +Ojala FA1,Functional Alteration Patient cells,"Ojala M, et al., 2015, PMID: 27057166","Cells showed pathological phenotype of HCM (abnormal calcium transients, prolonged action potential, increased arrhythmogenic events).",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_32e7ed58-ee49-4719-b48e-7fad58012319-2023-12-18T170000.000Z,2227,PubMed:27057166 +TPM2 Human and Mouse Myoblast Mutant Expression,Functional Alteration Non-patient cells,"Abdul-Hussein S, et al., 2013, PMID: 24039757","The expression of these TPM2 mutants in cultured cells demonstrated several morphological abnormalities reminiscent of those seen in nemaline myopathy patients. In the human myoblasts/differentiated cells, these included various types of aggregates including nuclear, cytoplasmic, endogenous, and perinuclear. Large accumulations of actin along with clouds around the nucleus and cytoplasm with unorganized structure were also present. Poor incorporation of stress fibers, what appeared to be disorganized sarcomeric structure, and rod-like structures both intranuclear and in the myotubes in particular all demonstrate clear similarities to those phenotypes seen in nemaline myopathy, namely the presence of nemaline rods, disorganized sarcomeres, and z-disc abnormalities. These two groups of pathologies also seem to share the same mechanism, specifically the TPM2 mutations destabilizing the actin-myosin structures and causing accumulation and abnormal structures to form. Similarly, the modified C2C12 myoblasts/myotubes also displayed peripheral and perinuclear aggregates in both stages of development as well as diffuse cytoplasmic labeling of stress fibers. They had difficulty differentiating, as they appeared to be fused rather than elongated and multinucleated. This further supports the connection between the gene disruption and the pathologies that are demonstrated here.",Score,1 (0.5),"This functional alteration definitively demonstrates the connection between the TPM2 functional alteration in myoblasts and the displayed phenotypes, most notably the numerous aggregates and rod-like structures that were displayed. Not only does this paper provide a notably through investigation and expression of 5 different variants, it also expresses each of these and the wild-type in both human and mouse myocytes and myotubes to confirm the results. For the quality and quantity of evidence, this earns 1.0 points.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_f137b6cf-247a-4af0-b41f-6cb976239175-2021-01-04T170000.000Z,2229,PubMed:24039757 +Lyly-TPP1-CLN5-interaction,Protein Interaction,"Lyly A, et al., 2009, PMID: 19941651",TPP1 in lysates from COS-1 and HeLa cells transiently expressing TPP1 was pulled down by GST-CLN5. TPP1 was also pulled down by GST-CLN5 in mouse brain extract.,Score,0 (0.5),This confirmed the result of Vesa et al. 2002 PMID: 12134079.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9b2f3b20-fb9a-4b5e-ad8e-e03be5ebb8e5-2020-09-26T005342.102Z,2232,PubMed:19941651 +Katz-Dog-ERT,Rescue Non-human model organism,"Katz ML, et al., 2014, PMID: 24938720","The three TPP1–/– dogs that received vehicle reached end-stage disease requiring euthanasia between 39 and 47 weeks of age. Dogs that received 4 mg rhTPP1 every other week reached endstage disease requiring euthanasia between 51 and 57 weeks of age. The dogs that received a 16 mg dose of rhTPP1 survived to between 57 and 67 weeks of age. A dog that received a 48 mg dose of rhTPP1 had not reached end-stage disease by 87 weeks of age but was euthanized at this time because of the development of obstructive hydrocephalus that had an acute onset between 83 and 87 weeks of age. Treatment with infusions of rhTPP1 into the CSF significantly delayed the onset of most of the neurological +signs, in a dose-dependent manner. These include, cerebellar ataxia, unilateral menace loss, intention tremor, persistent head tremor, delayed proprioception, myoclonus, visual tracking deficit, and nystagmus. Except for the vehicle-treated TPP1–/– dogs, the T-maze performance of the dogs improved progressively at subsequent monthly testing sessions. There were no significant differences in performance between the rhTPP1-treated affected dogs and the homozygous normal dogs at any of the time points. In contrast, the TPP1–/– dogs that received vehicle showed no improvement in T-maze performance. In fact, the +performance of these dogs deteriorated sharply after 7 months of age. CSF infusion of rhTPP1 significantly reduced the disease-related ventricular enlargement. Relative to vehicle-treated TPP1–/– dogs, the group that included all affected dogs treated with +rhTPP1 exhibited a significant reduction in age-related ventricular enlargement (P<0.01).",Score,0 (2),"While many neurological phenotypes were improved by the treatment with rhTPP1, seizures and storage materials were not studied. Furthermore, they did not check the TPP1 activity in the treated brain. Vuillemenot et al. 2015: 25257657 did an accompanying neuropathological study, but their finding was not convincing.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9b2f3b20-fb9a-4b5e-ad8e-e03be5ebb8e5-2020-09-26T005342.102Z,2232,PubMed:24938720 +Wiseman-Mouse-ERT,Rescue Non-human model organism,"Wiseman JA, et al., 2017, PMID: 28345005","While premature death was observed in some of the treated animals, a weekly administration of 2.3 mg rhTPP1 (Figure 1A) significantly (log-rank test p < 0.0001 and p < 0.0001 compared to vehicle-treated or untreated, respectively) extended the survival of half of the cohort to more than 300 days (median survival > 259 days), at which point the study was terminated. In untreated or vehicle-treated animals, stride length started to decline at ~90 days and decreased precipitously from ~7 to ~2 cm until death between 100 and 150 days. When mice were treated with IT rhTPP1 in the three survival studies, there was no significant decline in motor function, and, prior to their natural death, animals appeared relatively healthy compared to untreated end-stage LINCL mice. At the conclusion of the study (42 weeks), surviving animals treated with 2.3 mg weekly appeared to be healthy. There was no visible tremor; animals were hydrated, feeding, and nesting normally; and they lacked the hunched appearance characteristic of symptomatic LINCL mice. At 17 weeks, there was a significant accumulation of SCMAS (subunit C of mitochondrial ATP synthase) in vehicle-treated LINCL mice (6.1-fold higher than wild-type animals). Levels of SCMAS in treated animals were higher than in wild-type mice but significantly lower than in vehicle-treated animals.When 15-week old knockout mice were treated by IT rhTPP1, for most of the animals, IT ERT resulted in a modest increase in lifespan, with median survival increased from 126 to 167 days. However, one-third of the treated late-stage animals was still alive at 42 weeks when the study was terminated. Locomotor function in long-term survivors started to improve significantly after 10 weeks of treatment, and it was continuing to improve at the conclusion of the study. At 42 weeks, levels of SCMAS were somewhat elevated compared to control but were lower than younger (17-week) untreated knockout mice.",Score,0 (2),This is another enzyme replacement therapy on the knockout mice. Phenotypes studied were still limited.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9b2f3b20-fb9a-4b5e-ad8e-e03be5ebb8e5-2020-09-26T005342.102Z,2232,PubMed:28345005 +Mouse-Knockin-Geraets,Model Systems Non-human model organism,"Geraets RD, et al., 2017, PMID: 28464005","It is similar because they both have motor deterioration, tremor, neurodegeneration, and premature death. The increased mitochondrial ATPase C is one aspect of lysosomal storage materials seen in CLN2 disease patients. But some crucial human phenotypes were not observed in the mouse model, such as seizures, cognitive decline, visual impairment, and autofluorescent storage materials.",Score,0 (2),"Although evidence on motor deterioration, increased mitochondrial ATPase subunit C, tremors, neurodegeneration, and premature death are similar to NCL2 patients, some of the characteristic findings in human patients such as seizures, visual impairment, cognitive decline, and autofluorescent storage materials were not detected.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9b2f3b20-fb9a-4b5e-ad8e-e03be5ebb8e5-2020-09-26T005342.102Z,2232,PubMed:28464005 +Knockdown of traf7 in zebrafish,Model Systems Non-human model organism,"Mishra-Gorur K, et al., 2023, PMID: 37043537","Morpholino-mediated knockdown; zebrafish model shows cardiac, craniofacial and kidney defects similar to those seen in humans with pathogenic TRAF7 variants; the zebrafish mutants also displayed the classic features of ciliopathy: curved body axis, hydrocephaly, and kidney cysts.""",Score,0.5 (2),Downgraded to 0.5 for non-mammalian model,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c6291da3-f236-4abe-ba39-ed00366e894a-2023-09-06T190000.000Z,2236,PubMed:37043537 +Knockdown and overexpression of traf7 in Xenopus,Model Systems Non-human model organism,"Mishra-Gorur K, et al., 2023, PMID: 37043537","Overexpression and Morpholino/CRISPR/Cas9 mediated knockdown of traf7; Xenopus model shows cardiac, craniofacial and kidney defects similar to those seen in humans with pathogenic TRAF7 variants; the Xenopus mutants also displayed the classic features of ciliopathy: curved body axis, hydrocephaly, and kidney cysts.""",Score,0.5 (2),Downgraded to 0.5 for non-mammalian model,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c6291da3-f236-4abe-ba39-ed00366e894a-2023-09-06T190000.000Z,2236,PubMed:37043537 +TRAPPC4 complex,Protein Interaction,"Yip CK, et al., 2010, PMID: 20972447","TRAPPC9 is definitive for intellectual disability-obesity-brain malformations-facial dysmorphism syndrome, which is autosomal recessive. TRAPPC9, along with TRAPPC4 and seven other proteins, forms the three-layer TRAP complex. This was demonstrated by electron microscopy in yeast cells.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_51f66c13-6d48-48c0-b8d7-2ba58dd7a09d-2024-01-08T170000.000Z,2237,PubMed:20972447 +Kettunen_Mouse,Model Systems Non-human model organism,"Kettunen KM, et al., 2016, PMID: 27044324","Trim37-/- pups were viable with no visible abnormalities. Mice started to lose weight at 6m (males) to 12m (females). CT analysis revealed 6mo mice had smaller skull size than normal. At 12m, upto 20% weight loss, reduced mobility and behavioral changes were noted, with severity increasing with age. +Trim37-/- mice were infertile due to gonadal degeneration. Males showed histological evidence of testicular degeneration by postnatal day 13. In females, germ cell aplasia and hilus cell hyperplasia were noted in the ovaries, with some 6mo mice showing ovarian lipid cell hyperplasia. Ovarian cysts and Sertoli cell tumors were also seen. +Non-compaction cardiomyopathy was also observed in mice. 22-24mo lice showed enlarged relative liver size with prominent hepatomegaly. Progressive vacuolization was noted in 1-, 4-, 6- and 18-mo mice. Mice >1mo showed neutral lipid accumulation in the liver. FBS was elevated in adult 6mo mice compared to wild-type. No difference was observed between Trim37-/- and control mice in serum triacylglycerol, cholesterol, free fatty acids, long chain fatty acids, very long chain fatty acids, branched chain fatty acid, phytanic acid, docosanoic acid, tetracosanoic acid, hexacosanoic acid or docosahexaenoic acid. Pristanic acid values were below detection levels in KO and wild-type mice. No overt peroxisome pathology (size, shape or abundance) was seen in Trim37-/- mice.",Score,0.5 (2),The evidence is scored reduced points for partial recapitulation of the human phenotype.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0faa569d-4e0c-4809-a1b2-a93d460751e8-2020-05-01T160000.000Z,2242,PubMed:27044324 +Wang_Interaction with PEX5,Protein Interaction,"Wang W, et al., 2017, PMID: 28724525","Using a yeast 2-hybrid system, the authors show that wild-type TRIM37 and PEX5 proteins interact and that this interaction is dirupted by a the PEX5 mutation involving the deletion of the C-terminal 51 amino acids. Since the interaction is transient, this was not demonstrable using coIP methods.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0faa569d-4e0c-4809-a1b2-a93d460751e8-2020-05-01T160000.000Z,2242,PubMed:28724525 +Wang_ABCD3,Biochemical Function A,"Wang W, et al., 2017, PMID: 28724525",ABCD3 is a peroxisome ABC half-transporter that is implicated in a bile acid synthesis defect.,Score,0 (0.5),"ABCD3 is a peroxisome ABC half-transporter that is implicated in a bile acid synthesis defect. However, it is classified as a ""limited"" relationship and therefore no points are awarded.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0faa569d-4e0c-4809-a1b2-a93d460751e8-2020-05-01T160000.000Z,2242,PubMed:28724525 +Wang_Function consistent with phenotype,Biochemical Function B,"Wang W, et al., 2017, PMID: 28724525","In fibroblasts from a patient with mulibrey nanism and the TRIM37 c.493-2A>G splice site mutation, the authors show that endogenous PTS1-containing proteins were cytoplasmic and only a few peroxisomal structures were seen when compared to normal cells.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0faa569d-4e0c-4809-a1b2-a93d460751e8-2020-05-01T160000.000Z,2242,PubMed:28724525 +Wang_Functional Alteration_PEX5,Functional Alteration Non-patient cells,"Wang W, et al., 2017, PMID: 28724525","TRIM37 is shown to ubiquitylate PEX5 (at K464), and the E3 ligase activity of TRIM37 depended on its RING domain. In cells depleted of TRIM37 and in the presence of a proteasome inhibitor, the authors show that nonubiquitylated PEX5 aggregates are formed and that these aggregates localize near the nucleus and colocalized with proteasome markers and/or ubiquitin aggregates. TRIM37 depletion in HepG2 cells as well as TRIM37 mutations in patient cells show a 40-50% reduction of endogenous PEX5 protein.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0faa569d-4e0c-4809-a1b2-a93d460751e8-2020-05-01T160000.000Z,2242,PubMed:28724525 +Review of TRIO function,Biochemical Function B,"van Rijssel J, et al., 2012, PMID: 23076143","Review article: TRIO is involved in neurogenesis, migration and synapse formation, among other roles.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ff3b6c9b-4c51-4414-b92c-20e45758ab61-2021-11-18T192046.961Z,2245,PubMed:23076143 +In vitro functional characterization of ID/ASD variants,Functional Alteration Non-patient cells,"Sadybekov A, et al., 2017, PMID: 28928363","In vitro functional characterization of ID/ASD-associated de novo variants in TRIO’s Rac1 activating domain GEF1 in rat hippocampal CA1 pyramidal neurons showed that these variants produce either hypofunctional or hyperfunctional forms of Trio. The variants give rise to either decreased or increased glutamatergic synaptic function resulting from reduced synaptic AMPA receptor expression or enhanced glutamatergic synaptogenesis, respectively.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ff3b6c9b-4c51-4414-b92c-20e45758ab61-2021-11-18T192046.961Z,2245,PubMed:28928363 +Reduced head size in mutant frog,Model Systems Non-human model organism,"Barbosa S, et al., 2020, PMID: 32109419","Truncation in the TRIO GEFD1 reduces head size in Xenopus, which is similar to the microcephaly phenotype seen in human patients with LOF variants in the TRIO GEFD1 domain.",Score,0.5 (2),"Non-mammalian model, only head size studied.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ff3b6c9b-4c51-4414-b92c-20e45758ab61-2021-11-18T192046.961Z,2245,PubMed:32109419 +"Yarham et al., 2014_Functional alteration, patient cells",Functional Alteration Patient cells,"Yarham JW, et al., 2014, PMID: 24901367","Decreased basal (p=0.0451) and maximal (p=0.0078) oxygen consumption rates +Reduced spare respiratory capacity (p=0.0102)",Score,1 (1),"Decreased basal (p=0.0451) and maximal (p=0.0078) oxygen consumption rates +Reduced spare respiratory capacity (p=0.0102) +Decrease in mtDNA-encoded protein synthesis (loss of ND1, ND5, CYTB, COXI, COXII, COXIII) +Decreased steady-state levels of mtDNA-encoded OXPHOS components +Normal TOMM20 levels (indicating OXPHOS protein synthesis defect vs general loss of mitochondrial proteins)",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0473ea4b-40cb-4f4c-b986-e96b1ae18a9f-2022-09-13T160000.000Z,2248,PubMed:24901367 +"Yarham et al., 2014_Rescue, patient cells",Rescue Patient cells,"Yarham JW, et al., 2014, PMID: 24901367",i6A37 modification is severely decreased in tRNAs from patient-derived fibroblasts carrying the p.Arg323Gln variant; wild-type TRIT1 rescues the i6A modification in patient fibroblasts,Score,1 (1),i6A37 modification is severely decreased in tRNAs from patient-derived fibroblasts carrying the p.Arg323Gln variant; wild-type TRIT1 rescues the i6A modification in patient fibroblasts,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0473ea4b-40cb-4f4c-b986-e96b1ae18a9f-2022-09-13T160000.000Z,2248,PubMed:24901367 +"Yarham et al., 2014_yeast",Model Systems Non-human model organism,"Yarham JW, et al., 2014, PMID: 24901367",Growth defect in oxidative carbon source,Score,0.5 (2),Growth defect in oxidative carbon source,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0473ea4b-40cb-4f4c-b986-e96b1ae18a9f-2022-09-13T160000.000Z,2248,PubMed:24901367 +"Yarham et al., 2014_biochemical function",Biochemical Function A,"Yarham JW, et al., 2014, PMID: 24901367",Disorder of mitochondrial gene expression,Score,2 (0.5),>10 genes associated with PMD,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0473ea4b-40cb-4f4c-b986-e96b1ae18a9f-2022-09-13T160000.000Z,2248,PubMed:24901367 +"Lamichhane et al., 2016_yeast",Model Systems Non-human model organism,"Lamichhane TN, et al., 2016, PMID: 26857223","Lower ATP levels in tit1-Δ relative to tit1+ cells are more decreased by an inhibitor of oxidative phosphorylation, indicative of mitochondrial dysfunction",Score,0.5 (2),"Lower ATP levels in tit1-Δ relative to tit1+ cells are more decreased by an inhibitor of oxidative phosphorylation, indicative of mitochondrial dysfunction",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0473ea4b-40cb-4f4c-b986-e96b1ae18a9f-2022-09-13T160000.000Z,2248,PubMed:26857223 +Metodiev_Mitochondrial protein synthesis impairment,Functional Alteration Patient cells,"Metodiev MD, et al., 2016, PMID: 27132592","Decreased MRPP1 protein levels correlate with decreased steady-state levels of complex I (NDUFB8) and IV (COXI) subunits​ +BN-PAGE: marked decrease of fully assembled complex I and complex IV, with a slight decrease in complex III levels​ +Reduced incorporation of 35S-labeled methionine and cysteine (impaired mito protein synthesis)",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_f5406ef5-ce74-4762-9709-8791775bccac-2022-09-13T160000.000Z,2249,PubMed:27132592 +Metodiev_Impaired mito RNA processing,Functional Alteration Patient cells,"Metodiev MD, et al., 2016, PMID: 27132592","NB: Increase in RNA precursor RNA19 (large RNA intermediate) when detected with either MT-ND1 or MT-RNR2 probe​ +--Steady-state levels of the mature mRNAs were not significantly affected ​ +No increase in precursors of MT-CO2 or MT-CO3 were observed, although the steady-state levels of mature MT-CO3 appeared to be slightly decreased in subject 2​. +mt-tRNAPhe and mt-tRNALeu(UUR) appeared to have slightly lower steady-state levels in subject fibroblasts relative to controls.​ +RNA-seq analysis of mitochondrial RNA: no significant differences in mitochondrially encoded mt-mRNA, mt-rRNA, and mt-tRNA levels between the samples​ +Investigated the changes in the abundance of reads across the entire mitochondrial transcriptome, saw increase in the regions that span gene boundaries (where RNA processing is required to release individual mitochondrial RNAs from the precursor transcripts )​",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_f5406ef5-ce74-4762-9709-8791775bccac-2022-09-13T160000.000Z,2249,PubMed:27132592 +Disorder of mitochondrial gene expression,Biochemical Function A,"Metodiev MD, et al., 2016, PMID: 27132592",Disorders of mitochondrial gene expression,Score,2 (0.5),Disorders of mitochondrial gene expression.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_f5406ef5-ce74-4762-9709-8791775bccac-2022-09-13T160000.000Z,2249,PubMed:27132592 +Complementation Assay in Yeast,Model Systems Non-human model organism,"Powell CA, et al., 2015, PMID: 26189817","In order to accentuate this effect, we expressed trm5D1- 33 in a ParR strain that exhibits destabilized mt-tRNA mitoribosome interaction, as a result of paromomycin resistant +mutation in its mitochondrial 15S rRNA gene, which renders the 15S RNA site A structurally similar to the human 12S RNA site A. +In this genetic background, the trm5D1-33 mutant showed ~40% reduction of respiratory +activity (Figure 5B). The respiratory phenotype was rescued by expression of a wild-type copy of TRM5 (Figure 5B). +However, expression of alleles carrying either the trm5R270H or the trm5M396V mutation did not lead to a full recovery of the decreased mitochondrial respiratory activity (Figure 5B)",Score,1.5 (2),"0.5 for reduction in respiratory activity in null, 0.5 for trm5R270H and trm5M368V showing reduction similar to ""mitochondrial null"", + 0.5 for rescue with Wild-type",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_4d1268d1-4c34-4ab0-a7fd-ef5ccc90415f-2022-07-18T160000.000Z,2250,PubMed:26189817 +m1G37 Modification of tRNA,Biochemical Function A,"Powell CA, et al., 2015, PMID: 26189817",Mitochondrial tRNA's have been implicated in multiple different mitochondrial diseases,Score,2 (0.5),22 human mitochondrial tRNAs which will undergo m1G37 Modification,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_4d1268d1-4c34-4ab0-a7fd-ef5ccc90415f-2022-07-18T160000.000Z,2250,PubMed:26189817 +KO mouse,Model Systems Non-human model organism,"Wu Y, et al., 2016, PMID: 27689697","Biochemical recapitulation of mitochondrial disease. +The Liver specific Mtu KO mouse model recapitulated the phenotype and histology of reversible infantile liver injury. +Fig 4. Analyis of mt-tRNAGln, mt-tRNAGlu and mt-tRNALys by mass specttrometry showed that the s2 modification was nearly absent in the three mt-tRNAs. +Mitochondrial translation in primary hepatocytes isolated from hepatocyte-specific Mtu1 knockout (LKO) mice was reduced compared to control (Flox) mice. As determined by western blot the levels of complex I, III and IV proteins were reduced compared to the controlm, complex III levels were equivalent. Lysates from LKO livers showed reduced complex I, II and IV levels (Fig 5). +Fig 6. Histological analysis showed abberant morphology of mitochondria of the LKO liver, the average mitochondrial area inMtu1-deficient hepatocytes was 4.3-fold larger than that in control hepatocytes. the cristae were either abnormally swollen or lost in most of the mitochondria.",Score,0.5 (2),Biochemical recapitulation of disease,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d1d9d958-be13-4018-ab9c-305788171d1e-2021-01-21T004755.799Z,2251,PubMed:27689697 +Biochemical function in mtDNA transcription/ translation,Biochemical Function A,"Boczonadi V, et al., 2018, PMID: 29980628","Other genes involved in Mt-tRNA modifications have been associated with mitochondrial disease, specifically MTFMT encoding the Methionyl-tRNA has been associated with AR leigh syndrome formyltransferase",Score,2 (0.5),According to the agreed scoring rubric >10 genes,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d1d9d958-be13-4018-ab9c-305788171d1e-2021-01-21T004755.799Z,2251,PubMed:29980628 +Defect in maturation of the 3’ end of mt-tRNA,Biochemical Function B,"Wedatilake Y, et al., 2016, PMID: 27370603",TRNT1 mutations were confirmed to result in impaired its of TRNT1 to catalyze the formation of the CCA trinucleotide. Most mutant proteins detected in TRNT1 deficient patients had no detectable activity,Score,1 (0.5),"TRNT1 performs an essential post- transcriptional modification by adding on the cytosine- cytosine-adenine (CCA) trinucleotide sequence to the 3′ end of all newly produced tRNAs. +TRNT1- dependent tRNA modification is essential for both cytosolic and mitochondrial tRNAs (mt-tRNAs) to participate in protein biosynthesis. +The CCA trinucleotide sequence is required to accurately attach amino acids, to position the tRNA on the ribosome and to conclude protein translation. Impaired ability of the mutant protein to catalyze the formation of the CCA trinucleotide has been demonstrated in most of the patients and in the Zebrafish model system.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6df64a62-650c-4659-b2e8-ee51263fcdbc-2022-10-30T120000.000Z,2252,PubMed:27370603 +Trpm7fl/fl-Pf4Cre mouse,Model Systems Non-human model organism,"Stritt S, et al., 2016, PMID: 27020697","Megakaryocyte and platelet specific TRPM7 KO mice (Trpm7fl/fl-Pf4Cre) show several abnormalities in megakaryocytes, including aberrant Mg2+ and Ca2+ homeostasis as well as dysregulated actomyosin complexes, resulting in impaired platelet production and macrothrombocytopenia in mice. +Macrothrombocytopenia is also present in patients with rare TRPM7 variants.",Score,2 (2),Trpm7fl/fl-Pf4Cre mice show the same phenotype (macrothrombocytopenia) of patients with variants in the channel domain.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_54c99d3f-327b-46d6-9f3b-701fdc65eab9-2024-06-03T160000.000Z,2255,PubMed:27020697 +Expression of mutant TRPM7 in HEK293 cells,Functional Alteration Non-patient cells,"Stritt S, et al., 2016, PMID: 27020697","Patch clamp studies on HEK293 cells confirmed that the p.C721G +variant reduced TRPM7 channel activity by 85±4% as compared +with WT controls (Fig. 7c) despite being localized to the cell +membrane (Supplementary Fig. 18). Likewise, in vitro studies on +the p.R902C variant revealed, although less pronounced, a +reduced TRPM7 channel activity by 39±6% (Supplementary +Fig. 19)",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_54c99d3f-327b-46d6-9f3b-701fdc65eab9-2024-06-03T160000.000Z,2255,PubMed:27020697 +RT-PCR on mouse platelets and megakaryocytes,Expression A,"Stritt S, et al., 2016, PMID: 27020697",The mRNA for TRPM7 is expressed in mouse platelets (Supplementary figure 1a) and mouse megakaryocytes (Supplementary figure 1c),Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_54c99d3f-327b-46d6-9f3b-701fdc65eab9-2024-06-03T160000.000Z,2255,PubMed:27020697 +In vitro study of patient-derived dental pulp stem cells,Functional Alteration Patient cells,"Nonaka K, et al., 2019, PMID: 31463371","Dental pulp stem cells (mesenchymal stem cells that differentiate into bone lineage cells) from a patient with non-lethal metatropic dysplasia carrying c.1855C>T (p.Leu619Phe) showed increased intracellular calcium concentration, accelerated early chondrocyte differentiation, and SOX9 upregulation after stimulation with TRPV4 agonist.",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_13bce420-9049-41ae-b1e8-ebcae68a3f9e-2023-10-20T160000.000Z,2256,PubMed:31463371 +Roundworm TRPV4 Knockout,Model Systems Non-human model organism,"Soh MS, et al., 2020, PMID: 32294113","The closest analogues for various CMT-related genes were tested for altered function and morphology in C. elegans. For this purpose, a number of tests and observations were performed on the models in order to characterize the phenotypes and potential mechanisms affecting them. Swimming thrash assays and crawling capacity for mechanical reststance were both tested, with knockouts having reduced function and motility compared to the WT. Motor neuron morphology appeared relatively unchanged, suggesting neuronal degeneration is not a major driver of defects which supports the calcium-related toxicity pathogenic mechanism. Body wall muscles were characterized via multiple tests, with the osm-9 KO animals showing muscle cell degeneration and deposits, a moderate decrease in average filament length, and an increased gap to total muscle cell ratio compared to the WT. Most notably, the osm-9 KO animals responded poorly to levamisole, having an overall less significant change in body length, indicating functional defecits of body wall muscle contractility. They also took significantly less time to reach full paralysis than WT animals.",Score,0.5 (2),"Although this model does demonstrate that TRPV4 has a similar function in roundworms as in humans, there is a signficant difference between the phenotypes observed in each generally due to the wide species gap. Additionally, it's important to note that the mechanism for the neurological disorders in humans is a gain-of-function leading to increased activity. Therefore, due to the limitations and different mechanisms utilized, this model scores 0.5 points.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b89b03c3-24c7-4424-989c-abd65eb2b7ec-2021-12-14T145310.482Z,2257,PubMed:32294113 +TRPV4 Drosophilia Model,Model Systems Non-human model organism,"Woolums BM, et al., 2020, PMID: 32471994","Lines of transgenic flies were produced with three types, including WT, R269C, and R269C+M680K, the latter of which includes a TRPV4 ion-conducting pore block mutant. The R269C flies showed inability to expand their wings after eclosion, indicating a neuronal and muscular defect. This was not observed in either of the other two lines, with the co-expression of both R269C and R269C+M680K suppressing the phenotype due to the tetrameric ion channel structure. Expressing the R269C variant later in life also impacted climbing performance, compared to the other two which showed no detrimental effects. The R269C flies showed marked loss of axonal projections and dendritic arborizations compared to the other two lines, indicating neuronal degeneration similar to that in human probands. Investigation revealed that this resulted from impaired development and toxicity in a dose-dependent manner consistent with a gain-of-function mechanism. A TRPV4 antagonist, GSK219, suppressed the neurodegeneration phenotype further supporting TRPV4 as the phenotypic mediator. Further testing identified a potent genetic modifier, CaMKII, that could ameliorate the wing phenotype when knocked out or enhance it when overexpressed in flies. This relationship influences the N_CCAP in Drosophilia, producing hyperexcitability dependent on the intracellular Ca2+ levels. Studies on neurons with R269C demonstrated an increased Ca2+ response than WT in response to agonist stimulation and spontaneous calcium transients, indicating that this mutation sensitizes the channels consistent with the gain-of-function mechanism predicted. Mitochondrial transport was also affected, with the R269C flies showing inhibited axonal transport and resulting stationary anterograde and retrograde mitochondria.",Score,1.5 (2),"This paper uses a transgenic fruit fly model, specifically the R269C variant, to show the effects of TRPV4 modification. This model does address the specific mechanism utilized in humans, gain-of-function calcium influx, and modulates the level of expression as the tetrameric structure is essential to the altered function. Although the motor phenotypes observed do not have an exact duplicate in humans, and possible complications could arise from differing transgene expression levels, this still provides significant evidence towards the gene's pathogenicity. Therefore, this earns 1.5 points.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b89b03c3-24c7-4424-989c-abd65eb2b7ec-2021-12-14T145310.482Z,2257,PubMed:32471994 +TRPV4 Neuropathy Mutants Disrupt RhoA Interaction,Functional Alteration Non-patient cells,"McCray BA, et al., 2021, PMID: 33664271","Following initial studies suggesting that TRPV4 had an enriched role with the small GTPase RhoA, the interaction between them was confirmed via co-immunoprecipitation. Time-dependent TRPV4 expression experiments also showed similar results, with specificity and direct interaction confirmed with further experiments. Four neuropathy-causing variants and two skeletal dysplasia variants were transfected into cell lines to test their effect on the RhoA interaction, with the neuropathy variants universally resulting in near-complete disruption and the dysplasia variants displayed variably preserved interactions. Given that WT and mutant TRPV4 are co-expressed in a tetramer, studies with both WT and neuropathy mutants showed a striking reduction of WT TRPV4-RhoA interaction when in a tetramer with the mutant indicating a gain-of-function mechanism. Furthermore, investigation into the structural consequences of these neuropathy mutants demonstrated that the areas commonly mutated were key for interaction. TRPV4 and RhoA interactions are essential for proper cell development regulation, causing loss of neurite growth and potential overactivation of RhoA if disrupted.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b89b03c3-24c7-4424-989c-abd65eb2b7ec-2021-12-14T145310.482Z,2257,PubMed:33664271 +Biochemical function,Biochemical Function A,"Rahman J, et al., 2017, PMID: 27977873","According to Leigh Map, 13 nuclear genes involved in mitochondrial translation are associated with Leigh syndrome: GFM1, GFM2, TSFM, TRMU, MTFMT,GTPBP3, TACO1, C12ORF65, LRPPRC,EARS2, FARS2, IARS2, NARS2.",Score,2 (0.5),Based on scoring guidelines (>10),https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e3d30a3f-a054-4812-9b97-116a8834fcb1-2020-02-12T195529.785Z,2262,PubMed:27977873 +TSPAN7 RNAi on embryonic rats hippocampal neuron culture,Functional Alteration Non-patient cells,"Bassani S, et al., 2012, PMID: 22445342","TSPAN7 overexpression (transfection) promotes the formation of filopodia and dendritic spines in cultured hippocampal neurons from embryonic rats +TSPAN7 silencing (siRNA) reduces head size and stability of spines and AMPA receptor currents",Score,0.5 (0.5),"0.25 , unknown human phenotype, change to default according to CB suggestion",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_2716e7b3-e038-421a-b584-55f6797502a4-2020-12-02T170000.000Z,2263,PubMed:22445342 +Coimmunoprecipitation and pull-down experiments with TSPAN7,Protein Interaction,"Bassani S, et al., 2012, PMID: 22445342","TSPAN7 Directly Interacts with PICK1, Associates with b1 Integrin and GluA2/3, and Regulates PICK1-GluA2/3 Interaction",Score,0 (0.5),not direct evidence support the role of PICK1,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_2716e7b3-e038-421a-b584-55f6797502a4-2020-12-02T170000.000Z,2263,PubMed:22445342 +Coimmunoprecipitation and pull-down experiments with TSPAN7,Protein Interaction,"Bassani S, et al., 2012, PMID: 22445342","TSPAN7 Directly Interacts with PICK1, Associates with b1 Integrin and GluA2/3, and Regulates PICK1-GluA2/3 Interaction",Score,0 (0.5),not direct evidence support the role of PICK1,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_2716e7b3-e038-421a-b584-55f6797502a4-2020-12-02T170000.000Z,2263,PubMed:22445342 +Yeast two-hybrid test with TSPAN and PICK1,Protein Interaction,"Bassani S, et al., 2012, PMID: 22445342","TSPAN7 Directly Interacts with PICK1, Associates with b1 Integrin and GluA2/3, and Regulates PICK1-GluA2/3 Interaction",Score,0 (0.5),not direct evidence support the role of PICK1,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_2716e7b3-e038-421a-b584-55f6797502a4-2020-12-02T170000.000Z,2263,PubMed:22445342 +Tm4sf2−/y mice,Model Systems Non-human model organism,"Murru L, et al., 2017, PMID: 28968657","loss of TSPAN7 function in mice causes alterations in excitatory postsynapse structure, function and plasticity as well as impairment in hippocampal-related learning and memory behavior. (Novel object recognition test, fear conditioning)",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_2716e7b3-e038-421a-b584-55f6797502a4-2020-12-02T170000.000Z,2263,PubMed:28968657 +Cell culture and transfection,Model Systems Non-human model organism,"Davis EE, et al., 2011, PMID: 21258341",mIMCD3 cells stably transfected with Ttc21b short hairpin RNA (shRNA) displayed shortened cilia in comparison to wildtype cells. Davis et al subsequently used these cell lines to test allele pathogenicity based on the ability of transiently transfected mutant constructs to rescue.,Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_60f93fe0-145f-47a7-9ecf-613b1b1dfa7f-2021-11-10T170000.000Z,2265,PubMed:21258341 +Zebrafish Model (RT-PCR),Model Systems Non-human model organism,"Davis EE, et al., 2011, PMID: 21258341","The identification of causal and modifier mutations in TTC21B supports this model. Importantly, this is the first locus for which systematic ciliopathy resequencing was undertaken in the absence of prior genetic data linking this locus to a human disorder. The association of specific alleles with discrete ciliopathy endophenotypes. Comparison of mouse and human data provide some limited insights, in that homozygous null Ttc21b is embryonic lethal in mice and the same genotype is unlikely to be found in affected humans, yet a hypomorphic allele coupled to a null mutation appears sufficient to cause Jeune asphyxiating thoracic dystrophy.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_60f93fe0-145f-47a7-9ecf-613b1b1dfa7f-2021-11-10T170000.000Z,2265,PubMed:21258341 +In vivo electroporation of rat retinas,Rescue Non-human model organism,"Davis EE, et al., 2011, PMID: 21258341",,Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_60f93fe0-145f-47a7-9ecf-613b1b1dfa7f-2021-11-10T170000.000Z,2265,PubMed:21258341 +Zebrafish embryo manipulation and morpholino injection,Rescue Non-human model organism,"Davis EE, et al., 2011, PMID: 21258341","In vivo rescue assay of ttc21b MO with human mRNA. Co-injection of wildtype (WT) human TTC21B with ttc21b translation-blocking MO (tb-MO) results in significant rescue at the ten-somite stage, whereas mRNAs encoding missense alleles result in either partial rescue of shortened anterior-posterior body axis with small anterior structures and mild somite defects.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_60f93fe0-145f-47a7-9ecf-613b1b1dfa7f-2021-11-10T170000.000Z,2265,PubMed:21258341 +Activation induced cell death,Functional Alteration Patient cells,"El-Daher MT, et al., 2018, PMID: 30455981","In the experiment, naive CD4 T cells were isolated from the patient and stimulated with CD3/CD28 in an imaging incubator. The cells were in a media contained a viability dye, so when cells died, they could be identified. Patient CD4 T cells were shown to be lost at a faster rate than control cells, suggesting that the patient CD4 T cells were more prone to activation induced cell death.",Score,1 (1),"This paper shows that TTC7A is important of chromatin structure and nuclear organization. However, there is very little data on immunological functional consequences when there are alterations of TTC7A. One panel shows that CD4 T cells are more prone to activation induced cell death when they contain the p.E71K TTC7A variant, and may explain lymphopenia seen in some patients.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_80cadac5-067c-49e7-a021-ee4eec83984a-2021-10-21T184517.744Z,2266,PubMed:30455981 +Ttn Ser14450fsX4 knock-in DCM mouse embryos,Rescue Non-human model organism,"Gramlich M, et al., 2015, PMID: 25759365","Mutants treated with mTtnAONs exhibited rescued sarcomere assembly and Z-disk formation and a significant increase in contractile function when compared to untreated or mScrAON-treated homozygous littermates. +Partial skipping of the mutated exon 326 with restoration of Ttn open reading frame is sufficient to prevent the development of the DCM phenotype in vivo.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1ec53217-814e-44b3-a7b7-0f18311c20f3-2020-11-06T182152.992Z,2267,PubMed:25759365 +Rescue of TTN Ser14450fsX4 iPSC-derived cardiomyocytes,Rescue Human,"Gramlich M, et al., 2015, PMID: 25759365",Excision of TTN exon 326 has a negligible effect on sarcomere structure in both HL-1 cells and human healthy iPSC-derived cardiomyocytes. Skipping of the mutated exon in patient-specific cardiomyocytes carrying the TTN Ser14450fsX4 mutation improved myofibril assembly and stability and normalized the expression of muscle genes regulated by TK.,Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1ec53217-814e-44b3-a7b7-0f18311c20f3-2020-11-06T182152.992Z,2267,PubMed:25759365 +Characterization of Ser14450fsX4 iPSC-derived cardiomyocytes,Functional Alteration Patient cells,"Gramlich M, et al., 2015, PMID: 25759365","Immunocytochemical analysis for titin and various proteins marking different +portions of the sarcomere—a-actinin (Z-disk), cardiac troponin T +(cTNT, A-band), and myosin heavy chain (MHC, M-line)—revealed, in the DCM group, a higher percentage of cardiomyocytes in which organized myofibrils occupied only half of the whole cytoplasm or less . Moreover, the immunofluorescence signal of Z-disk titin in striated myofibrils appeared more diffuse in patient cells. These results suggested that truncated titin mutants could alter assembly and/or stability of the sarcomeric units in human +embryonic myocytes.",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1ec53217-814e-44b3-a7b7-0f18311c20f3-2020-11-06T182152.992Z,2267,PubMed:25759365 +Rat TTNtv models,Model Systems Non-human model organism,"Schafer S, et al., 2017, PMID: 27869827","Truncating mutations in TTN (TTNtv) impaired cardiac performance during stress in rats. TTNtv rat hearts tended to have higher strain rates and LV developed pressures, perhaps reflecting compensatory metabolism and signalling but, when subjected to sequential volume overload stress, mutant heart function became increasingly impaired.",Score,1.5 (2),Rat model does not spontaneously develop DCM,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1ec53217-814e-44b3-a7b7-0f18311c20f3-2020-11-06T182152.992Z,2267,PubMed:27869827 +functional analysis of cardiac myofibrils with TTN mutations,Functional Alteration Patient cells,"Vikhorev PG, et al., 2017, PMID: 29093449",Authors observed reduced passive stiffness in TTN mutant cells with no difference in isoform expression (N2BA/N2B or presence of foetal isoforms) and no haploinsufficiency; nor was there incorporation of predicted truncated peptides into the myofibrils in common with other researchers.,Score,0 (1),Experiment does not show that TTNtv is the cause of DCM,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1ec53217-814e-44b3-a7b7-0f18311c20f3-2020-11-06T182152.992Z,2267,PubMed:29093449 +Mouse model,Model Systems Non-human model organism,"Leca I, et al., 2020, PMID: 33137126","The R402H mutation causes a reduction in the size of the striatum and cerebellum, and defects in cerebellar lamination in humans. This phenotype is recapitulated in the mouse animal model and demonstrates that TUBA1A is necessary for cortical development in vertebrates",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6ee155a3-371d-4618-849c-38adc95728ee-2024-03-25T160000.000Z,2272,PubMed:33137126 +Functional Alteration,Functional Alteration Non-patient cells,"Leca I, et al., 2020, PMID: 33137126","They confirmed that multiple microtubule associated proteins are dysregulated in the homozygous mutants. This was demonstrated by isolating microtubules from the forebrain of E18.5 animals and undertook western blot analyses. For each candidates, they quantitated the total amount of protein in forebrain lysates, as well as the amount that sedimented with microtubules. There was decreased protein observed in lysates and that was attributed to post-translation dysfunction, and not a transcriptional phenotype. Only in the case of dynein intermediate chain (DYNC1l1/2) were there comparable amounts of protein in control brain lysates but a significant reduction in protein levels that sedimented with microtubules in the homozygous mutants. Additionally, they showed that R402H mutation impairs dynein-mediated transport which is associated with a decoupling of the nucleus to the microtubule organizing center. This data support a model whereby the R402H variant is able to fold and incorporate into microtubules, but acts as a gain of function by perturbing the binding of MAPs.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6ee155a3-371d-4618-849c-38adc95728ee-2024-03-25T160000.000Z,2272,PubMed:33137126 +Mouse Model,Model Systems Non-human model organism,"Buscaglia G, et al., 2022, PMID: 35127710","This supported the idea that TUBA1A is a major component of developing neuronal microtubules and is critical for proper brain development. Human TUBA1A tubulinopathy patients with heterozygous mutations in TUBA1A show severe brain malformations including defects in commissure formation and changes to cortical folding patterns (lissencephaly, polymicrogyria, pachygyria).",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6ee155a3-371d-4618-849c-38adc95728ee-2024-03-25T160000.000Z,2272,PubMed:35127710 +Plt68 mice,Model Systems Non-human model organism,"Strassel C, et al., 2019, PMID: 30760556","Plt68 mice exhibited decreased platelet counts (a 21% reduction compared with wild-type mice, 943 × 103/μl versus 1,199 × 103/μl). In addition, platelets from these mice exhibited an increased size with mean platelet volumes representing 143% of those in wild-type mice (7.0 fL versus 4.9 fL). +Scanning and transmission electron microscopy reveraled the loss of the platele's typical flat discoid shape and a reduction in the number of MT coils in the marginal band. Consistent with this, a dramatic reduction in labelling of the marginal band using the α4A-tubulin antibodies was observed in mutant platelets relative to those from wild-type mice. +Furthermore, the authors analyzed each step of megakaryopoiesis in Tuba4aV260E/V260E mice a notable proportion (∼30%) of stage III MKs exhibited an abnormal structure with a more compact demarcation membrane system. MKs from these mice were unable to extend well-developed proplatelets, which are typically observed in wild-type MKs at this stage.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7d595dc4-2fa3-478a-a7b7-ffb499fa2ab7-2023-11-06T170000.000Z,2273,PubMed:30760556 +megakaryocyte expression,Expression A,"Strassel C, et al., 2019, PMID: 30760556","The authors quantified mRNA levels during megakaryocyte (MK) differentiation of human CD34+ cells, finding TUBA4A transcripts progressively increased form D4 until D12, just preceding proplatelet extension and marginal band formation. +Furthermore, they compared the level of α4A-tubulin in microtubules (MTs) purified from platelets, brain tissue, and HeLa cells. Western blot analysis revealed that the levels of α4A-tubulin in platelet MTs are well above those in HeLa cells and also higher than those in brain. This confirmed that α4A-tubulin is particularly enriched in platelet MTs and indicates that it might play a particular role in the formation of the marginal band.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7d595dc4-2fa3-478a-a7b7-ffb499fa2ab7-2023-11-06T170000.000Z,2273,PubMed:30760556 +TUBB4A Knock-in Mouse Model,Model Systems Non-human model organism,", , PMID: 32463361","This is the first model to demonstrate both neuronal and oligodendroglial defects, and replicate the behavioral and neurodegenerative features of classical H-ABC disease. The mice show early deficits in gait and motor skills, consistent with ataxia and tremor seen in H-ABC affected individuals.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_37d63695-b5d4-48e2-8c20-38cfafaea017-2024-03-07T170000.000Z,2279,PubMed:32463361 +Microtubule dynamics,Functional Alteration Non-patient cells,"Ivanova EL, et al., 2019, PMID: 31086189",Plus end binding protein EB3-GFP constructs demonstrated decreased polymerization rate for disease causing mutants.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_f773acb3-c59f-4c34-90f7-b5396b2dbfac-2022-04-26T160000.000Z,2281,PubMed:31086189 +Mouse knock p.Y92C,Model Systems Non-human model organism,"Ivanova EL, et al., 2019, PMID: 31086189",Abnormal neuronal precursor migration,Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_f773acb3-c59f-4c34-90f7-b5396b2dbfac-2022-04-26T160000.000Z,2281,PubMed:31086189 +In utero mouse cerebral cortex electroporation,Model Systems Non-human model organism,"Ivanova EL, et al., 2019, PMID: 31086189",Abnormal neuronal migration,Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_f773acb3-c59f-4c34-90f7-b5396b2dbfac-2022-04-26T160000.000Z,2281,PubMed:31086189 +Functional alteration evidence: non-patient cells,Functional Alteration Non-patient cells,"Park EM, et al., 2020, PMID: 31874114","Degradation of TUBGCP6 caused a clear failure of centriole duplication. Cells with TUBGCP6 deleted had mitotic problems, such as decreased centrosome-triggered microtubule nucleation and mitotic arrest with a monopolar spindle. Cell division of the TUBGCP6 mutated cells was significantly reduced.",Score,1 (0.5),"It wasn't from this article but there is expression level data from GTEx, which is linked below. Gene expression is high in the cerebellum and cerebral hemisphere of brain, consistent with microcephaly. This expression level data is worth 0.5 points (https://www.gtexportal.org/home/gene/TUBGCP6).",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ccb03ff1-94d3-4387-b312-ac8e38d83d89-2023-06-05T160000.000Z,2282,PubMed:31874114 +Inactivation of zebrafish tulp3,Model Systems Non-human model organism,"Devane J, et al., 2022, PMID: 35397207","Individuals with disease have cystic kidney disease and liver disease like the model. Individuals additionally have cardiac involvement, but no indication of cardiac fibrosis was seen on models.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6f45b6a3-7f38-436f-bfde-beac067fdb88-2022-07-27T160000.000Z,2284,PubMed:35397207 +"Devane, zebrafish expression",Expression A,"Devane J, et al., 2022, PMID: 35397207","Figure 3, Tulp3 expressions on zebrafish embryos, KO zebrafish embryos, adult zebrafish",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6f45b6a3-7f38-436f-bfde-beac067fdb88-2022-07-27T160000.000Z,2284,PubMed:35397207 +Polygenic mouse model,Model Systems Non-human model organism,"Gustafson JA, et al., 2019, PMID: 31442251",Craniosynostosis was observed in the mice as well as humans with variants in TWIST1.,Score,0 (2),This mouse has been previously scored,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_bda425f8-b760-4484-9336-b3e572d402ab-2021-06-10T160000.000Z,2287,PubMed:31442251 +Functional alteration in patient iPSCs,Functional Alteration Patient cells,"Wood KA, et al., 2020, PMID: 32735620","BMKS patient-derived iPSCs exhibited slow proliferation rate and increased apoptosis as compared with both mother- and unrelated control-derived iPSCs, and RNA-Seq analysis revealed significant differences in gene expression and alternative splicing. Patient iPSCs displayed defective differentiation into iNCCs compared to maternal and unrelated control iPSCs, in particular a delay in undergoing an epithelial-to-mesenchymal transition (EMT), a fundamental process for the dissemination of neural crest cells in the embryo. RNA-Seq analysis of differentiated iNCCs revealed widespread gene expression changes and mis-splicing in genes relevant to craniofacial and embryonic development that highlight a dampened response to WNT signalling, the key pathway activated during iNCC differentiation",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_bac99de0-8f34-4166-b8ef-a5c44290281c-2024-02-16T170000.000Z,2288,PubMed:32735620 +Rescue in MO-knockdown Xenopus,Rescue Non-human model organism,"Park BY, et al., 2022, PMID: 35893124",The modified version of Xenopus Txnl4a restored the proportion of normal embryos from 14% to 62%.,Score,1 (2),Downgraded for the lack of replication/rescue of other phenotypes in the model.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_bac99de0-8f34-4166-b8ef-a5c44290281c-2024-02-16T170000.000Z,2288,PubMed:35893124 +Levene enzyme replacement therapy,Rescue Human,"Levene M, et al., 2019, PMID: 30959750","Delivered intravenous escalating doses of erythrocyte encapsulated thymidine phosphorylase to 3 adult MNGIE patients: A genetically engineered recombinant E. coli thymidine phosphorylase sharing a 40% sequence homology with the human was encapsulated into the patient’s autologous erythrocytes ex vivo to produce EE-TP, which was then administered to the patient. Reductions in the disease-associated plasma metabolites, thymidine, and deoxyuridine were observed in all three patients. +Clinical improvements, including weight gain and improved disease scores, were observed in two patients. Did not stop leukodystrophy progression. +Patient 1: decreased nausea and vomiting, increased walking distance and physical and mental health and well-being +Patient 2: Improvements in sensory ataxia, balance and gait, fine finger movements, distal sensation in hands and feet",Score,2 (2),"Rescue with delivery of genetically engineered protein product, not WT gene - are we comfortable with score?",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_4efaa60a-76b6-4f99-bf9d-1c91b2b3ce74-2023-10-02T040000.000Z,2289,PubMed:30959750 +Truncation of Ube3a-ATS rescue,Model Systems Non-human model organism,"Meng L, et al., 2013, PMID: 24385930","poly(A) cassette inserted in Ube3a-ATS, which was shown to unsilence paternal UBe3A expression in mice in vivo. Ube3a mRNA levels were doubled. Other deletions affecting Ube3a-ATS were also studied. Unsilenced paternal Ube3a ameliorated phenotypic defects in mouse model of AS- same one generated in Jiang 1998.",Score,1 (2),"Rescue, not of WT gene product, but by disrupting a known imprinting mechanism",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_df25de82-ea9a-4d86-8b42-6587a39650e3-2018-05-02T132344.716Z,2293,PubMed:24385930 +Defective proteasome binding,Functional Alteration Non-patient cells,"Chang L, et al., 2015, PMID: 26075709","Overexpression of ubiquilin-2 proteins containing any one of five different ALS mutations, found that the mutant proteins are generally capable of binding polyubiquitinated proteins, but defective in binding the proteasome (shown by immunoprecipitation). Mutant proteins are unable to deliver their captured cargo to the proteasome for degradation (leading to an increased half life), which presumably leads to toxicity. Quantification of cell death is consistent with this idea (significant increase in cell death for all mutants).",Score,1 (0.5),"Reported on the underlying defect of ubiquilin-2 proteins containing ALS-linked mutations (P497H, P497S, P506T, P509S, P525S) in affecting proteasome-mediated degradation, resulting in toxicity.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_17c06f6e-6fe1-4a61-bc35-026416e31dbb-2021-04-13T194634.543Z,2295,PubMed:26075709 +E210K expression in Drosophila neurons,Model Systems Non-human model organism,"Toro C, et al., 2018, PMID: 29300972",E210K expression in Drosophila neurons led to loss of eye development and failure of head development/lethality at the pupal stage in flies.,Score,0 (2),Findings of unclear significance for ID/ASD.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1a5d6060-b955-49a0-9804-265838495310-2023-08-16T190000.000Z,2296,PubMed:29300972 +"Ubtf+/- mice expression, motor, and behavioral assessments",Model Systems Non-human model organism,"Toro C, et al., 2018, PMID: 29300972","The expression of total Ubtf was reduced by approximately half in cerebral cortex, cerebellum and liver, but Ubtf1 levels were not significantly reduced in Ubtf+/− mice. +There were no differences between Ubtf+/− mice and WT littermates in expression of putative UBTF2 targets (as opposed to changes observed in patient fibroblasts with the GoF variant). +Ubtf+/- mice (3 month old) exhibited mild motor abnormalities in the rotarod and were more aggressive than WT littermates in the dominance tube.",Score,0 (2),"These mice have a null allele, whereas the patients have a GoF variant. In addition, the behavioral parameters assessed are not relevant for ID/ASD.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1a5d6060-b955-49a0-9804-265838495310-2023-08-16T190000.000Z,2296,PubMed:29300972 +E210K DNA/cell damage assays,Functional Alteration Patient cells,"Toro C, et al., 2018, PMID: 29300972","Patient fibroblasts showed markedly increased number of DNA breaks, defective cell-cycle progression, and apoptosis.",Score,0 (1),Findings of unclear significance for ID/ASD.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1a5d6060-b955-49a0-9804-265838495310-2023-08-16T190000.000Z,2296,PubMed:29300972 +Expression of putative UBTF2 targets,Expression B,"Toro C, et al., 2018, PMID: 29300972","Up-regulation of PPARGC1A, and down-regulation of SLC4A4, and HIST1H4B in patient fibroblasts.",Score,0 (0.5),"PPARGC1A, HIST1H4B, and SLC4A4 have not been implicated in ID/ASD in OMIM/ClinGen, so the significance of these alterations is unknown.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1a5d6060-b955-49a0-9804-265838495310-2023-08-16T190000.000Z,2296,PubMed:29300972 +Ubtf E210K expression in mouse fibroblasts,Functional Alteration Non-patient cells,"Tremblay MG, et al., 2022, PMID: 35139074","Ubtf E210K/E210K mouse embryonic fibroblasts had >40% lower rate of pre-rRNA synthesis, >40% less RNA polymerase I loading across the rDNA, reduced SL1 (another transcription factor for RNA polymerase I) and UBTF recruitment to the rDNA promoter, and 30% less total cellular RNA. Unexpectedly, the Ubtf E210K mouse fibroblasts also showed a significant increase in the fraction of activated rDNA copies leading to an increased expression of UBTF1 (at both the transcript and protein levels). The authors proposed that the underlying cause of the UBTF-E210K syndrome is a reduction in cooperative UBTF1-SL1 promoter recruitment that may be partially compensated by enhanced rDNA activation.",Score,0.25 (0.5),These experiments were performed in fibroblasts from embryonic mice homozygous for the E210K variant whereas patients are heterozygous.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1a5d6060-b955-49a0-9804-265838495310-2023-08-16T190000.000Z,2296,PubMed:35139074 +In-vitro score,Functional Alteration Non-patient cells,"Kidd K, et al., 2020, PMID: 32954071","Western blot performed on cell lysates. Mature protein that has processed along the secretory pathway towards the plasma membrane are glycosylated and therefore have a higher molecular weight. Mutant UMOD that is retained in the ER will not be glycosylated and have a lower molecular weight. Based upon ER retention, the mutations were subdivided into 4 distinct subgroups. Class 1 being less severe/higher ratio of glycosylated mature UMOD to Class 4 being more severe with a higher ratio of non-glycosylated UMOD.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_39233b4e-a491-47b4-8407-2e15dda89221-2021-01-13T170000.000Z,2298,PubMed:32954071 +UNC13D knockout mice have features of FHL3,Model Systems Non-human model organism,"Crozat K, et al., 2007, PMID: 17420270","Patients with FHL3 display defects in T- and NK-cell degranulation but decreased killing, T cell and macrophages show increased activation, splenomegaly, and anemia. This is consistent with the mouse model. The caveat is that the mouse model only displays these during infection-they do not occur spontaneously.",Score,1 (2),This mouse model presents with many features of human disease. Downgraded the score because it was an ENU-induced mutation (although mapping and subsequent studies increase confidence in this model) and because FHL3 features only occur following infection.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1b2b30c4-5544-476f-8c2f-c2511c69ccfc-2024-01-03T170000.000Z,2300,PubMed:17420270 +Munc13-4 levels correlate with lymphocyte cytotoxicity,Expression A,"Cichocki F, et al., 2014, PMID: 24842371",Western blot of different immune cell subsets revealed Munc13-4 levels are higher in cytotoxic cells,Score,0.5 (0.5),"Munc13-4 levels are higher in cytotoxic cells, which is consistent with FHL3 patient pheno/the role of Munc13-4 in degranulation regulation",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1b2b30c4-5544-476f-8c2f-c2511c69ccfc-2024-01-03T170000.000Z,2300,PubMed:24842371 +Rescue in c. elegans,Rescue Non-human model organism,"Yeh E, et al., 2008, PMID: 18336069","In C. elegans, co-injection of genomic fragments only containing F25C8.3 resulted in rescue of the fainter phenotype in unc-80 mutant e1272 (Videos S9). In addition, expression of unc-80 driven by a pan-neuronal promoter also rescued the fainter phenotype in unc-80 mutant e1272 (Video S12).",Score,0.5 (2),"Reduced points. While the full phenotype is rescued, there is limited phenotype overlap with what is observed in humans",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7639160a-1761-4dcb-98de-2aeb61b2b080-2021-07-30T134337.292Z,2301,PubMed:18336069 +C. elegans model,Model Systems Non-human model organism,"Yeh E, et al., 2008, PMID: 18336069","In C. elegans, three unc-80 alleles (hp369 (stop gained; Arg649Ter), e1272 (stop gained; Trp2463Ter), and e1069 (splice site variant resulting in premature stop codon after Leu2428)) (Figure S4A shows details on these variants) all individually showed recessive fainter phenotypes (locomotion defects including paralysis and crawling defects) (video S6); RNAi knockdown of an open reading frame F25C8.3, which corresponds to unc-80, also showed the fainter phenotype.",Score,1 (2),"Reduced points since recapitulation of phenotype; however, overlap is limited considering phenotypes observed in humans",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7639160a-1761-4dcb-98de-2aeb61b2b080-2021-07-30T134337.292Z,2301,PubMed:18336069 +Drosophila model,Model Systems Non-human model organism,"Lear BC, et al., 2013, PMID: 24223770","Through backcrossing for 6-8 generations in Drosophila melanogaster, homozygous mutant strains were produced (two strains: P-element insertion GS12792 into exon 18 [Unc80GS12792] and imprecise excision GS12792 retaining 14 bp which results in a shift in the reading frame [Unc80x42]) introducing a stop codon. Both showed defects in locomotor activity levels (anticipatory behavior and free-running rhythmicity - P<0.05) when compared to wild-type controls. (Figure 1 and Table 1)",Score,0.5 (2),"Reduced points since recapitulation of phenotype; however, overlap is limited considering phenotypes observed in humans",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7639160a-1761-4dcb-98de-2aeb61b2b080-2021-07-30T134337.292Z,2301,PubMed:24223770 +Mouse model,Model Systems Non-human model organism,"Wie J, et al., 2020, PMID: 32620897",Knock out mice generated using the CRISPR/Cas9 technique (UNC80 truncated at amino acid position 47) did not survive beyond 24 hours and showed sleep apnea. No other phenotypes were noted (Figure 1). Heterozygous mice were viable with no abnormalities.,Score,0 (2),Points not awarded for complete KO is lethal within 24 hours and only phenotype observed is sleep apnea.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7639160a-1761-4dcb-98de-2aeb61b2b080-2021-07-30T134337.292Z,2301,PubMed:32620897 +Patch clamp testing,Functional Alteration Non-patient cells,"Wie J, et al., 2020, PMID: 32620897","Using patch clamp testing, NALCN-dependent sodium leak current was compared between hippocampal neurons cultured from wild-type and UNC80 KO mice. UNC80 KO neurons showed decreased current. NALCN protein levels were comparable to wild-type, but the NALCN current was significantly reduced (Figure 2f). Transfection of UNC80 cDNA into the KO neurons fully restored the NALCN-dependent sodium leak current.",Score,0.5 (0.5),Default points awarded,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7639160a-1761-4dcb-98de-2aeb61b2b080-2021-07-30T134337.292Z,2301,PubMed:32620897 +Localization defect in mouse hippocampal neurons,Functional Alteration Non-patient cells,"Wie J, et al., 2020, PMID: 32620897","When WT RFP-tagged UNC80 was transfected in cultured hippocampal neurons from mice, imaging showed presence in the soma, axons, and dendrites. However, five RFP-tagged UNC80 constructs truncated at various positions, where the C-terminus was removed, only localized to the soma and not the dendrites or axons. Additional experiments to identify the specific region, showed that the distal C-terminal ~300 amino acids (but before position 3000) is likely to be involved in trafficking of UNC80 (Figure 7 and supplementary figure 2)",Score,0.5 (0.5),Default points awarded,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7639160a-1761-4dcb-98de-2aeb61b2b080-2021-07-30T134337.292Z,2301,PubMed:32620897 +Hu_Mouse,Model Systems Non-human model organism,"Hu P, et al., 2000, PMID: 11085999",Findings indicated that UPK3A is an integral subunit of the urothelial plaque and contributes to the permeability barrier function of the urothelium; Upk3 deficiency in mice can result in global anomalies of the urinary tract,Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_825a0eca-b652-43f4-a258-98cdd32751df-2023-01-09T170000.000Z,2303,PubMed:11085999 +Rudat_Expression,Expression A,"Rudat C, et al., 2014, PMID: 25389758","Analysis of whole embryos at E9.5 and E10.5 and sections of E9.5 to E14.5 embryos showed: +In E9.5 and E10.5 embryos, researchers did not detect expression of Upk3a +At E12.5, they found weak neuronal expression in the central nervous system +At E14.5, the urothelium of the renal pelvis, the bladder and the ureter was positive for UPK3A expression as well as a subpopulation of alveolar epithelial cells and the olfactory epithelium +Additionally, In 6-month-old mice UPK3A expression was not detected in the epicardial layer of the heart but was found in the urothelium of the renal pelvis, the ureter and the bladder",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_825a0eca-b652-43f4-a258-98cdd32751df-2023-01-09T170000.000Z,2303,PubMed:25389758 +Usp9x cKO mouse model,Model Systems Non-human model organism,"Stegeman S, et al., 2013, PMID: 23861879","Human patients show global developmental delay, variable intellectual disability and brain abnormalities.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_bd411e83-8373-44b7-8ad5-00894c873880-2021-11-17T180000.000Z,2313,PubMed:23861879 +Autophagy functional alteraltion,Functional Alteration Patient cells,"Tripathi P, et al., 2021, PMID: 33972508",Muscle biopsy study of tissue from ALS8 case showed defective autophagy. Colocalization of of P56S VAPB with autophagy markers. Accumulation of autophagic vacuoles in cells expressing P56S VAPB. Other experiments showed early and late autophagic pathway altered by VAPB,Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_da78d57d-1525-47b3-a649-743186d28eff-2021-12-15T183034.352Z,2314,PubMed:33972508 +Zebrafish model,Model Systems Non-human model organism,"Siekierska A, et al., 2019, PMID: 30755616","Recapitulation of brain malformation, developmental delay and seizures.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a8f282f2-3313-44b8-a0f8-b3f52374a11a-2023-12-06T170000.000Z,2315,PubMed:30755616 +Expression in zebrafish,Expression A,"Siekierska A, et al., 2019, PMID: 30755616","vars mRNA was found to be ubiquitously expressed at +18-somite stage at 18 hours post fertilization (hpf), with more +distinctive expression in the brain region and in the prospective +eye as well as in the hematopoietic intermediate cell mass and +somites, which was maintained till 24 hpf. From 36 hpf the +expression of vars became restricted to the developing brain, and +after 48 hpf it was also observed in other developing organs, +including branchial arches, liver, pancreas, and intestine Fig 3a. +expression pattern suggests a role for vars in brain development as well as during broader organogenesis",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a8f282f2-3313-44b8-a0f8-b3f52374a11a-2023-12-06T170000.000Z,2315,PubMed:30755616 +Fibroblast VARS2 rescue,Rescue Cell culture model,"Diodato D, et al., 2014, PMID: 24827421","Found a clear decrease in the maximal respiration rate in both P1 (VARS2) immortalized cells compared to immortalized control fibroblasts. This increased to normal values with recombinant lentivral construct with wt CDNA of VARS2 +Western blot on P1 and P2 fibroblasts after transduction showed an increase in the amount of VARS2 and TARS2 proteins, respectively (Fig. 4C and D).",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ca9dc1e7-f79c-472e-b6ea-5d38aaf61bea-2022-05-19T160000.000Z,2316,PubMed:24827421 +Yeast VARS2 complementation study,Model Systems Non-human model organism,"Diodato D, et al., 2014, PMID: 24827421","The strain expressing vas1T380I showed a division time in ethanol higher than the strain expressing VAS1 (Fig. ​(Fig.3),3), suggesting an OXPHOS-dependent growth defect.  +The respiration rate in vas1T380I strain was slightly but significantly lower than in VAS1 strain (Supp. Fig. S5).",Score,1 (2),(default is 2 but max experimental score has been reached),https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ca9dc1e7-f79c-472e-b6ea-5d38aaf61bea-2022-05-19T160000.000Z,2316,PubMed:24827421 +P1 Lymphoblast WB complex I and IV defect,Functional Alteration Patient cells,"Bruni F, et al., 2018, PMID: 29314548","Additionally, decreased protein levels for NDUFB8, representing Complex I, and MTCOII, representing Complex IV, were noted in P1 lymphoblasts. +Figure 3B",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ca9dc1e7-f79c-472e-b6ea-5d38aaf61bea-2022-05-19T160000.000Z,2316,PubMed:29314548 +Review of mitochondrial translation disorders,Biochemical Function A,"Boczonadi V, et al., 2018, PMID: 29980628","(PMID: 12056939, PMID: 9450773)",Score,2 (0.5),>10+ genes with mitochondrial disease association implicated in mitochondrial translation,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ca9dc1e7-f79c-472e-b6ea-5d38aaf61bea-2022-05-19T160000.000Z,2316,PubMed:29980628 +Respiratory Chain Activity in Msk of Proband,Functional Alteration Patient cells,"Kušíková K, et al., 2021, PMID: 33937156","Complex I activity reduced when normalized for CS and for complex II (24%, 10% of control, respectively) +Complex IV reduced when normalized for complex II (36%) but not CS +Upregulation of II+III",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ca9dc1e7-f79c-472e-b6ea-5d38aaf61bea-2022-05-19T160000.000Z,2316,PubMed:33937156 +Co-transfection of SH-SY5Y with mutant VCP and TDP construct,Functional Alteration Non-patient cells,"Bajc Česnik A, et al., 2020, PMID: 32731393","The mutant increased the aggregation propensity of TDP-43 lacking NLS in cells in comparison with the WT VCP or TDP-43 lacking NLS and IDR2 domains. There was a larger aggregate size, with Western blot confirming their insolubility.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6ea2bc4d-3b58-4b59-a5bc-9d8a96c452cb-2021-12-23T223510.433Z,2320,PubMed:32731393 +Re-expression of R155C in VCP cKO mouse neurons,Model Systems Non-human model organism,"Wani A, et al., 2021, PMID: 34289347","Between 6-12 months of age, progressive neuronal loss is seen, with decreased total cortical TDP-43 and an increase in phosphorylated TDP-43 in the cortex. Furthermore, LAMP1/2 and LC3-positive structures were seen in cortical neurons and CA1 hippocampal neurons, with accumulation of insoluble TDP-43, SQSTM1, ubiquitin conjugates and ER stress markers that were not due to the loss of one VCP WT allele.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6ea2bc4d-3b58-4b59-a5bc-9d8a96c452cb-2021-12-23T223510.433Z,2320,PubMed:34289347 +NCBI fetal expression data (not from this PMID),Expression A,"Reuter MS, et al., 2019, PMID: 30232381","According to NCBI data, fetal expression of VEGFA fluctuates a bit in the heart, as it is decent between 10-18 weeks gestation, but then notably drops between 18-20 weeks gestation.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_bd2d1e9f-ef0b-4294-8f70-2ed0ab594332-2024-05-07T160000.000Z,2321,PubMed:30232381 +VHL-R167Q transgenic mouse,Model Systems Non-human model organism,"Lee CM, et al., 2009, PMID: 19252526","The development of pathogenic renal adenocarcinomas is indicative the the renal cell carcinoma observed in VHL, and specifically in VHL type 2B, which the R167Q mutant is implicated in causing. Even thought ENU treatment was needed to cause the development of pathogenic tumors, this is similar to the two hit model (LOH) seen in tumors from VHL individuals.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_30c04ced-b74d-465a-8d7d-eb822109b7f1-2020-05-14T004116.004Z,2322,PubMed:19252526 +Vipas39 ko mouse,Model Systems Non-human model organism,"Banushi B, et al., 2016, PMID: 27435297","The ko mice showed no visceral abnormalities but did develop dry, scaly skin and hair loss similar to the ichthyosis of patients. Abnormal collagen fibril morphology was also found in tail tendons, consistent with procollagen I accumulation found in patient fibroblasts.",Score,1 (2),"The collagen abnormalities identified in skin fibroblasts and tendons consistent with the characteristic ARC features of ichthyosis, arthrogryposis, osteopenia and bone fractures suggest an important role for VIPAS39 dependent trafficking in connective tissue. However, the mice do not recapitulate the severity of the disease seen in humans.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b87d2443-a34d-41b1-8712-bcd346e3cf52-2020-12-16T170000.000Z,2323,PubMed:27435297 +Eurasier Dogs,Model Systems Non-human model organism,"Gerber M, et al., 2015, PMID: 25668033","Both humans and dogs experience cerebellar hypolasia, nystagmus, and some level of ataxia.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6dace100-8e75-4da9-a893-4a694d031a7b-2023-06-13T160000.000Z,2325,PubMed:25668033 +Role of VSP33A,Biochemical Function B,"Wartosch L, et al., 2015, PMID: 25783203","VPS33A is a member of the mammalian homotypic fusion and vacuole protein sorting (HOPS) complex, which had been predicted to be a tethering complex required for fusion of intracellular compartments with lysosomes. In this study, the authors show that interaction between VPS33A and VPS16 is required for fusion of endosomes or autophagosomes with lysosomes. Various methods were used including siRNA knockdown and mutagenesis, followed by assays to meaure endosome-lysosome and autophagosome-lysosome fusion. +This role is consistent with the features observed in patients that are typical of lysosomal diseases. This includes clinical features of MPS and elevation of urine GAGs, vacuolation with disordered endosomal/lysosomal compartments observed in sphingolipid diseases, abnormal endocytic trafficking of lactosylceramide, and accumulation of cholesterol shown by filipin staining of fibroblasts. Importantly, the endocytic and autophagic pathways have been shown to be normal in fibroblasts of patients with biallelic variants in VPS33A (Kondo et al, Vasilev et al). However, it has been speculated that assays to detects defects in these pathways may not be sensitive enough to detect defects in these pathways. Alternatively, VPS33A may have a role in lysosomal acidification, suggested because lysosomal pH is lower in fibroblasts from patients.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_70662e64-a50a-49d1-aaac-46429d840062-2023-10-03T160000.000Z,2328,PubMed:25783203 +V1316M Knock-in Mice,Model Systems Non-human model organism,"Adam F, et al., 2016, PMID: 27212476","Homozygous KI-mice replicated human VWD-type 2B with macrothrombocytopenia (platelet counts reduced from 1019x10^3 to 455x10^3/uL, platelet volume increased by 44%), circulating platelet aggregates, reduced high molecular weight multimers, and a severe bleeding tendency with all mice failing to stop bleeding in a tail clip-bleeding assay. Heterozygous mice also had a modest, but significant reduction in platelet count (914x10^3/uL) and 6% increase in platelet volume, as well as presence of platelet aggregates, reduction of high molecular weight multimers, and a heterogeneous bleeding phenotype with either prolonged bleeding of failure to stop bleeding.",Score,3 (2),"The V1316M, initially identified in humans, was knocked in to mice, which display a distinct VWD-type 2B phenotype, severe for the homozygous KI-mice and more moderate for the HET-mice. In humans, VWD-type 2B is of dominant inheritance and is usually present in a heterozygous state. In the murine model, although HET-mice do display some features of the disease, only homozygous-KI-mice fully phenocopy the human clinical picture.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ecfe8bc1-5a4b-4d41-80d1-217af5b5b77f-2020-09-23T160000.000Z,2332,PubMed:27212476 +Review of mitochondrial translation disorders,Biochemical Function A,"Boczonadi V, et al., 2018, PMID: 29980628",All genes listed cause primary mitochondrial disease due to deficits in translation. MT-TW reported in mitochondrial myopathy PMID: 9673981,Score,2 (0.5),>10+ genes with mitochondrial disease association implicated in mitochondrial translation,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3fae4b08-08dc-42da-86a0-2d63ad202ef0-2022-06-16T160000.000Z,2335,PubMed:29980628 +ENU induced V117L mouse knock in model,Model Systems Non-human model organism,"Agnew T, et al., 2018, PMID: 30566859","Wars2 compound het and V117L homozygote showed +hearing loss, failure to gain fat mass, hypertrophic cardiomyopathy +Failure of the Wars2 alleles to complement confirms the Wars2V117L lesion as the causal mutation underlying the observed phenotypes. Homozygous null (Wars2−/−) mice were embryonic lethal, and Wars2V117L/− and Wars2V117L/V117L mice were subviable and viable, respectively; thus, the Wars2V117L allele is hypomorphic, rather than a complete loss of function",Score,2 (2),"Compelling mouse model with compound heterozygote V117L/- both showing hearing loss, failure to thrive,cardiomyopathy, and splicing abnormalities, in addition to OXPHOS deficiency in heart specifically but not in other tissues,",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3fae4b08-08dc-42da-86a0-2d63ad202ef0-2022-06-16T160000.000Z,2335,PubMed:30566859 +Drosophila knockdown of WARS2 with two siRNA,Model Systems Non-human model organism,"Maffezzini C, et al., 2019, PMID: 30920170","RNA from third‐instar larvae was isolated using the ToTALLY RNAT +Significant reductions in respiratory chain activity in drosophila (knock down siRNA 2) +increased amounts of uncharged tRNA trp in both KDs +larval or pupal lethality seen in DM knock downs",Score,1.5 (2),"0.5 for larval/pupal lethality, 0.5 for increased in uncharged tRNA trp, 0.5 for respiratory chain defect",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3fae4b08-08dc-42da-86a0-2d63ad202ef0-2022-06-16T160000.000Z,2335,PubMed:30920170 +I294T Zebrafish,Model Systems Non-human model organism,"Jones RA, et al., 2013, PMID: 23868979","Mirroring the neutropenic phenotype of XLN patients, the authors found that expression of hWASp-I294T, using the neutrophil-specific Lysozyme C promoter in otherwise WASp mutant fish, leads to a reduced overall number of neutrophils. Analysis of the remaining neutrophils expressing the constitutively active form of hWASpI294T showed these cells to be hyperprotrusive when responding to a wound, and with significantly increased velocity and increased protrusion and uropod retraction rates.",Score,1 (2),Zebrafish expressing the I294T variant modeled neutropenia but didn't address additional features of disease.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_49c66050-ab36-4359-8d78-b7ba5bef80d2-2021-11-18T171012.085Z,2336,PubMed:23868979 +Zebrafish WASp mutant can be rescued by WT hWASp,Rescue Non-human model organism,"Jones RA, et al., 2013, PMID: 23868979","The Zebrafish WASp mutant can be rescued to varying degrees by introduction of WT hWASp and clinical WASp mutants. Transgenic expression of full-length hWASp, again in otherwise WASp mutant fish, rescues both the numbers of neutrophils recruited to a wound (Fig. 2C) and their velocity and pause times en route to the wound (Fig. 2D).",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a936b3ba-f1d0-4f14-bd56-14f64ad4de3a-2018-10-12T205425.459Z,2337,PubMed:23868979 +Model of WAS mutants in zebrafish larvae using live imaging,Model Systems Non-human model organism,"Jones RA, et al., 2013, PMID: 23868979","A null mutant of zebrafish WASp shows defects in both the wound-induced inflammatory response and in immune-cell-mediated resistance to bacterial infection, thus mimicking the symptoms of human WAS patients. The WASp mutant also models susceptibility to bacterial +infection, just as in human patients.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a936b3ba-f1d0-4f14-bd56-14f64ad4de3a-2018-10-12T205425.459Z,2337,PubMed:23868979 +Long isoform of Wbp2 is predominant in the organ of Corti,Expression A,"Buniello A, et al., 2016, PMID: 26881968","There are 10 protein-coding variants of human WBP2 and only 2 isoforms in the mouse homolog. Both mouse isoforms were found to be present in brain and the inner ear, with the longer isoform, which contains exon 5, much more abundant in the inner ear, and the shorter isoform, which lacks exon 5, much more abundant in brain. Two of the three variants identified in the probands were located in exon 5; the third was in exon seven.",Score,0.5 (0.5),"There are 10 protein-coding variants of human WBP2 and only 2 isoforms in the mouse homolog. Both mouse isoforms were found to be present in brain and the inner ear, with the longer isoform, which contains exon 5, much more abundant in the inner ear, and the shorter isoform, which lacks exon 5, much more abundant in brain. Two of the three variants identified in the probands were located in exon 5; the third was in exon seven.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_baa7931c-1d6a-4260-9816-fbca764c5a0e-2018-12-09T170000.000Z,2339,PubMed:26881968 +WBP2-deficient mice show progressive high-frequency HL,Model Systems Non-human model organism,"Buniello A, et al., 2016, PMID: 26881968",These phenotypes are connected because they both describe in hearing loss,Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_baa7931c-1d6a-4260-9816-fbca764c5a0e-2018-12-09T170000.000Z,2339,PubMed:26881968 +Homozygous and heterozygous LOF mouse model,Model Systems Non-human model organism,"Orosco LA, et al., 2014, PMID: 25198012","Loss of Wdfy3 in mice leads to a regionally enlarged cerebral cortex +resembling early brain overgrowth described in many children on the autism spectrum. In +addition, affected mouse mutants display migration defects of cortical projection neurons, a +recognized cause of epilepsy, which is significantly comorbid with autism.",Score,0.5 (2),multiple models,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a9300a41-dcac-4842-855d-01804e18d599-2022-01-19T170000.000Z,2340,PubMed:25198012 +Homozygous and heterozyous LOF mouse model,Model Systems Non-human model organism,"Dragich JM, et al., 2016, PMID: 27648578",Smaller brain and impaired neural development,Score,0.5 (2),multiple models,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a9300a41-dcac-4842-855d-01804e18d599-2022-01-19T170000.000Z,2340,PubMed:27648578 +Chi_Wdr36 mouse,Model Systems Non-human model organism,"Chi ZL, et al., 2010, PMID: 20631153",Intra-ocular pressure measurement was similar in WT and mutant mice. ~25% reduction in the peripheral retina thickness was observed for del605–607 mice compared with the WT mice. Disruption of synapses between RGC and amacrine cells was observed in del605-607 mice. RGC axon outgrowth was reduced by ∼60%.,Score,0 (2),Mice with WDR36 variants do not show a glaucoma phenotype. Authors note the their results suggest an essential role for Wdr36 in the mouse retina. The evidence is not scored as the causal role of WDR36 variants in humans is not clearly established.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_173858d9-f695-470f-b8b0-22940c60c074-2022-08-18T160000.000Z,2343,PubMed:20631153 +Footz_WDR36 modifier,Biochemical Function B,"Footz T, et al., 2011, PMID: 21850170",The study does not provide evidence for the function of WDR36 protein.,Score,0 (0.5),"The study assessed the modifier effect of STI1 in the context of WDR36 variation; however, does not provide evidence for the function of WDR36.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_173858d9-f695-470f-b8b0-22940c60c074-2022-08-18T160000.000Z,2343,PubMed:21850170 +Developing Murine Model,Expression A,"Bilgüvar K, et al., 2010, PMID: 20729831",Supplemental Figure 6 and Figure 4 show WDR62 is enriched in the subventricular and ventricular zones of the brain. This is shown by in situ hybridization and immunohistochemical staining.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_bdbcb9de-2ded-46a0-a6d0-16b34ea22008-2020-05-26T160000.000Z,2345,PubMed:20729831 +Mouse Model,Model Systems Non-human model organism,"Sgourdou P, et al., 2017, PMID: 28272472",Both mice and humans have microcephaly. Mice show cortical thickness and this is also seen in humans.,Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_bdbcb9de-2ded-46a0-a6d0-16b34ea22008-2020-05-26T160000.000Z,2345,PubMed:28272472 +Patient-Derived Fibroblast,Functional Alteration Patient cells,"Sgourdou P, et al., 2017, PMID: 28272472","We show that mitotic progression is defective in patient-derived fibroblasts, which, similar to mouse neocortical progenitors, transiently arrest at prometaphase. We also find that expression of WDR62 closely correlates to core components of the CPC, a major regulator of mitosis. We demonstrate that staining of CPC components at centromeres is altered in patient-derived fibroblasts and that, at least upon overexpression, mutant forms of WDR62 disrupt interactions with AURKB, the CPC enzymatic core.",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_bdbcb9de-2ded-46a0-a6d0-16b34ea22008-2020-05-26T160000.000Z,2345,PubMed:28272472 +Functional alteration in knockout mice,Model Systems Non-human model organism,"Katsura KA, et al., 2014, PMID: 25008349",Identical phenotype,Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_af7fe285-29ab-4f6c-bba1-a582d03972af-2021-12-16T013000.000Z,2346,PubMed:25008349 +Immunohistochemistry,Expression A,"Wang SK, et al., 2015, PMID: 26247047",Hypomineralised teeth,Score,1 (0.5),"Subcellular localisation of SLC24A4 was altered in Wdr72-/- ameloblasts suggested that hypomaturation enamel defects of Wdr72-/- mice might result from disturbance of calcium excretion from ameloblasts +SLC24A4 is a K-dependent Na/Ca exchanger (Li, 2002). Also associated with amelogenesis, but not apparently in the kidney",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_af7fe285-29ab-4f6c-bba1-a582d03972af-2021-12-16T013000.000Z,2346,PubMed:26247047 +Knockout/knockin mouse,Model Systems Non-human model organism,"Wang SK, et al., 2015, PMID: 26247047",Identical phenotype to human disease in teeth,Score,1 (2),Already scored one knockout mouse model - and neither was examined the kidney tubular function,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_af7fe285-29ab-4f6c-bba1-a582d03972af-2021-12-16T013000.000Z,2346,PubMed:26247047 +Bonnet Animal Model,Model Systems Non-human model organism,"Bonnet Wersinger D, et al., 2014, PMID: 24823368","Studied visual function and retinal/optic nerve histopathology of same mouse model as Ishihara 2004. 9 month old mice showed reduction in visual evoked potentials. In retinas from 12 month old mice there was increased markers unfolded protein response, indicating ER stress. Retinal ganglion cells were not significantly absent, indicating mouse is not perfect model of optic atrophy phenotype in humans",Score,0.5 (2),"Retinal ganglion cells were not significantly absent, indicating mouse is not perfect model of optic atrophy phenotype in humans. Downgraded for additional phenotypic information of a previously described animal model.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1e81eeda-4dd0-431c-ad52-90304fb761c8-2018-04-17T160000.000Z,2348,PubMed:24823368 +WASP is degraded in the absence of WIP,Functional Alteration Non-patient cells,"Chou HC, et al., 2006, PMID: 17141616",WIP−/− DCs express low levels of WASP at the protein level (Figure 3A). Levels of WIP expression were not affected by the lack of WASP in WASP−/− DCs (Figure 3B). mRNA levels of WASP in WIP−/− DCs were comparable to those of wild-type DCs (Figure 3C).,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_93bc67d5-b9f8-4eab-8f8a-cdc10595be30-2023-04-10T170000.000Z,2349,PubMed:17141616 +Lanzi rescue,Rescue Patient cells,"Lanzi G, et al., 2012, PMID: 22231303","Introduction of EGFP-hWIP, but not EGFP, in the patient’s T cells resulted in increased WASP expression by EGFP + cells (Fig. 3 B). WASP expression in the EGFP- hWIP–transfected cells from the patient correlated with WIP +expression (Fig. 3 C).",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_93bc67d5-b9f8-4eab-8f8a-cdc10595be30-2023-04-10T170000.000Z,2349,PubMed:22231303 +Lanzi functional alteration,Functional Alteration Patient cells,"Lanzi G, et al., 2012, PMID: 22231303",Western blot analysis revealed no detectable WASP in lysates of the patient’s PHA T blasts (Fig. 2A) despite normal results from WAS sequencing and normal WAS mRNA expression levels (Fig. 2B),Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_93bc67d5-b9f8-4eab-8f8a-cdc10595be30-2023-04-10T170000.000Z,2349,PubMed:22231303 +Drosophila Wnk1 knockdown,Model Systems Non-human model organism,"Bercier V, et al., 2013, PMID: 23300475",Knockdown of Wnk1 in zebrafish leads to abnormal development of the peripheral sensory system (posterior lateral line).,Score,1 (2),"Although this is a relevant model to study the sensory system, it was downgraded because the it doesn't truly reflects the human phenotype.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_28b83a4d-4a0f-4617-bc11-1effb9efe719-2023-05-05T160000.000Z,2350,PubMed:23300475 +Neurite outgrowth assay,Functional Alteration Non-patient cells,"Shimizu M, et al., 2022, PMID: 36151370",Knockdown of Wnk1 with siRNA inhibits induction of neurite outgrowth.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_28b83a4d-4a0f-4617-bc11-1effb9efe719-2023-05-05T160000.000Z,2350,PubMed:36151370 +Mouse Model 1,Model Systems Non-human model organism,"Yang J, et al., 2015, PMID: 25629078","Mice did not fully recapitulate the phenotype seen in humans and authors suggest that mice may not be the best model organism for evaluation of WNT10A. +Mice did recapitulate features of teeth seen in affected humans. The recapitulation was specific to tooth morphology",Score,1 (2),"Due to the phenotype not being fully recapitulated between mice and humans, the points for this model are reduced to 1.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e2a537f1-f04c-4e08-9cca-80122e36f51a-2022-05-21T025524.674Z,2351,PubMed:25629078 +Zebrafish Model,Model Systems Non-human model organism,"Yuan Q, et al., 2017, PMID: 29178643","To evaluate the effects of wnt10a loss of function on tooth development, on-cell stage fish were injected with either a translation blocking (tbMO) or splice-blocking (sbMO) morpholino (Fig 3) and observed for up to 8 days. Uninjected and mismatch MO-injected embryos were used for comparison. Neither the tbMO- or sbMO-injected embryos has gross whole -body abnormalities, some cartilage formation defects were observed (Fig 3, S3). Tooth development was arrested in 94-97% of the fish by 5 dpf. Demonstrating recaptitulation of tooth agenesis phenotype observed in humans (Fig 3, Table S3). Uninjected control fish presented with normal teeth. Mismatch control-morpholino injected embryos did not present any phenotype identical to uninjected control embryos (Fig 3) and indicates that off-target effects are unlikely. +This experiment focused specifically on tooth development and was not evaluated for full recapitulation of phenotype seen in humans, but abnormal or arrested tooth development is seen in affected individuals.",Score,1 (2),This experiment focused specifically on tooth development and was not evaluated for full recapitulation of phenotype seen in humans. Due to the focused evaluation points are reduced.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e2a537f1-f04c-4e08-9cca-80122e36f51a-2022-05-21T025524.674Z,2351,PubMed:29178643 +Conditional KO,Model Systems Non-human model organism,"Berry RL, et al., 2015, PMID: 26035382","To knock out Wt1 in different cell types during renal development, the authors used 3 Cre strains. Nes, which encodes intermediate filament protein Nestin, is expressed as early as E12.5 in embryonic kidney mesenchyme and is likely a transcriptional target for Wt1. The authors used a Nex-Cre allele to create a conditional KO. Cre-positive/ Wt1 conditional homozygous genotypes were not compatible with postnatal life. However, one mouse did survive and developed a lump on its back at 25 weeks of age. Macroscopic analysis identified a large mass in place of the right kidney and it was identified as a Wilms' tumor.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_65010002-ff97-4dc0-a89f-6c77abf0982a-2020-07-30T205501.047Z,2353,PubMed:26035382 +subcellular localization of mutati YARS proteins in Fly,Model Systems Non-human model organism,"Niehues S, et al., 2015, PMID: 26138142","transgenic lines for expression of YARS_WT and three CMT-mutant variants (G41R, 153-156delVKQV andE196K; ref. 15) were regenerated using site-specific transgenesis. WT YARS is localized in third instar larval motor neurons throughout the cytoplasm, with homogeneous staining of cell bodies, axons and NMJs; no differences in the subcellular localization could be detected for any of the mutant YARS proteins; in class IV multidendritic sensory neurons, YARS_WT localized to the cell body, azon and the major dendritic branches, and to a much lesser extent to smaller dendritic branches. The CMT-mutant YARS proteins displayed a similar subcellular localization pattern, thus ltered subcellular localization of mutant YARS proteins is not the cause of structural and functional defects in motor and sensory neurons in this Drosophila CMT models",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9c326f90-be08-4bb3-9593-b2df48f29ca1-2020-04-28T160000.000Z,2360,PubMed:26138142 +Retinal organization in fly,Model Systems Non-human model organism,"Bervoets S, et al., 2019, PMID: 31695036","retinal disorganization, increased pupae formation",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9c326f90-be08-4bb3-9593-b2df48f29ca1-2020-04-28T160000.000Z,2360,PubMed:31695036 +Co-immunoprecipitation and Western blot analysis,Functional Alteration Non-patient cells,"Bervoets S, et al., 2019, PMID: 31695036","Immunoprecipitation of TRIM28 showed co-purification with TyrRS WT while the TyrRS mutants showed enhancement of TyrRS-TRIM28 and TyrRS-HDAC1 interactions (Fig. 1C,D) while the control (TyrRS-Y341A) showed reduction of TyrRS-TRIM28/HDAC1 binding (Fig. 1C,D). There was a reduction in TRIM28-E2F1 interaction due to the increased TyrRS-TRIM28 interaction in cells expressing the neurotoxic alleles (Fig. 1E), this resulted in E2F1 lacking deacetylation by HDAC1 and increased E2F1 acetylation levels (Fig. 1F) - the opposite was observed in cells expressing controls (Fig. 1E-F). RT-qPCR of HEK293 cells showed upregulation of E2F1 target genes in response to TyrRS-E196K overexpression (Fig. 1G). +Treating cells expressing TyrRS-WT or TyrRS-E196K with HDAC1 activator (dexamethasone) or SIRT1 activator (resvartrol) showed reduction in acetylation levels of E2F1 (Fig. 2M).",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9c326f90-be08-4bb3-9593-b2df48f29ca1-2020-04-28T160000.000Z,2360,PubMed:31695036 +Immunoprecipitation and western blotting,Functional Alteration Patient cells,"Bervoets S, et al., 2019, PMID: 31695036",Stronger TyrRS-TRIM28 interaction and a significant increase in E2F1-regulated transcription in CMT patients’ PBMCs endogenously,Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9c326f90-be08-4bb3-9593-b2df48f29ca1-2020-04-28T160000.000Z,2360,PubMed:31695036 +shRNA KD & dendritic spine morphology,Model Systems Cell culture model,"Shah BS, et al., 2019, PMID: 31189538",Alteration of spine number and morphology is believed to underlie many neurological disorders including ASD (PMID: 32460854).,Score,0 (1),"Since genetic evidence was not scored, this experimental evidence was also not scored to be consistent.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a2519945-2acd-4484-9811-487ff5189da9-2021-07-30T160000.000Z,2368,PubMed:31189538 +MOUSE MODEL KO male - Behavioral tests,Model Systems Non-human model organism,"Mejias R, et al., 2021, PMID: 33462194","behavioral tests: age-matched WT and zdhhc15-KO males (2–4 months) +Open-field test - significant +Sociability and preference for social novelty -Not Significant +Elevated-plus maze -Not Significant +Y-maze of spontaneous alternations and blocked arms- Not Significant +Morris water maze - Not Significant +Prepulse inhibition - Not Significant +Rotarod test - Not Significant +Fear-conditioning test - Not Significant +Novel object recognition test - Not Significant +enhanced locomotion of zdhhc15 KO mice in response to acute administration of amphetamine and methylphenidate.",Score,0 (2),"As there is no clear ID-related phenotype and even the increased locomotion is only secondary to pharmacological intervention, no scores were given for the mouse model.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a2519945-2acd-4484-9811-487ff5189da9-2021-07-30T160000.000Z,2368,PubMed:33462194 +Kouskou Knock out mouse model,Model Systems Non-human model organism,"Kouskou M, et al., 2018, PMID: 29944857","The knock out mice showed altered behaviors consistent with a reduced anxiety level, a reduced hang time in the hanging wire test that suggests underlying hypotonia, deficits in the Morris water maze test of hippocampal-dependent spatial learning and memory, and a 36% reduction in corpus callosum volume revealed by MRI.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_2156b925-1ee6-4edb-a514-3650aa5b780e-2020-05-19T160000.000Z,2369,PubMed:29944857 +Functional alteration: Xenopus oocytes,Functional Alteration Non-patient cells,"Twigg SR, et al., 2015, PMID: 26340333","Compared with the wild-type, these mutations each resulted in a statistically significant disruption of Xenopus embryos and increase in Wnt expression.",Score,1 (0.5),"Since two mutations were found to have an impact (although p.Thr414Ala appears to be associated with reduced penetrance), this is scored at 1.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e70d90a2-6365-49ac-a21f-599ff5906d88-2024-01-18T170000.000Z,2373,PubMed:26340333 +"Xenopus Oocytes, truncating mutation 36 aa shorter",Functional Alteration Non-patient cells,"Twigg SR, et al., 2015, PMID: 26340333",The mutant embryos had significantly enhanced Wnt expression and more disrupted embyros than the wildtype.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e70d90a2-6365-49ac-a21f-599ff5906d88-2024-01-18T170000.000Z,2373,PubMed:26340333 +GTEX Expression data,Expression A,"Twigg SR, et al., 2015, PMID: 26340333","There is extremely high expression in the cerebellum, relative to elsewhere in the body.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e70d90a2-6365-49ac-a21f-599ff5906d88-2024-01-18T170000.000Z,2373,PubMed:26340333 +CRISPR-based deletion of Zmynd10 in mice,Model Systems Non-human model organism,"Mali GR, et al., 2018, PMID: 29916806","CRISPR-based knockout animals lacking Zmynd10 resembled human patients in that they exhibited hydrocephalus (Figures 1E, 1S2E), Absent outer and inner dynein arms by TEM (Figure 1F), Situs inversus totalis (Figures 1G, 1S2F), Abnormal nasal mucus secretion, specifically the presence of mucopurulent plugs in nasal turbinates (Figure 1H), Reduced sperm motility (Figure 1S2C, Video 6), Decreased testicular size (Figure 1S2A), Absence of gross ciliary or cytoskeletal defects (Figure 1S3), Immotile cilia (Videos 2, 4), and destabilization of the dynein proteins DNAH5, DNAH9, DNAI1, and DNAI2 in the trachea and oviduct (Figures 2A, 2B).",Score,2.5 (2),"The model recapitulates both cellular and organ-level phenotypes of the human patients, including one of the respiratory features, and so is considered strong evidence supporting the relationship of Zmynd10 loss-of-function to PCD.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9549c727-fece-494c-9892-83c0ac05f3b4-2023-02-07T170000.000Z,2377,PubMed:29916806 +ZMYND10 interacts with cytoplasmic chaperone proteins.,Biochemical Function B,"Mali GR, et al., 2018, PMID: 29916806","Interaction with the immunophilin FKBP8 and the chaperone HSP90 is consistent with the hypothesis that ZMYND10 acts as a required chaperone during cytoplasmic pre-assembly of dyneins, and is consistent with the destabilization of dynein arm components in animal models lacking Zmynd10 (PMID: 29916806, Figure 2).",Score,0.5 (0.5),These data support the hypothesis that ZMYND10 performs a chaperone function during cytoplasmic pre-assembly of dyneins.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9549c727-fece-494c-9892-83c0ac05f3b4-2023-02-07T170000.000Z,2377,PubMed:29916806 +Zebrafish rescue,Rescue Non-human model organism,"Halbig KM, et al., 2012, PMID: 22268977","75% of embryos showed wt morphology with ZNF143 injection, compared to 12% in the MO knockdown group",Score,1.5 (2),Downscored 0.5 points due to lack of laboratory phenotype reported within this rescue system.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d2961595-2f51-45d6-af4d-988ec5a7628a-2024-03-05T170000.000Z,2379,PubMed:22268977 +Zebrafish model,Model Systems Non-human model organism,"Halbig KM, et al., 2012, PMID: 22268977","The Zebrafish demonstrates heart defects, ear abnormalities, and other bodily malformations that are also seen in humans.",Score,1.5 (2),Downscored 0.5 points due to lack of laboratory phenotype reported within this model system.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d2961595-2f51-45d6-af4d-988ec5a7628a-2024-03-05T170000.000Z,2379,PubMed:22268977 +ABCD4 function,Biochemical Function A,"Kitai K, et al., 2021, PMID: 33845046","ABCD4 is implicated in a similar disease, methylmalonic acidemia with homocystinuria type cblJ",Score,0.25 (0.5),Moderate classification,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d2961595-2f51-45d6-af4d-988ec5a7628a-2024-03-05T170000.000Z,2379,PubMed:33845046 +Kdm3b+/− mice show deficits in memory consolidation,Model Systems Non-human model organism,"Kim YG, et al., 2021, PMID: 34217333","Kdm3b+/− mice show deficits in memory consolidation, whereas they are normal in basal oculomotor performance and optokinetic response acquisition. Kdm3b+/− mice also exhibit reduced H3K9 demethylase activity. H3K9 di-methylation is significantly increased in the granule cell layer of the cerebellum.",Score,1 (2),Score downgraded because only cerebellum-dependent motor memory was explored.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_4be69167-24df-4a3b-81c7-429399d0c727-2024-02-21T050000.000Z,2491,PubMed:34217333 +KO Mouse,Model Systems Non-human model organism,"Dickinson ME, et al., 2016, PMID: 27626380","Both have elevated blood levels of components of acid metabolism. However, in humans there is elevated lysine while in the mice there was elevated aspartate transaminase and alanine transaminase. The mouse also had enlarged lymph nodes and bladder, as well as an abnormal sternum morphology.",Score,0 (2),"The knockout mouse model was evaluated as part of the International Mouse Phenotyping Consortium, it has not been published and does not recapitulate human disease.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_92e04f9e-f03e-4295-baac-e9fb6b48a258-2022-10-14T160000.000Z,2500,PubMed:27626380 +Review of ACTN2 function,Biochemical Function B,"Bagnall RD, et al., 2014, PMID: 25224718","The gene product of ACTN2, alpha-actinin 2, has multiple functions that are consistent with the hypertrophic cardiomyopathy disease process including acting as a structural anchor, stretch sensor, signaling node, and in ion channel organization. Disruption of these functions could result in myocardial disarray, left ventricular dysfunction, hypertrophic response, and arrhythmia respectively.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6710e329-d391-4355-85a5-02d03f8791a3-2023-05-10T160000.000Z,2501,PubMed:25224718 +ACTN2 hiPSC-CM Functional Alteration,Functional Alteration Non-patient cells,", , PMID: 36078153","Compared to ACTN2wt, ACTN2mut hiPSC-CMs exhibited (i) cellular hypertrophy, myofibrillar disarray, multinucleation, ACTN2 protein aggregation, and activation of both the UPS and ALP in 2D culture, (ii) a marked reduction in the levels of sarcomere-associated proteins in 2D and EHTs, and (iii) force impairment in EHTs. These findings indicate impaired sarcomerogenesis and proteopathy as typical features in ACTN2mut.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6710e329-d391-4355-85a5-02d03f8791a3-2023-05-10T160000.000Z,2501,PubMed:36078153 +ACTN2 Mouse Model,Model Systems Non-human model organism,"Broadway-Stringer S, et al., 2023, PMID: 36899856","In summary, the heterozygous mouse model (in mature male mice) supports a pathological role of the ACTN2 p.Met228Thr variant but provides little insight into the disease mechanisms. Differences in physiology between humans and mice, the relatively young age of the mice and lack of stressors might explain this lack of an overt phenotype.",Score,1 (2),"In summary, the heterozygous mouse model (in mature male mice) supports a pathological role of the ACTN2 p.Met228Thr variant but provides little insight into the disease mechanisms. Differences in physiology between humans and mice, the relatively young age of the mice and lack of stressors might explain this lack of an overt phenotype.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6710e329-d391-4355-85a5-02d03f8791a3-2023-05-10T160000.000Z,2501,PubMed:36899856 +Tual-Chalot_Mouse,Model Systems Non-human model organism,"Tual-Chalot S, et al., 2014, PMID: 24896812","Efficient loss of Acvrl1 was accomplished in neonates. Examination of neonatal lungs 40 hrs post-injection revealed hemorrhage, enlarged veins, hyperbranching and AVMs from distal small capillaries, but no loss of vascular smooth muscle cells. Capillaries showed reduced pericyte coverage in knockout mutants. Increased endothelial cell proliferation and loss of arterial identity were also significant in knockout mice. Reduction in Smad 1/5/8 activity, expression of vasorgulators and key transcription factors and 33-fold reduction of endoglin was also observed in mutant mice. +In adult mice, Acvrl1 depletion led to GI bleeding (cecal hemorrhage), while vessel organization and branching were unaffected.",Score,0.5 (2),The mouse model is scored reduced points since two other models have been previously scored for phenotype recapitulation.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_fbbb72c5-84a0-4096-8d49-6df506cfee0e-2022-12-05T170000.000Z,2502,PubMed:24896812 +Agps KO mice,Model Systems Non-human model organism,"Liegel RP, et al., 2014, PMID: 25197626","Homozygous Agps-KOMP mice (which gemerate about 11% normal levels of Agps transcripts) and homozygous Agps Agps-KOMP EIIa-Cre (which generate about 5% normal levels of Agps transcripts) have several clinical features in common with human patients with variants in AGPS. Agps-KOMP EIIa-Cre mice exhibit growth delay although this resolves by adulthood. Agps-KOMP mice do not exhibit growth delay. Both mouse models and humans have early onset cataracts. No rhizomelia was observed for the mice, unlike human patients.",Score,1 (2),"The score is reduced because, while some features of RCDP are recapitulated in AGPS KO mice, rhizomelic shortening was not observed, and plasmalogen level was not reported.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_aba640e2-c95d-414b-8c72-d22769e4366a-2022-04-22T160000.000Z,2503,PubMed:25197626 +"Aldh7a1 knock out zebrafish (exon 4, 5 bp del)",Model Systems Non-human model organism,"Zabinyakov N, et al., 2017, PMID: 29053735","Humans who are homozygous for ALDH7A1 loss of function variants develop seizures which are non-responsive to anticonvulsant medications but improve upon treatment with pyridoxine. Human patients have elevated alpha-aminoadipic acid semialdehyde and pipecolic acid. Knock out Aldh7a1 zebrafish, generated here by CRISPR-Cas9 technology mimic the disease mechanism in humans (loss of function) in addition to the clinical (seizure-like behavior including spontaneous rapid increase in locomotion and rapid circling swim behavior followed by loss of posture; and abnormal EEG) and biochemical features (elevated AASA and pipecolic acid) of the disease, as well as the lack of response to anticonvulsant medication and responsiveness to pyridoxine (measured by EEG).",Score,3 (2),"The score is increased because this model recapitulates mechanism in humans (loss of function) in addition to the clinical and biochemical features of the disease, as well as the lack of response to anticonvulsant medication and responsiveness to pyridoxine. Note that another aldh7a1 zebrafish knock out with similar features has been described (PMID 29061647)",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7a982307-d8bd-43d1-b356-ef7ee6f32045-2019-07-26T160000.000Z,2506,PubMed:29053735 +"Aldh7a1 zebrafish knock out (exon 1, 5 bp insertion)",Model Systems Non-human model organism,"Pena IA, et al., 2017, PMID: 29061647","Humans who are homozygous for ALDH7A1 loss of function variants develop seizures that improve upon treatment with pyridoxine. Human patients have elevated alpha-aminoadipic acid semialdehyde (AASA). Knock out Aldh7a1 zebrafish, generated by CRISPR-Cas9 technology, mimic the disease mechanism in humans (loss of function) in addition to the clinical (behavioral signs of seizures including hyperactivity, whirlpool-like circular swimming, and whole-body convulsions leading to loss of posture; and abnormal EEG) and biochemical features (elevated AASA) of the disease, as well responsiveness of seizures to pyridoxine (measured behaviorally and on EEG).",Score,3 (2),"The score is increased because the disease mechanism, and clinical and biochemical features in this zebrafish model, in addition to responsiveness to pyridoxine mimics the findings in humans. Note that another aldh7a1 zebrafish knock out with similar features has been described (PMID 29053735).",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7a982307-d8bd-43d1-b356-ef7ee6f32045-2019-07-26T160000.000Z,2506,PubMed:29061647 +transforming Ba/F3 cells to cytokine independent growth,Functional Alteration Non-patient cells,"George RE, et al., 2008, PMID: 18923525","Reduction in IL-3 concentration by 100-fold to 0.01 ng/ml resulted in a clear difference in cell proliferation, with the Ba/F3 cells expressing F1174L mutations exhibiting much higher cell numbers relative to those transduced with wild-type ALK.",Score,0.5 (0.5),ALK mutant proteins F1174L possess gain-of-function kinase activity.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ba9f692d-9b6d-4d46-8bfa-009ec20ae538-2022-12-30T180000.000Z,2508,PubMed:18923525 +Peden_Function shared with AP3B1,Biochemical Function A,"Peden AA, et al., 2002, PMID: 11807095",Ap3B1 is shown to form the AP3 adaptor complex with AP3D1 as well as the σ3 and μ3 subunits,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3ec9ffa2-efda-446d-a848-e6d4d5b92fb6-2023-06-07T160000.000Z,2510,PubMed:11807095 +Peden_Rescue,Rescue Cell culture model,"Peden AA, et al., 2002, PMID: 11807095","Cells expressing the wild-type Ap3d1 take up less anti–LAMP-1 than non-trandfected cells, indicating less misrouting of LAMP-1 to the plasma membrane in them.",Score,0.5 (1),The evidence is awarded minimum points as the rescue pertains to a molecular aspect and not the disease phenotype.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3ec9ffa2-efda-446d-a848-e6d4d5b92fb6-2023-06-07T160000.000Z,2510,PubMed:11807095 +crasher and *AB zebrafish,Model Systems Non-human model organism,"Neuffer SJ, et al., 2022, PMID: 35816398","ap3d1 loss‐of‐function mutations in zebrafish cause significant expression changes in the melanogenesis genes, dopachrome tautomerase (dct) and tyrosinase‐related protein 1b (tyrp1b). Melanophores were lighter, indicative of a melanin synthesis problem, this recapitulates the albinism in patients.",Score,1 (2),Crasher is a novel syndromic albinism zebrafish model for human HPS10. Whether mutants display the neurological and immunological symptoms in HPS10 remains to be tested.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3ec9ffa2-efda-446d-a848-e6d4d5b92fb6-2023-06-07T160000.000Z,2510,PubMed:35816398 +Sprague-Dawley rat natural model,Model Systems Non-human model organism,"Zigler JS, et al., 2016, PMID: 27472223","Sprague-Dawley rats homozygous for a naturally occurring variant (p.G639E) in the Bckdk gene have multiple abnormalities including splaying of the hind limbs (due to neurological dysfunction), decreased brain weight, ventricular dilatation, seizures, reduced fertility, reduced levels of plasma branched chain amino acids. While these features do not completely recapitulate the findings in humans with BCKDK deficiency the low plasma levels of BCAAs, seizures, and poor growth are in common. Rats were noted to have reduced brain weight; patients can have microcephaly. While rats have ventriculomegaly, patients have normal brain MRIs. Cognition was not assessed in rats.",Score,1 (2),"The phenotype in this natural rat model, homozygous for a missense variant in Bckdk, does not completely recapitulate the human phenotype for BCKDK deficiency, although there are some striking similarities.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_f90aaad0-b56a-41dc-8d1f-9d12fc66113f-2019-01-18T170000.000Z,2519,PubMed:27472223 +Girotto Expression,Expression A,"Girotto G, et al., 2013, PMID: 24312468","BDP1 expression was observed in mice in endothelial cells of stria vascularis capillaries, and mesenchyme-derived cells and surrounding extracellular matrix around the cochlear duct including the spiral ligament and basilar membrane",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d300a54b-171c-4445-a138-a24409e99aae-2021-03-26T160000.000Z,2520,PubMed:24312468 +Zebrafish knock in for 9 different variants,Model Systems Non-human model organism,"Anastasaki C, et al., 2009, PMID: 19376813",This model demonstrates that these variants cause RASopathy -like features in zebrafish,Score,0.5 (2),These changes do not implicate CFC explicitly,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a53e5a92-126f-4b00-a89b-af55d4f342ca-2018-07-24T160000.000Z,2523,PubMed:19376813 +Cellular sensitivity to PARP inhibitor,Functional Alteration Patient cells,"Keupp K, et al., 2019, PMID: 31347298",Patient cells were highly sensitive to olaparib treatment as compared to the control and to cells from the mother,Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_aa39798d-9b6e-430d-8bc1-2a01f81f1f72-2020-05-14T003137.538Z,2525,PubMed:31347298 +Nuclear foci analyses by IF,Functional Alteration Patient cells,"Keupp K, et al., 2019, PMID: 31347298","acquisition of the BRCA1 variant causing the p.Cys61Gly mutation on top of p.Arg1699Gln exchange severely altered HR in the patient, resulting in accumulation of basal DNA damage and failure to assemble functional RAD51 nucleofilaments.",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_aa39798d-9b6e-430d-8bc1-2a01f81f1f72-2020-05-14T003137.538Z,2525,PubMed:31347298 +DSB repair measurements,Functional Alteration Patient cells,"Keupp K, et al., 2019, PMID: 31347298","two fold decrease in HR was scored for the LCLs from the mother carrying the BRCA1 p.Arg1699Gln mutation and sixfold for the LCLs from the index patient carrying both mutations; in addition, both LCLs showed four‐ to fivefold elevated microhomology‐mediated end joining compared with three wild‐type LCLs",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_aa39798d-9b6e-430d-8bc1-2a01f81f1f72-2020-05-14T003137.538Z,2525,PubMed:31347298 +DNA fiber assay,Functional Alteration Patient cells,"Keupp K, et al., 2019, PMID: 31347298","both the mother carrying the p.Arg1699Gln mutation and the patient with both the p.Cys61Gly and the p.Arg1699Gln mutations are compromised in protecting nascent DNA from nucleolytic degradation during replication stress, whereas defective RAD51 foci formation postirradiation and olaparib hypersensitivity was observed with patient cells only.",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_aa39798d-9b6e-430d-8bc1-2a01f81f1f72-2020-05-14T003137.538Z,2525,PubMed:31347298 +RT-PCR expression,Expression A,"Pickel S, et al., 2021, PMID: 34307509",RT-PCR analysis shows expression of CACNB2 in heart,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e7a08ba4-6024-449c-b824-c762a85277a1-2022-04-13T160000.000Z,2528,PubMed:34307509 +sh-RNA mediated knockdown,Model Systems Non-human model organism,"Pickel S, et al., 2021, PMID: 34307509",Myocyte enlargement indicative of cellular hypertrophy seen in human HCM.,Score,1 (2),Indirect model,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e7a08ba4-6024-449c-b824-c762a85277a1-2022-04-13T160000.000Z,2528,PubMed:34307509 +Nuclear targeting of truncated B4 protein,Functional Alteration Non-patient cells,"Etemad S, et al., 2014, PMID: 24875574","Evidence does not support altered function. Nuclear targeting of β4b(1–481) was not reduced compared with full-length β4b in any of three cell systems, indicating the β4 distal C-terminus does not play an essential role of in nuclear targeting and bringing into question whether nuclear function of calcium channel β4 subunits is critically involved in etiology of epilepsy and ataxia in patients and mouse models with CACNB4 variants",Score,0 (0.5),"This experimental evidence was downgraded for a number of reasons. First, this experiment contradicts prior studies that suggested nuclear localization might be explanation for the functional effects but doesn't exclude another possible mechanism for change in electrophysiological properties in prior studies. Secondly, the Epilepsy GCEP has decided that with a lack of genetic evidence, no experimental evidence will be counted.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d2fad131-8e91-4874-9394-8b86d6d62abb-2022-07-05T160000.000Z,2529,PubMed:24875574 +Ivliev Expression,Expression A,"Ivliev AE, et al., 2012, PMID: 22558177",This was a large meta-analysis of genes coexpressed with known cilia-related genes. The analysis revealed that DCDC2 may be related to cilia due to its coexpression with other cilia-related genes.,Score,0 (0.5),"Gene was expressed in ciliated cells (fallopian tube, testis, bronchus, etc). No connection made to cochlea or hearing.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_86802e37-e2a5-43b9-8538-e104859b4c55-2020-08-31T170000.000Z,2538,PubMed:22558177 +Brain of zebrafish,Expression A,"de Calbiac H, et al., 2018, PMID: 29761115",depdc5 transcript is expressed in the brain of zebrafish embryos via in situ hybridization,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_82a82c75-f9a5-4f51-a15c-6513c13df57c-2018-08-07T040000.000Z,2539,PubMed:29761115 +DEPDC5 Zebrafish,Model Systems Non-human model organism,"de Calbiac H, et al., 2018, PMID: 29761115","The epileptic phenotype seen in the zebrafish is similar to that found in humans. This was measured by changes in swimming patterns, amplitude of movement, total activity.",Score,2 (2),"While zebrafish knockdowns are sometimes nonspecific this model has a convincing phenotype and showed a rescue using mTORC1 inhibitor, rapamycin, and overexpression of human WT DEPDC5. The phenotype was not rescued with DEPDC5 mutations (p.Arg487* and p.Arg485Gln).",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_82a82c75-f9a5-4f51-a15c-6513c13df57c-2018-08-07T040000.000Z,2539,PubMed:29761115 +Jaworek Expression,Expression A,"Jaworek TJ, et al., 2013, PMID: 24039609",This study performed expression experiments of the ELMOD3 protein in human and mouse tissue. They also performed localization experiments on both WT and p.Leu265Ser proteins in the rat and mouse cochlea and organ of Corti. The ELMOD3 protein is expressed ubiquitously in both mouse and human tissue. p.Leu265Ser variant protein did not localized to stereocilia in the cochlea like WT protein. The variant protein also failed to localize to microvilli in CL4 cells.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_95f5efe3-e0d1-4cef-b475-7ff1cd3c417c-2021-11-17T170000.000Z,2545,PubMed:24039609 +Jaworek Function,Biochemical Function B,"Jaworek TJ, et al., 2013, PMID: 24039609",Protein unable to localize properly in the cochlear stereocilia,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_95f5efe3-e0d1-4cef-b475-7ff1cd3c417c-2021-11-17T170000.000Z,2545,PubMed:24039609 +5961SB CRISPR Rescue,Rescue Non-human model organism,"Yin H, et al., 2016, PMID: 26829318","Systemic delivery of Cas9 mRNA by lipid nanoparticles and sgRNA/HDR template by AAV can efficiently cure Fah mut/mut mice with an initial Fah correction in more than 6% of hepatocytes. Treatment rescued disease symptoms such as weight loss and liver damage, as assessed by serum biomarkers (AST, ALT and bilirubin).",Score,1.5 (2),"Treatment rescued disease symptoms such as weight loss and liver damage, however the mouse is still not well phenotyped for Tyrosinemia I and the authors did not measure levels of succinylacetone or FAH activity.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_39c50699-f422-4bae-89ac-af13ef7cb8cc-2020-06-29T174149.440Z,2548,PubMed:26829318 +Down-regulation of serum response factor (SRF),Functional Alteration Patient cells,"Adam J, et al., 2011, PMID: 22014577","FH-deficiency fibroblast cells and leiomyomas showed down-regulation of serum response factor (SRF)signaling, which has a key function in smooth muscle differentiation.",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_59e42ccd-2b0b-441c-8529-6eb1e9dde330-2020-05-14T002334.007Z,2549,PubMed:22014577 +FAD synthesis,Functional Alteration Patient cells,"Olsen RKJ, et al., 2016, PMID: 27259049",The rate of FAD synthesis from patient cells was compared to 3 controls. All 3 patients showed reduced rate of FAD synthesis compared to controls.,Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_769764bf-09c5-4a7d-8501-5fcf154fcdda-2020-12-16T181902.981Z,2550,PubMed:27259049 +Hahn2011 HL-60 cells,Functional Alteration Non-patient cells,"Hahn CN, et al., 2011, PMID: 21892162","In HL-60 promyelocytes with WT GATA2 there is differentiation into granulocytes upon exposure to ATRA, resulting in cessation of proliferation and promotion of apoptosis. However, 355del inhibited differentiation while 354Met allowed differentiation but did not result in cessation of proliferation and promotion of apoptosis. Microarray analysis was also performed to compare global gene expression in HL-60 cells expressing wild-type GATA2 and three GATA2 mutants.",Score,0.5 (0.5),"Site-directed mutagenesis was used to generate p.Thr354Met, p.Thr355del and p.Leu359Val mutants. The coding regions of wild-type, p.Thr354Met and p.Leu359Val were cloned into a dual lentiviral vector system which was used to generate HL-60 cells expressing wild-type or mutant GATA2 upon addition of 4HT.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7c0449f7-e20b-4610-95ad-896eee265492-2022-12-30T180000.000Z,2554,PubMed:21892162 +Function of P protein (GLDC),Biochemical Function B,"Kikuchi G, et al., 2008, PMID: 18941301","Patients with glycine encephalopathy (NKH) have elevated glycine in CSF and plasma, and a high CSF/plasma glycine level. The high levels of glycine observed in this condition are toxic to the nervous system. Deficiency of P-protein (glycine decarboxylase) activity would be expected to result in elevated glycine levels, as seen in this condition.",Score,2 (0.5),"Glycine decarboxylase (P protein) has a well-known function in the glycine cleavage system, which is described in detail in this paper, and its function is consistent with the biochemical abnormalities observed in patients.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_14d991f3-25f3-40c9-aacd-c1a008d9eaea-2019-02-06T170000.000Z,2558,PubMed:18941301 +Glycine decarboxylase deficiency in mice,Model Systems Non-human model organism,"Pai YJ, et al., 2015, PMID: 25736695","Gldc knock out mice had an increase in plasma and urine glycine levels consistent with the observation of elevated glycine levels in body fluids of NKH patients with deficient GCS function. These mice had decreased survival (55% died beween 2 and 12 weeks of age). Isotope-tracing analysis of glycine flux in adult humans suggests a major contribution of glycine-derived one-carbon units to folate one carbon metabolism (FOCM) (Lamers et al, 2009; 19244382)",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_14d991f3-25f3-40c9-aacd-c1a008d9eaea-2019-02-06T170000.000Z,2558,PubMed:25736695 +Marmoset cochlea expression of GRHL2,Expression A,"Hosoya M, et al., 2016, PMID: 26915689","Expression pattern in marmoset cochlea of GRHL2 examined by immunofluorescent staining. Expression observed in spiral ligament, hair cells, supporting cells, SGNs, but not stria vascularis. Expression pattern was different from that in mouse cochleae, suggesting expression differences may cause phenotypic difference in mice",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a2ca9952-b611-4e6f-bbf8-aa5175248d01-2020-05-01T160000.000Z,2562,PubMed:26915689 +CRISPR/cas9 of post-mitotic pyramidal mouse neurons,Model Systems Cell culture model,"Straub C, et al., 2014, PMID: 25140704",This model is a proof of concept showing that these neurons can be post-mitotically altered via crispr/cas9. The neurons displayed altered NMDA current/signalling,Review,1 (1),This model showed significantly reduced NMDAR currents compared to untransfected neighboring control cells which may be indicative of impact on the complex neurodevelopmental disorder.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_22693f82-fde1-4123-9cfb-6ec27e0c1ac6-2023-04-04T070000.000Z,2564,PubMed:25140704 +GRIN1 cre knockout in parvalbumin positive interneurons,Model Systems Non-human model organism,"Bygrave AM, et al., 2016, PMID: 27070406","Previous studies have reported impairments in Grin1ΔPV knockout mice on cognitive tasks, such as working/short-term memory,15–17 although others have failed to detect such +deficits.18,20. This study found that memory was largely inaffected in these mice",Review,2 (2),"This mouse exhibited no intellectual abnormalities, there was only a significant increase in locomotor activity that later disappeared. This study cannot be scored. Of note other studies of this mouse have had varying results as well.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_22693f82-fde1-4123-9cfb-6ec27e0c1ac6-2023-04-04T070000.000Z,2564,PubMed:27070406 +Ppp1r2-Cre/Grin1 knockout mouse,Model Systems Non-human model organism,"Nakao K, et al., 2019, PMID: 29394409","This model may show that GRIN1 knockout causes a complex neurodevelopmental disorder, however it also is not assessing the impact of the alteration of GRIN1 on development in the embryo. Mice were postnatally altered. Still, the symptoms of schizophrenia that seem to be linked to the GRIN1 alteration are noteworthy.",Review,2 (2),"Cannot fully score postnatally altered mouse model demonstrating schizophrenia. However, this mouse does demonstrate a neurological disorder and it may be that homozygous knockout of the NMDA receptor is embryonic lethal.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_22693f82-fde1-4123-9cfb-6ec27e0c1ac6-2023-04-04T070000.000Z,2564,PubMed:29394409 +Conditional NMDAR knockout model of schizophrenia,Model Systems Non-human model organism,"Bygrave AM, et al., 2019, PMID: 30687034","found that GRIN1 conditional knockout mice were largely normal when maintained in enriched environments but displayed some cognitive deficits (spatial and object related STM impairments) when housed under reduced environmental enrichment. May be indicative of intellectual disability in patients with homozygous variants but again, supposedly a model for schizophrenia.",Review,2 (2),"found that GRIN1 conditional knockout mice were largely normal when maintained in enriched environments but displayed some cognitive deficits (spatial and object related STM impairments) when housed under reduced environmental enrichment. May be indicative of intellectual disability in patients with homozygous variants but again, supposedly a model for schizophrenia.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_22693f82-fde1-4123-9cfb-6ec27e0c1ac6-2023-04-04T070000.000Z,2564,PubMed:30687034 +Gain- and loss-of-function LBD mutants are both associated,Biochemical Function A,"Elmasri M, et al., 2022, PMID: 35228668","Functional NMDA receptors require assembly of two GluN1 subunits together with either two GluN2 subunits or a combination of GluN2 and GluN3 subunits. The GluN2 subunits are the glutamate-binding components and are interchangeable: GRIN2A, GRIN2B, GRIN2C, GRIN2D",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a52befb3-e9e0-46f1-9abf-8ead03151230-2022-03-15T190000.000Z,2565,PubMed:35228668 +Targeted deletion of exon 1 mouse,Model Systems Non-human model organism,"Avenarius MR, et al., 2018, PMID: 30157177","This mouse demonstrates that homozygous LOF of the GRXCR2 gene causes a progressive hearing loss in mice. Full length GRXCR2 mRNA transcripts were absent in mice homozygous for the mutant allele, assessed by RT-PCR. Grxcr2 protein levels were also significantly diminished, assessed by immunofluorescent staining.",Score,3 (2),"This is the same mouse model from the Avenarius 2012 GRXCR2 thesis; Additional points were added for the flox-neo homozygous hypomorphic mice that also displayed progressive hearing loss due to less than half of the GRXCR2 mRNA expressed in the +/- mice. Additionally, the phenotype of progressive, early-onset hearing loss is consistent with the human case with a LOF variant.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_207f12b7-3148-4a8f-88f8-f78ac5bb294c-2021-03-26T155748.643Z,2566,PubMed:30157177 +GRXCR2 cochlear expression,Expression A,"Avenarius MR, et al., 2018, PMID: 30157177",RT-PCR analysis of mice missing exon 1 of GRXCR2 and heterozygous mice showed that heterozygous and WT mice expressed GRXCR2 in the sterocilia of the cochlea while KO mice did not have full length transcripts of GRXCR2 and exhibited disorganized sterocilia,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_207f12b7-3148-4a8f-88f8-f78ac5bb294c-2021-03-26T155748.643Z,2566,PubMed:30157177 +CRISPR/cas9 GRXCR2 deficient mice,Model Systems Non-human model organism,"Liu C, et al., 2018, PMID: 30380417",Both of the deletions in exon 1 causing loss of expression of GRXCR2 resulted in profound deafness in the mice based on ABR studies.,Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_207f12b7-3148-4a8f-88f8-f78ac5bb294c-2021-03-26T155748.643Z,2566,PubMed:30380417 +GRXCR2 interaction with TPRN,Protein Interaction,"Liu C, et al., 2018, PMID: 30380417","This study showed that GRXCR2 forms a complex with TPRN by geneticlaly engineering mice (using CRISPR cas9) that were TPRN deficient, GRXCR2 deficient, or both TPRN deficient and GRXCR2 deficient. They found that the TPRN mislocalized with dysmorphic stereocilia without GRXCR2. They also used coimmunoprecipitation to show that the proteins directly interacted.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_207f12b7-3148-4a8f-88f8-f78ac5bb294c-2021-03-26T155748.643Z,2566,PubMed:30380417 +Stereocilia expression of GRXCR2,Expression A,"Liu C, et al., 2018, PMID: 30380417",Found that GRXCR2 was concentrated at the base of the stereocilia and was critical for taperin localization using whole mount staining,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_207f12b7-3148-4a8f-88f8-f78ac5bb294c-2021-03-26T155748.643Z,2566,PubMed:30380417 +Analysis of S-loop variants,Functional Alteration Non-patient cells,"Ingle BL, et al., 2018, PMID: 30581542","Eleven missense variants altering residues in the S loop of glutathione synthetase, a series of residues near the gamma-glutamylcysteine substrate binding site, were generated and expressed in E. coli for measurement of GS activity and kinetic studies. Some of these variants had previously been reported in human patients; some have not been observed in humans but were generated for the purposes of studying the role of specific amino acids in glutathione synthetase function. All of the missense changes resulted in decreased glutathione synthtase activity; the greatest residual activity (about 50%) was observed for p.D268A and p.D268E). For R267A, R267W, G269V and Y270A the glutathione synthetase activity was too low for the study of kinetic parametes. Further kinetic and computational studies determined the role of S-loop residues responsible for forming the curve of the S-loop (G269, Y275, and P272), maintaining active site structure (D268), and binding gamma-glutamylcysteine (R267 and Y270).",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_69a8e645-0e10-4ea9-8545-212ce9b0dcbf-2019-04-26T160000.000Z,2567,PubMed:30581542 +MODY Stem Cell Model,Model Systems Cell culture model,"Teo AK, et al., 2016, PMID: 26876668","MODY5-hiPSCs differentiated into definitive endoderm showed an early (day 5) compensatory increase in definitive endoderm markers in the mutant hiPSCs (Fig. 1E and Fig 2) +mutant cell lines showed increased PDX1 gene expressions, confirmed by luciferase assay, and overexpression of both WT and mutant (Fig. 4) +mutant cells also showed down-regulation of PAX6 gene expression as an indirect effect of the variant confirmed by overexpression of both WT and mutant HNF1B (Fig. 3A, Fig. 5)",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_4174ea0a-6901-4070-ad93-d92614fd55c0-2021-01-19T170000.000Z,2570,PubMed:26876668 +Serum miRNA profiling,Expression B,"Fendler W, et al., 2016, PMID: 27059371","Through serum miRNA profiling, patients exhibiting HNF1B-MODY how lower expression levels in miR-223, miR-24, miR-27b, and miR-199a (Fig. 1) +Subsequent siRNA induced knockdowns of HNF1B in human hepatocytes (HepG2) showed reduction of all previous mentioned miRNAs with miR-223 being reduced by 99% (Fig. 3) +Cell culture media was tested 48h after HNF1B silencing in the HepG2 cells for miRNA levels which showed reduction in extracellular levels of miR-223, miR-27b, and miR-199a compared to controls (Fig. 3e)",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_4174ea0a-6901-4070-ad93-d92614fd55c0-2021-01-19T170000.000Z,2570,PubMed:27059371 +Azaiez Mouse,Model Systems Non-human model organism,"Azaiez H, et al., 2015, PMID: 25816005","Homer2 -/- mice showed progressive hearing loss. ABoV thresholds were significantly lower compared to Homer2+/- and WT mice. Homer2-/- were profoundly deaf at all frequencies by P56. Immunolabeling of these mice showed no obvious hair cell death in cochleae in P56 Homer2-/-. Immunolabeling results indicate absence of Homer2 does not impair hair cell development, and hearing loss in knockout mice is not due to hair cell death. Hair bundle morphology data was not collected.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9158c2a6-f11b-47b4-ac7d-45471f7255a1-2020-08-31T170000.000Z,2571,PubMed:25816005 +Azaiez Zebrafish,Model Systems Non-human model organism,"Azaiez H, et al., 2015, PMID: 25816005","This resulted in significantly smaller ear size compared to WT HOMER2-injected embryos, and the number of kinocilia per neuromast was significantly decreased. These results suggest the pArg185Pro has a dominant-negative effect on protein function (not haploinsufficiency).",Score,1 (2),Downgraded because hearing was never assessed in postnatal zebrafish and small ear size was not phenotype in humans with variant.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9158c2a6-f11b-47b4-ac7d-45471f7255a1-2020-08-31T170000.000Z,2571,PubMed:25816005 +Azaiez Expression,Expression A,"Azaiez H, et al., 2015, PMID: 25816005",Immunolabeling whole mount P2 mouse cochlea with HOMER2 antibody showed enriched expression in IHC and OHC stereocilia tips. A separate experiment showed p.Arg185Pro did not affect subcellular localization of HOMER2.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9158c2a6-f11b-47b4-ac7d-45471f7255a1-2020-08-31T170000.000Z,2571,PubMed:25816005 +Disruption of Interaction Domain,Functional Alteration Non-patient cells,"Lomberk G, et al., 2013, PMID: 23589285","Immunoprecipitation in Panc1 cells of His-tagged KLF11 A347S showed disruption of interaction with GB2 (Fig. 4A), this disruption results in decreased KLF11-mediated insulin promotor activity and glucose-stimulated insulin secretion shown in INS-1 cells (Fig. 6)",Score,0 (0.5),"The p. Ala347Ser variant in KLF11 has a population frequency in gnomAD that is cosidered too high to be pathognic. Therefore, no points were scored for this experimental evidence with a proposed benign allele.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b1e38a49-7c12-4514-a2a1-109e04da146f-2023-02-08T170000.000Z,2580,PubMed:23589285 +Fear conditioning,Model Systems Non-human model organism,"Camarena V, et al., 2014, PMID: 25001218",The Mbd5 gene-trap mouse (Mbd5 +/GT) is a Mbd5 hypomorph model. Deficit in fear conditioning test is similar to intellectual disability in human patients with heterozygous loss function variants in MBD5.,Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_952cb4f8-e59b-4edb-a393-0266e0008963-2023-02-15T170000.000Z,2592,PubMed:25001218 +Mbd5+/GT cultured cortical neurons,Model Systems Cell culture model,"Camarena V, et al., 2014, PMID: 25001218",The cultured cortical neurons isolated from embryonic day 16 (E16) embryos of Mbd5+/GT showed reduced neurite outgrowth and branching. These neuronal structural deficits correlate with abnormal behavior observed in humans with MBD5 haploinsufficiency.,Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_952cb4f8-e59b-4edb-a393-0266e0008963-2023-02-15T170000.000Z,2592,PubMed:25001218 +Diminuendo heterozygous and homozygous mice,Model Systems Non-human model organism,"Lewis MA, et al., 2009, PMID: 19363478","Heterozygotes (Dmdo/+) show a progressive loss of the Preyer reflex (ear flick response to sound) between 4 and 6 weeks. Homozygotes (Dmdo/Dmdo) do not demonstrate a Preyer reflex at any age, adn show head bobbing and a staggering, circling gait. The pattern of human hearing loss associated with this gene is also autosomal dominant. +They mapped the mutant phenotype to proximal chormosome 6 and a 4.96 interval and then sequenced 87% of the 900 exons within the interval and located two mutations. The first was a silent C>T substitution in exon 5 of 2310005E10Rik- which is actually identical to the human WT ref sequence so they concluded that the second mutation, the n.15A>T substitution in Mirn96 was the causative mutation in Dmdo.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_01d1a7f4-8421-4be3-8fe7-2c2025f03ac9-2023-09-26T160000.000Z,2594,PubMed:19363478 +Expression of MIR96 gene targets in Cochlea,Expression B,"Lewis MA, et al., 2009, PMID: 19363478","Used RT-PCR, in situ hybridization, and immunohistochemistry to quantify the expression of various targets of MIR96 in diminuendo mice with the n.15A>T variant. They found that expressio variaed significantly especially for Ocm and Slc26a5 proteins in mice with the variant. This is thought to be due to MIR96's regulatory role in transcription.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_01d1a7f4-8421-4be3-8fe7-2c2025f03ac9-2023-09-26T160000.000Z,2594,PubMed:19363478 +Ex-vivo analysis of miRNA expression and biogenesis,Functional Alteration Non-patient cells,"Soldà G, et al., 2012, PMID: 22038834","Luciferase assays showed that the miR96(+57T>C) mutation impairs the regulation of MYRIP by reducing mature miR-96 levels.They also found that the loss of MYRIP activity could be recovered by introducing a double mutation +23A>G, +57T>C because it rescues the secondary structure of the miRNA.",Score,0 (0.5),"There is no link between MYRIP and hearing loss so this shouldn’t be scored, and due to non-segs in family this was needed to score a variant.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_01d1a7f4-8421-4be3-8fe7-2c2025f03ac9-2023-09-26T160000.000Z,2594,PubMed:22038834 +Homozygous MIR96 Mutants,Model Systems Non-human model organism,"Thoenes M, et al., 2015, PMID: 25759012","Both display hearing loss, however the human inheritance pattern is dominant, so a homozygous mouse should be downgraded. THis mouse was also used to study the effects of MIR96 on OSBPL2, a suspected novel deafness gene.",Score,0 (2),"Did not score, genetic evidence maxed out and homozygous mouse model is less relevant than the other heterozygous Dmdo models.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_01d1a7f4-8421-4be3-8fe7-2c2025f03ac9-2023-09-26T160000.000Z,2594,PubMed:25759012 +Role of MIR96,Biochemical Function A,"Lewis MA, et al., 2016, PMID: 26988146","The above are cited to be known hearing loss genes. Microarray analysis, protein-protein interactome analysis, gene set enrichment analysis, Ago2 pulldown assay for identifying targets of MIR96.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_01d1a7f4-8421-4be3-8fe7-2c2025f03ac9-2023-09-26T160000.000Z,2594,PubMed:26988146 +"Mir96, Mir182, Mir183 mice (TG 1MDW)",Model Systems Non-human model organism,"Weston MD, et al., 2018, PMID: 29476110",Loss of the preyer reflex and progressive hearing loss in the mice is consistent with the human phenotype.,Score,0 (2),"The mice in this study had modifications to 3 different micro RNA's and MIR96 was one of the miRNA's overexpressed. Therefore, despite the inclusion of MIR96, this mouse model should not be scored. However this model did thoroughly investigate the expression of MIR182 , MYO6, and other downstream targets of these genes.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_01d1a7f4-8421-4be3-8fe7-2c2025f03ac9-2023-09-26T160000.000Z,2594,PubMed:29476110 +Analysis of MUT missense variants,Functional Alteration Non-patient cells,"Forny P, et al., 2014, PMID: 25125334","23 MUT missense variants were analyzed for stability and activity by expression in E. coli and MUT-deficient fibroblasts, (Table 1B). The mut0 mutants had folding or catalytic defects, resulting in very low residual enzyme activities (<2% normal) consistent with their predominance in neonatal onset patients with severe long-term complications. By comparison, the mut– mutants had higher enzyme activity (ranging from 2.7-85%). KM values were determined for Mut- variants, all of which had higher KM values for AdoCbl than wild type; seven variants had >200 times the normal KM value. No variants had +large increases in KM for methylmalonyl-CoA, suggesting that substrate binding was not defective.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3c5301da-0dad-417a-8257-5b1c6155e8fa-2019-05-09T160000.000Z,2596,PubMed:25125334 +MYH14 KO Mouse,Model Systems Non-human model organism,"Fu X, et al., 2016, PMID: 28101381","Used Auditory brainstem response to find that the auditory thresholds were increased in the MYH14 KO mice. Also did expression studies, (scored separately). Found that at 5 months of age MYH14 -/- mice have significant high frequency hearing loss relative to controls. They also found that these mice are less capable of recovering from noise damage, and that OHC loss was significantly increased 2 weeks after acoustic trauma in MYH14 -/- .",Score,1 (2),Downgraded to one point because KO -/- is not consistent with inheritance pattern.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_007697a5-2f83-40d0-b2ea-914e458a1452-2020-08-31T170000.000Z,2599,PubMed:28101381 +Cochlear expression of MYH14 in mice,Expression A,"Fu X, et al., 2016, PMID: 28101381","RT-PCR and western blot analysis confirmed cochlear expression of MYH14, but they also found that the expression levels of MYH14 were dependent on noise exposure. Upgrading to 1 point for this experiment. In knockout mice, the levlels of MYH10 expression were even higher after noise exposure.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_007697a5-2f83-40d0-b2ea-914e458a1452-2020-08-31T170000.000Z,2599,PubMed:28101381 +RC phosphorylation,Biochemical Function B,"Muthu P, et al., 2012, PMID: 21696541",Show that MLCK (MYLK2) can phosphorylate RLC (MLC2/MYL2) and modulate myofibrillar ATPase activity. Looking at the WT OE transgenic human ventricular mysoin RLC mouse and tissue.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6f0f41e3-7b5b-477c-b45d-598b5f8f3df0-2023-02-08T170000.000Z,2600,PubMed:21696541 +MYOM1 expression,Expression A,"Schoenauer R, et al., 2011, PMID: 21069531","Expressed in healthy human heart, detected by qRT-PCR and immunofluorescence. However, Myom1 has been shown to be expressed in mouse skeletal muscle, so its expression is not limited to cardiomyocytes.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_8ff00fbf-6b20-49cd-8af8-0f6404240db5-2023-02-23T170000.000Z,2602,PubMed:21069531 +Mitochondrial Expression,Expression A,"Ohashi K, et al., 2012, PMID: 23212377",NADK2 protein was predicted to localize to mitochondria due to the presence of a mitochondrial-targeting sequence. HEK293A cells were transiently transfected with a plasmid expressing FLAG-tagged NADK2 and it was shown to localize to mitochondria by immunostaining.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_285bdfcd-10c2-48f9-9be9-d77894b26f19-2020-12-01T170000.000Z,2604,PubMed:23212377 +Leigh syndrome p.Asn381Ser and p.Val213Phe,Functional Alteration Non-patient cells,"Simon M, et al., 2015, PMID: 25807530","Neither missense variant affected protein expression levels (by western blot). Localization was also not affected. However in vivo protein stability of p.Asn381Ser (the Leigh syndrome variant) was shown to be reduced in parent and proband whole fibroblast cell lysates. Cell lines were treated with a mitochondrial respiration inhibitor that allowed measurement of respiration due to non-mitochondrial oxygen consumption. Overexpression of WT partially rescued oxygen consumption, while the p.V213F and two other Leigh syndrome variants did not significantly increase consumption compared to cells transfected with empty vector. Additionally, the variant was transfected into Leigh syndrome patient fibroblast cells (compound het for p.N381S and p.Y323*) and did not rescue activity of mito complexes I, II, and IVk, while WT NARS2 did rescue activity.",Score,0 (0.5),No points given because unknown relavence to HL or no effect of the variants.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9db16e79-4c14-437f-9723-749f99053d5c-2021-11-17T170000.000Z,2606,PubMed:25807530 +Inner ear expression of NARS2,Expression A,"Simon M, et al., 2015, PMID: 25807530","Online databases report NARS2 expression in human and mouse cochlear and vestibular systems. Authors performed in situ hybridization of NARS2 in mouse spiral ganglion, the cochlear duct including organ of Corti, and some of the mesenchyme surrounding cochlear duct.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9db16e79-4c14-437f-9723-749f99053d5c-2021-11-17T170000.000Z,2606,PubMed:25807530 +Hypo-excitability in juvenile mouse somatosensory cortex,Functional Alteration Non-patient cells,"Delattre V, et al., 2013, PMID: 24104404",Measured neuron excitation of WT and NLGN4 KO mouse neurons pulled from the somatosensory cortex and found that it was decreased in the knockout mice.,Score,0.5 (0.5),Neuron excitation is decreased in mice without NGLN4,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_bed32aec-b1a6-41ff-9607-b4172888c46a-2018-08-01T160000.000Z,2611,PubMed:24104404 +Knock in zebrafish,Model Systems Non-human model organism,"Runtuwene V, et al., 2011, PMID: 21263000",Features similar to RASopathy,Score,0.5 (2),Implicate RASopathy phenotypes butdoes not provide evidence just for NS.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_34419b69-59c3-458b-a2a5-38a401679deb-2018-05-30T160000.000Z,2613,PubMed:21263000 +Rescue in I24N zebrafish,Rescue Non-human model organism,"Runtuwene V, et al., 2011, PMID: 21263000",The study used MAPK inhibitors to attempt to rescue the phenotype of the I24N zebrafish embryos.,Score,0.5 (2),Doesn't directly implicate NS but does provide further support that this gene is associated with RASopathies,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_34419b69-59c3-458b-a2a5-38a401679deb-2018-05-30T160000.000Z,2613,PubMed:21263000 +Variants in 293T cells,Functional Alteration Non-patient cells,"Runtuwene V, et al., 2011, PMID: 21263000","The I24N, G12V, and G60E variants all enhanced MAPK activation compared to the control. T50I did not enhance the MAPK activation.",Score,0 (0.5),Doesn't directly implicate NS,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_34419b69-59c3-458b-a2a5-38a401679deb-2018-05-30T160000.000Z,2613,PubMed:21263000 +rhg mouse,Model Systems Non-human model organism,"Bisaillon JJ, et al., 2014, PMID: 25264521","A missense variant in Oat, p.Gly353Ala, was found to be the cause of the “retarded hair growth” (rhg) phenotype in mice. Homozygous rhg mice appear normal at birth but they are smaller than their heterozygous littermates by 10 days of age, and have delayed development of a hairy coat that is most obvious at 7–10 days of age. This study found that adult rhg/rhg and rhg/Oat Δ mutants have profoundly elevated levels of plasma ornithine and decreased levels of plasma lysine similar to the levels previously reported for both mice and humans homozygous for recessive defects in Oat. Like human patients with OAT deficiency, who develop gyrate atrophy, histology of the retinas of rhg/rhg and rhg/OatΔ mice at 7 and 12 months of age showed evidence of retinal abnormalities including retinal pigment epithelium cells that were irregular in size and shape, and some appeared to have migrated into the outer segment layer, and photoreceptor outer segments that were shortened and disorganized.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_edbab666-9ae6-46db-b818-809a4bf8333e-2019-07-10T160000.000Z,2617,PubMed:25264521 +OBSCN Western blot,Expression A,"Young P, et al., 2001, PMID: 11448995","On Western blot, obscn is expressed in human cardiac and skeletal muscles. In neonatal rat cardiomyocytes, endogenous obscn localized to the M-band and transiently localized to z-disk.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_94265ca9-cf6a-468e-b12c-6ea173d09e51-2022-04-13T160000.000Z,2618,PubMed:11448995 +Two Hybrid yeast Screen,Protein Interaction,"Xia H, et al., 1997, PMID: 9334352","PDLIM3 PDZ domain interacts with ACTN2 by Yeast 2-hybrid. Endogenous Pdlim3 associates with endogeous Actn2 from rat skeletal muscle extracts. +ACTN2 has a moderate ClinGen clinical validity classification for intrinsic cardiomyopathy.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_76cba060-8080-42b1-b9ea-2193fea658b0-2023-02-23T170000.000Z,2621,PubMed:9334352 +PDLIM3 Northern blot,Expression A,"Xia H, et al., 1997, PMID: 9334352",Expression of PDLIM3 in human heart shown by Northern blot.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_76cba060-8080-42b1-b9ea-2193fea658b0-2023-02-23T170000.000Z,2621,PubMed:9334352 +Western Blot,Expression A,"Xia H, et al., 1997, PMID: 9334352",Western Blot showed protein expression in the skeletal muscle and heart,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_76cba060-8080-42b1-b9ea-2193fea658b0-2023-02-23T170000.000Z,2621,PubMed:9334352 +Immunoprecipitation studies,Protein Interaction,"Xia H, et al., 1997, PMID: 9334352",Immunoprecipitation studies showed it coimmunoprecipitated with ACTN2 from skeletal muscle,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_76cba060-8080-42b1-b9ea-2193fea658b0-2023-02-23T170000.000Z,2621,PubMed:9334352 +Mast_S2 cells function,Biochemical Function B,"Mast FD, et al., 2011, PMID: 21669930","In patients with mild forms of PBDs, a small number of import-competent, enlarged peroxisomes are observed (from PMID: 20647552)",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_fa073c77-0623-4e82-b5b2-9fcd0eb0dc6e-2023-04-27T160000.000Z,2623,PubMed:21669930 +PSAT1 Mouse,Model Systems Non-human model organism,"Dickinson ME, et al., 2016, PMID: 27626380",The homozygous knockout mouse exhibits preweaning lethality consistent with the stillbirth often observed in Neu-Laxova syndrome. Additionally there is intrauterine growth retardation and abnormal craniofacial morphology in both the mouse and human patients with serine deficiency.,Score,1 (2),MGI:2183441 PSAT1 knockout mouse had phenotypes consistent with those observed in human patients with serine deficiency particularly those diagnosed with Neu-Laxova syndrome which often results in stillbirth.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ca702099-7dc9-4434-b661-a6f9b8c72d5c-2020-06-29T165656.452Z,2628,PubMed:27626380 +ptpn11a/ptpn11b KO zebrafish,Model Systems Non-human model organism,"Bonetti M, et al., 2014, PMID: 24736444",The ptpn11 fish were embryonic lethal don't score,Score,0 (2),Double KO fish were embryonic lethal at dpf 5. At dpf 4 the fish exhibited facial dysmorphism. This study also did a rescue and showed thta the facial dysmrophism of the zebrafish was rescued but the fish's embryonic lethal phenotype makes this unscorable.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_2bb08565-4669-4633-b6ed-c04e2a431cf9-2018-07-24T160000.000Z,2629,PubMed:24736444 +Rab39b knockdown in mouse hippocampal neurons,Functional Alteration Non-patient cells,"Mignogna ML, et al., 2015, PMID: 25784538","AMPAR stands for alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor, which is involved in synaptic transmission. In hippocampal neurons, AMPARs are hetero-tetramers, usually comprised of GluA1/GluA2 or GluA2/GluA3 hetero-dimers. +Knock-down of Rab39b in mouse hippocampal neurons resulted in increased immature GluA2 suggesting ER retention, reduced GluA2 AMPAR subunits at the post-synaptic membrane, and formation of GluA2-lacking calcium-permeable AMPARs. GluA2-lacking calcium-permeable AMPARs lead to altered synaptic activity and are associated with immature synapses and cognitive impairment.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_01dc73a8-fbd2-4081-95cd-ab7cb59236d7-2018-06-04T040000.000Z,2634,PubMed:25784538 +G39dup C elegans model.,Model Systems Non-human model organism,"Flex E, et al., 2014, PMID: 24705357","The model exhibited a protruding vulva, a similar phenotype has been documented in a SHOC2 variant worm model.",Score,0.5 (2),"Downgraded points were given for this model because of the evolutionary distance between humans and C. elegans. Also, the phenotype relates to a phenotype seen in other RASopathy worm models and does not directly relate to the human phenoype. +This should only be given 0.25 not 0.5",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_96280a14-d8cd-4c9b-b3e0-d5fcd8bf9ef6-2018-07-24T160000.000Z,2642,PubMed:24705357 +V55M and G39dup variants,Functional Alteration Non-patient cells,"Flex E, et al., 2014, PMID: 24705357","Intrinsic and GEF-stimulated GDP dissociation rates were dramatically increased by the G39dup variant. The V55M variant dramatically increased the GEF-stimulated dissociation rate of GDP. G39dup also significantly reduced intrinsic and GAP-stimulated GTP hydrolysis. Both variants led to increased activation of MEK, ERK, and AKT. Both variants led to a higher proportion of active, GTP-bound forms of the protein compared to the WT.",Score,0 (0.5),these results/endpoints are not specific to NS even though they implicate variant pathogenicity,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_96280a14-d8cd-4c9b-b3e0-d5fcd8bf9ef6-2018-07-24T160000.000Z,2642,PubMed:24705357 +Dhifallah2018Fig6,Functional Alteration Non-patient cells,"Dhifallah S, et al., 2018, PMID: 30038559","The first half of this paper describes a caucasian family with the p.L1670W variant and FHM. This variant has been described by another group in a Chinese family with FHM. Then they trasnfected tsA201 cells with wild type and variant SCN1A and studied the electrophysiological properties of the variant NaV1.1 channel. The variant channel had reduced current density which was rescued by incubation at low temperatures (30C vs 37C), which suggests trafficking defects. The rescued currents of the variant NaV1.1 had both LOF and GOF effects with overall GOF effects that resulted in increased response to repetitive stimuli with resistance to use dependence. Then they transfected mouse neocortical neurons with the variant and wild type SCN1A with the TTX resistant p.F383S variant and eletrophysiological properties were studied with 1 uM TTX. The current density was significantly reduced, but still rescued compared to tsA201 cells at 37C with 50% current density compared to wild type. The variant channel had positively shifted voltage dependence of channel activation, which is an LOF effect, and positively shifted voltage dependence of fast inactivation and increased persistent current, which were GOF effects. When they applied repetitive stimuli similar to those in neuronal firing, the first current was slightly larger in wild type, but last currents were significantly higher in neurons expressing the variant channel. This is consistent with overall GOF effects and hyperexcitability. They have hypothesized that hyperexcitability of GABAergic neurons could cause extracellular potassium and neurotransmitter accumulation, inducing neuronal depolarization and initiation of cortical spreading depression, a wave of transient network hyperexcitability leading to a long-lasting depolarization block of neuronal firing that is a proposed pathological mechanism of migraine.",Review,0 (0.5),"This data is best treated as variant level functional evidence. Since the mechanism of FHM3 is not really clear, it is not clear whether variants with GOF or LOF effects are consistent with the mechanism.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c8c1e158-983d-4547-a739-7781961e5bb8-2021-09-14T163408.306Z,2648,PubMed:30038559 +Singh Animal Model,Model Systems Non-human model organism,"Singh NA, et al., 2009, PMID: 19763161","knock-in mice were subjected to corneal electrical stimulation using the staircase method to either clonic seizure endpoint or tonic hindlimb extension seizure endpoint that depolarize the forebrain and hindbrain regions, respectively. Homozygous knockin mice has significantly reduced thresholds to minimal clonic and minimal tonic hindlimb extension seizures relative to wildtype mice. Male and female mice has significantly lower CC(50) value compared to het. knockin and wildtype.",Score,0 (2),This mouse model was not scored because the variant has been refuted by the data published in Fasham et al (PMID 33216760),https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_72a91ef6-e052-44a4-b14e-6a5ba93393ff-2021-03-09T163649.218Z,2649,PubMed:19763161 +C elegans model p.S2G,Model Systems Non-human model organism,"Cordeddu V, et al., 2009, PMID: 19684605","These phenotypes don't really provide evidence convincing of a RASopathy and it is a worm model, so it must be downgraded to 0.25",Score,0 (2),This should be given at most 0.25 pts for evidence showing that the worms have malformations but it is not great evidence that the model is similar to RASopathies especially because the species is so far removed from humans,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0ecc1335-fb21-4d65-8df2-19558e8f5c07-2018-07-25T160000.000Z,2651,PubMed:19684605 +p.S2G localization and ERK activation,Functional Alteration Non-patient cells,"Cordeddu V, et al., 2009, PMID: 19684605","The WT protein was evenly distributed in the cytosol and nucleus of the cells. The p.S2G variant specifically targeted to the membrane of the cells. The researchers discovered that this was a result of inappropriate myristoylation of the S2G variant. Upon inhibiting the myristoylation process, the protein still was unable to localize to the nucleus. I awarded this study more points for its discovery of the mechanism of disease and attempt to rescue it. +A significant enhancement of ERK phosphorylation was found in S2G Neuro2A cells compared to the WT cells.",Score,0 (0.5),This doesn't provide support for NSLAH any more than the other RASopathies,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0ecc1335-fb21-4d65-8df2-19558e8f5c07-2018-07-25T160000.000Z,2651,PubMed:19684605 +Localization and activity of ERK1/2 and MEK1/2 w/SHOC2,Model Systems Cell culture model,"Galperin E, et al., 2012, PMID: 22606262",The S2G mutant protein did not rescue the ERK1/2 or MEK1/2 activity.,Score,0 (1),This doesn't provide support directly implicating SHOC2 with NS/LAH,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0ecc1335-fb21-4d65-8df2-19558e8f5c07-2018-07-25T160000.000Z,2651,PubMed:22606262 +Expression in mouse articular cartilage,Expression A,"Park JH, et al., 2014, PMID: 25373420",Immunohistochemistry showed that Slc26a2 was expressed in the chondrocytes of freshly isolated mouse articular cartilage explants.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b53d2317-709a-4b12-b846-fa51bfddf7e1-2020-04-06T160000.000Z,2657,PubMed:25373420 +shRNA knockdown,Functional Alteration Non-patient cells,"Park JH, et al., 2014, PMID: 25373420","shRNA knockdown of Slc26a2 caused decreased proliferation of chondrocytes (differentiated from mouse progenitor mesenchymal cells) and reduced basal proteoglycan synthesis, possibly by inhibiting the effect of IGF-1 on synthesis.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b53d2317-709a-4b12-b846-fa51bfddf7e1-2020-04-06T160000.000Z,2657,PubMed:25373420 +Haack Nonpatient Cells,Functional Alteration Non-patient cells,"Haack TB, et al., 2012, PMID: 22864630",Riboflavin uptake was 250 fmol/mg less than wildtype,Score,0 (0.5),In the recuration this was repurposed in the genetic evidence section as functional support for the missense variants.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5a500078-4cd5-49db-b22e-c5628ee07304-2023-09-04T160000.000Z,2661,PubMed:22864630 +Foley Nonpatient Cells,Functional Alteration Non-patient cells,"Foley AR, et al., 2014, PMID: 24253200","Uptake in 5/7 mutants was completely abolished, while uptake in the two other mutants showed a moderate but significant decrease in activity compared to WT. Western blot of transfected cells showed decreased expression of SLC52A2 in all mutants but one.",Score,0 (0.5),In the recuration this was repurposed in the genetic evidence section as functional support for the missense variants.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5a500078-4cd5-49db-b22e-c5628ee07304-2023-09-04T160000.000Z,2661,PubMed:24253200 +SLC52A3 -/-,Model Systems Non-human model organism,"Yoshimatsu H, et al., 2016, PMID: 27272163","Targeted disruption of the SLC52A3 gene causes death within 48 hours after birth. Lower body weight, normal organogenesis. Riboflavin supplementation in the knockout mice was found to increase birth weight and lifespan. These findings are consistent with the human phenotype.",Score,1.5 (2),"Several mouse models of BVVL have been phenotypically assessed and the mouse is considered a good model for the phenotype. (e.g. Intoh et al. 2016 26976849 ). Additionally, the supplementation of the riboflavin rescuing the phenotype provides further evidence for the impact of the gene. +However the model was downgraded because it does not replicate either the hearing loss or muscle weakness associated with Brown-Vialetto-van Laere syndrome.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b0ae82e2-4c39-45b2-ba2d-6fe2570dbcfc-2023-09-04T160000.000Z,2662,PubMed:27272163 +"Drosophila ""drift"" model",Model Systems Non-human model organism,"Manole A, et al., 2017, PMID: 29053833",The decreased respiratory activity and locomotive behavior in the flies is consistent with the overall phenotype seen in humans with BVVL. Additionally riboflavin supplementation rescuing the phenotype is consistent with human treatment,Score,1.5 (2),"Downgraded for fly homolog of gene, but didn't do a complete downgrade because of the rescue of the phenotypes with riboflavin supplementation.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b0ae82e2-4c39-45b2-ba2d-6fe2570dbcfc-2023-09-04T160000.000Z,2662,PubMed:29053833 +CrT knockout mice,Model Systems Non-human model organism,"Skelton MR, et al., 2011, PMID: 21249153","A ubiquitous CrT knockout mouse model was generated by deletion of 2–4 exons in the Slc6a8 gene (Figure 1). Learning and memory deficits, impaired motor activity, and creatine depletion in the brain and muscles (measured by colorimetric assay) were reported in male CrT-/y mice at 3-4 months of age. Similarly, human patients with SLC6A8 deficiency have no/reduced cerebral creatine based on brain proton-MRS, and intellectual disability. Knockout mice had reduced weight. Some patients with SLC6A8 have been reported to have failure to thrive. In contrast to SLC6A8-deficient patients, the knockout mice did not show any evidence of social impairment.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3795f0ae-7668-47b8-b69e-9c686b82bd0a-2020-02-10T170000.000Z,2664,PubMed:21249153 +SLC6A8 knockout mouse (exon 5-7 deletion),Model Systems Non-human model organism,"Baroncelli L, et al., 2014, PMID: 25485098","Male SLC6A8 knock out mice had a significant reduction of creatine in the brain (both cerebral cortex and hippocampus), similar to human patients. In addition, knock out mice showed cognitive impairments in various learning and memory tests including the Y maze and Morris water maze. The memory deficiency assessed across a variety of behavioral tasks indicates that the knockout mice have a general cognitive impairment, also found in all human patients. Motor delay and myopathy have been reported in human patients, although rarely. Knockout mice had reduced levels of muscle creatine in addition to decreased home-cage-locomotor activity (particularly during the night) and they were slower swimmers than control mice.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3795f0ae-7668-47b8-b69e-9c686b82bd0a-2020-02-10T170000.000Z,2664,PubMed:25485098 +Purification of human cohesin complexes.,Protein Interaction,"Sumara I, et al., 2000, PMID: 11076961",human cohesin complexes,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c281f5fd-d868-4425-a7b4-8e39e3b2090e-2019-06-19T160000.000Z,2666,PubMed:11076961 +Murine Expression,Expression A,"Reinholt BM, et al., 2013, PMID: 23626854","The authors examined the expression profile of Stac3 mRNA in adult mice by quantitative RT-PCR. Stac3 mRNA was abundantly expressed in skeletal muscle of four different locations, but was not expressed or expressed at very low levels in any of non-skeletal muscle tissues or organs examined, including brain, heart, and the smooth muscle-containing stomach.",Score,0.5 (0.5),"The specific expression of Stac3 in mouse skeletal muscle agrees with the human expression reported by The Human Protein Atlas, ""Group enriched (skeletal muscle, tongue)"".",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_940572b9-6a5a-4de1-8ee1-6394f589515f-2020-04-25T160000.000Z,2672,PubMed:23626854 +KO Mouse,Model Systems Non-human model organism,"Reinholt BM, et al., 2013, PMID: 23626854",Both the affected mice and humans biopsy revealed myopathic changes and fiber size variability.,Score,1 (2),"Showed that Stac3 is essential for development of functional skeletal muscle and viable mice. This knockout model had a phenotype more severe than that observed in humans, causing neonatal lethality.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_940572b9-6a5a-4de1-8ee1-6394f589515f-2020-04-25T160000.000Z,2672,PubMed:23626854 +mi34 zebrafish rescue,Rescue Non-human model organism,"Horstick EJ, et al., 2013, PMID: 23736855",Mutant embryos expressing human Stac3-EGFP swim as effectively as mutant embryos expressing zebrafish Stac3-EGFP.,Score,1 (2),The molecular identity of the mutation was confirmed by mutant rescue experiments with wildtype zebrafish stac3. WT rescued the behavioral phenotype and triadic localization of Stac3. The human wildtype STAC3 was also able to rescue the motor phenotype.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_940572b9-6a5a-4de1-8ee1-6394f589515f-2020-04-25T160000.000Z,2672,PubMed:23736855 +mi34 zebrafish,Model Systems Non-human model organism,"Horstick EJ, et al., 2013, PMID: 23736855",The mi34 zebrafish mutant recapitulated the motor defects of humans. In both humans and zebrafish there is reduced motility. The loss of Stac3 resulted in a progressive breakdown of myofibers during larval stages similar to myopathic features of congenital human myopathies.,Score,2 (2),"Although motor behaviors were greatly diminished in stac3mi34 mutants, they were not immotile. One possible reason for this might be the existence and action of Stac3 derived from maternally deposited stac3 mRNA. To address this the authors knocked down Stac3 by injecting a translation blocking antisense Morpholino oligonucleotide (MO) against stac3 message into embryos from crosses between heterozygous carriers. In antisense MO injected embryos, there was a significant increase in embryos that were either immotile (from 5% to ~40%) or shivered and decrease in embryos that swam compared with control progeny.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_940572b9-6a5a-4de1-8ee1-6394f589515f-2020-04-25T160000.000Z,2672,PubMed:23736855 +Myoblast Differentiation,Biochemical Function B,"Ge X, et al., 2014, PMID: 24788338","An inhibitory role of Stac3 in myoblast differentiation and myotube formation may explain the role of this gene in congenital myopathy. If myoblasts withdraw from the cell cycle and begin differentiation before an adequate number of founder myoblasts have developed, this will decrease the overall number of myofibers formed. Therefore, hastened myoblast differentiation and fusion into myotubes could also explain why Stac3 knockout mouse skeletal muscle had fewer total myofibers than wild-type or Stac3 heterozygous mutant skeletal muscle.",Score,0.5 (0.5),"The authors examined the role of Stac3 in myoblast differentiation and myotube formation by determining the effects of Stac3 knockdown, overexpression, and knockout on myoblast differentiation and fusion into myotubes in both C2C12 myoblast line and mouse embryonic myoblasts. The results suggest an inhibitory role of Stac3 in myoblast differentiation and myotube formation. Myogenesis is a tightly controlled program; myofibers formed from prematurely differentiated myoblasts are dysfunctional. Thus, Stac3 may play a role in preventing precocious myoblast differentiation during skeletal muscle development.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_940572b9-6a5a-4de1-8ee1-6394f589515f-2020-04-25T160000.000Z,2672,PubMed:24788338 +Analysis of TH missense variants,Functional Alteration Non-patient cells,"Fossbakk A, et al., 2014, PMID: 24753243","Enzyme activity, in vitro solubility, thermal stability, and kinetic properties of 23 TH variants were studied; the was heterogeneity among these properties. Some variants had no detectable enzyme activity (n=10), while others had less than 20% residual activity (n=10) and 3 had 50-100% activity. Kinetic properties was studied for all variants with measurable enzyme activity and revealed variable kinetic properties including increased Km for L-tyrosine and decreased Km BH4, altered substrate selectivity, reduced thermal stability and reduced solubility.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c4bf9fbb-0046-4a90-9e74-0b3b79f28f59-2019-03-22T160000.000Z,2675,PubMed:24753243 +Son Expression,Expression A,"Son EJ, et al., 2012, PMID: 22808246","Microarray was used to characterize expression profile of base, middle, and apex of P0 and P8 mouse cochlea. TNC was shown to be expressed in the basilar membrane in an increasing gradient toward the apex. This was supported by in situ hybridization of Tnc transcripts. Tnc was also detected in the differentiating hair cells at P0.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_fce4988a-fb20-4f95-b73a-799c47b67e3b-2022-07-13T160000.000Z,2678,PubMed:22808246 +MuRF1 relationship to hypertrophic response,Biochemical Function B,"Arya R, et al., 2004, PMID: 15596539","Overexpression of the MuRF1 gene results in reduced hypertrophic response to phenylephrine, which is what you would expect as the reverse of loss-of-function mutations in this gene (which have been associated with the development of hypertrophic cardiomyopathy).",Score,0 (0.5),Scored 0 points as max scoring for functional evidence has already been reached.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d9f35d3c-2d30-4947-9d10-87d21405586e-2022-10-27T160000.000Z,2679,PubMed:15596539 +Medaka Fish,Model Systems Non-human model organism,"Higashikuse Y, et al., 2019, PMID: 31628103",left ventricular hypertrophy and diastolic dysfunction are consistent with HCM.,Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c17e22eb-c6fc-487d-bcf6-001bb85fdabd-2023-07-27T160000.000Z,2680,PubMed:31628103 +HCM Cell Expression,Expression B,"Herwig M, et al., 2020, PMID: 32351396","Cardiomyocytes from hypertrophic cardiomyopathy (HCM) patients showed higher Fpassive compared to control hearts and significantly lower Fpassive after PKD treatment. In addition, we found higher phosphorylation at CaMKII-dependent titin sites in HCM compared to control hearts. Expression and phosphorylation of HSP27, a substrate of PKD, were elevated in HCM hearts, which was associated with increased PKD expression and phosphorylation. The relocalization of HSP27 in HCM away from the sarcomeric Z-disk and I-band suggested that HSP27 failed to exert its protective action on titin extensibility. This protection could, however, be restored by administration of HSP27, which significantly reduced Fpassive in HCM cardiomyocytes.",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c17e22eb-c6fc-487d-bcf6-001bb85fdabd-2023-07-27T160000.000Z,2680,PubMed:32351396 +Alrahbeni_FA,Functional Alteration Non-patient cells,"Alrahbeni T, et al., 2015, PMID: 26012578","Atf4 and Arhgap24 transcripts are known NMD targets, containing upstream open reading frames (uORFs). Overexpression of ARHGAP24 isoform 1 protein has been shown to affect neuronal branching, while Atf4 is involved in neuronal plasticity. +Levels of Atf4 and Arhgap24 mRNA were found to be elevated in cells expressing the missense variants compared to those expressing wild-type. The levels of other transcripts of Arhgap24, which were not NMD substrates, were similar between the cells expressing wild-type UPF3B and those expressing the missense variants. +When GFP-expressing missense variants were expressed in neural stem cells and induced to differentiate, the authors found that the mutant proteins did not affect the differentiation as measured by primary neurite ourgrowth. However, the number and complexity of branches (secondary and tertiary neurites arising from primary neurites) was reduced significantly, three- to six-fold reduction in 6d of differentiation.",Score,1 (0.5),Mutations in UPF3B affect neuronal development due to imapired NMD. This has been demonstrated with multiple variants.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a1caf030-ef58-4f8f-ba40-aabbf81cf6b1-2019-07-03T160000.000Z,2682,PubMed:26012578 +Huang_Mouse,Model Systems Non-human model organism,"Huang L, et al., 2018, PMID: 28948974","Upf3b-null male mice showed contextual (decreased freezing) and cued conditional fear-learning defects, but normal spatial memory, similar to Nlgn3-null ASD model. In homozygous females, this effect was significant and genotype dependent. Null mice also showed paw-clasping behavior as the only motor defect and abnormal sleep patterns. They also exhibited deficiency in the startle response and a profound defect in prepulse inhibition. +Significant reduction in dendritic spine density was observed in cortical pyramidal neurons. +In-vitro differentiation assays on cortical mouse neural stem cells revealed lower expression of several early neuronal marker genes that could impact neuronal differentiation. The authors report that 141 genes were significantly upregulated in null mice, compared to controls. 23 genes were found to be downregulated.",Score,1.5 (2),"The mouse model is awarded reduced points since the model does not specifically recapitulate the human phenotype. However, since the human phenotype associated with UPF3B mutations is variable and complex, the model evidence is scored 1.5 points.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a1caf030-ef58-4f8f-ba40-aabbf81cf6b1-2019-07-03T160000.000Z,2682,PubMed:28948974 +Expression in brain over development in humans and mice,Expression A,"Poeta L, et al., 2021, PMID: 34356104","Spatiotemporally concomitant expression of syntenic X-chromosomal genes (KDM5C, ZNF711, ARX, PHF8) associated with NDD and known to interact, and usage of their promoters (measured by CAGE) in brain areas and cellular sub-types over development in humans and mice.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_80a6e42d-f8ce-4bce-8bb4-579b78c94d21-2022-09-22T060000.000Z,2685,PubMed:34356104 +Decreased expression of KDM5C in patient-derived LCLs,Functional Alteration Patient cells,"Poeta L, et al., 2021, PMID: 34356104","Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines from a male patient with mild ID who carries the missense mutation c.731T>C [p.I244T] in ZNF711 (reported in van der Werf 2017, PMID: 27993705) showed decreased expression of KDM5C mRNA and protein compared to cells harboring WT ZNF711.",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_80a6e42d-f8ce-4bce-8bb4-579b78c94d21-2022-09-22T060000.000Z,2685,PubMed:34356104 +inhibition of MRP4,Functional Alteration Non-patient cells,"Wolf R, et al., 2022, PMID: 35295075","Studied platelet aggregation after short-time exposure to Ceefourin-1 (a specific inhibitor of MRP4) and observed a significant effect on aggregation when collagen (5 μg/mL) was used, but also with ADP (5 μM) or PAR1-AP (30 μM). MRP4 inhibition resulted in a reduction of maximum platelet aggregation, with the most prominent effect (about 50% inhibition at 10 μMCeefourin-1) being observed with the strong agonist collagen (5 μg/ml) (38.3 ± 10.3%aggregation vs. 77.3 ± 4.0% for the solvent control) as well as a significant effect on aggregation in ADP- and PAR1-AP-stimulated platelets (27% and 13% reduction at 10 μM Ceefourin-1,respectively).",Score,0.5 (0.5),"Pharmacological inhibition of MRP4 affects several signaling pathways in platelets mechanistically based on the transport inhibition not only of cAMP but +also cGMP as well as of the lipid mediators thromboxane and S1P.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_2828abac-5b4a-4dad-a703-10c0daf35dbd-2024-06-03T160000.000Z,2687,PubMed:35295075 +Lipodomic Analysis,Functional Alteration Non-patient cells,"Herzog K, et al., 2018, PMID: 28849344","Lipodomic analysis of cells derived from ACBD5 deficient patient showed increased levels of phospholipid species containing VLCFAs and increased total levels of VLCFAs in patient fibroblasts (Fig. 3b, c) +Total levels of mitochondrial phospholipid cardiolipin (CL) was significantly decreased in patient fibroblasts compared to controls (Supplemental Fig. 1) +Liquid chromatography and GC-MS showed decreased levels of all ether phospholipids in patient cells (Figure 2), both PE- and PC-ether phospholipids were significantly decreased suggesting defect in ether phospholipid biosynthesis (including plasmalogens)",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_8ac052f6-de8d-4c14-adf2-bbecb624defd-2024-06-21T160000.000Z,2689,PubMed:28849344 +ACBD5 knock-out mouse,Model Systems Non-human model organism,"Darwisch W, et al., 2020, PMID: 33244184","Mouse embryonic fibroblasts (MEFs) from ACBD5 knock-out (KO) mice showed comparable numbers of peroxisomes as those from WT mice. While WT MEFs had peroxisomes with spherical and elongated morphology, elongated peroxisomes were scarce in KO MEFs and hepatocytes. There was no increase in elongated peroxisomes even with induction by DHA. KO mice show cerebellar degeneration exemplified by striking kyphosis and hind limb clasping. In addition, retinal degeneration characterized by reduced photoreceptor cells. increase in microglia and astrocyte activation was observed. VLCFA levels were elevated. Authors note that the evidence suggests a novel pathological mechanism due to the disruption of exchange processes between ER and peroxisomes.",Score,1 (2),"The mouse model shows partial recapitulation of the human phenotype, with elevated VLCFAs and optic atrophy. The evidence is awarded 1 point as the disease mechanism is still not clearly understood.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_8ac052f6-de8d-4c14-adf2-bbecb624defd-2024-06-21T160000.000Z,2689,PubMed:33244184 +Latham - Western Blot,Expression B,"Latham SL, et al., 2018, PMID: 30315159","Western blot analysis of individuals harboring variants in ACTB demonstrate a reduction of beta- CYA expression, while gamma-CYA expression is increased.",Score,1 (1),Several studies have demonstrated that actin isoforms exist in equilibrium with one another to ensure that the cells total actin pool in constantly maintained. It is consistent that other actin isoforms are increased while beta-actin is decreased.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9cee7fd2-09f7-41dc-9742-542917d856b0-2024-06-03T160000.000Z,2691,PubMed:30315159 +Latham - Actin Cytoskeleton,Biochemical Function B,"Latham SL, et al., 2018, PMID: 30315159","Patients thrombocytes demonstrate aberrant ABP localization patterns. Additionally, the cortical band is perturbed in individuals with mutated ACTB, as compared to normal controls.",Score,0.5 (0.5),"Beta-actin, encoded by ACTB, is critical in forming actin cytoskeleton and function in conjunction with other ACTN binding proteins - including NM-IIA, alpha-actinin 1, and Filamin A.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9cee7fd2-09f7-41dc-9742-542917d856b0-2024-06-03T160000.000Z,2691,PubMed:30315159 +Latham - Cultured Fibroblasts,Functional Alteration Patient cells,"Latham SL, et al., 2018, PMID: 30315159","Proplatelet forming megakaryocytes from individuals with variants in ACTB and controls were labeled with beta-tubulin and assessed . Three distinct phenotypes were observed - microtubules assembled in thin marginal bands, microtubules assembled in thick marginal bands, and disorganized microtubules. Thick margninal bands comprise 41% of controls, but only 15% of ACTB-AST patient cells. Whereas 34-46% of ACTB-AST cells had disorgainzed microtubules, only 10% of control cells did. No difference was seen between controls and ACTB-AST individuals in the number of cells with thin marginal bands.",Score,1 (1),Patient cells demonstrated a significant increase over controls in the number of cells with disorganized microtubules.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9cee7fd2-09f7-41dc-9742-542917d856b0-2024-06-03T160000.000Z,2691,PubMed:30315159 +AP4 complex subunit western + immunoprecip in EBV-B cells,Protein Interaction,"Kong XF, et al., 2013, PMID: 23472171","AP4E1 encodes a subunit of the adaptor protein 4 (AP4) complex; defects in the 3 other AP4 subunits (AP4B1, AP4M1 and AP4S1) result in the same clinical phenotype/condition (AP4 deficiency). This study showed that EBV-B cells from a patient with a homozygous AP4E1 LOF variant had low/absent levels of the AP4E1 and AP4B1 proteins through western blotting and that coimmunoprecipitation studies compared to control",Score,1 (0.5),"The finding that all four AP4 subunits result in a very similar, distinct phenotype is very strong evidence; this also demonstrates biochemical functional evidence of the involvement of AP4E1 in the AP4 complex",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_be93d2e7-f302-41a7-9675-032510e46ad2-2020-12-16T170000.000Z,2698,PubMed:23472171 +AP4E1 Knockout mouse,Model Systems Non-human model organism,"De Pace R, et al., 2018, PMID: 29698489","Impaired motor coordination and weak grip strength seen in AP4E1 KO mice is consistent with impaired motor development, hypotonia and spastic paraplegia in humans +Thin corpus callosum found in AP4E1 KO mice is similar to thinning of corpus callosum in human patients. +Mislocalization of ATG9A (AP4 cargo) in AP4E1 KO mice is also seen in patient cells",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_be93d2e7-f302-41a7-9675-032510e46ad2-2020-12-16T170000.000Z,2698,PubMed:29698489 +Gabra2-1 mouse model,Model Systems Non-human model organism,"Hines DJ, et al., 2022, PMID: 35169261","The authors generated Gabra2-1 mice that express a 13 amnio acid substitution from the α1 subunit into the α2 subunit large intracellular loop, effectively replacing the Cb binding sequence with the gephyrin binding sequence. The Gabra2-1 mice phenotype revealed strong parallels with frequently reported behavioral symptoms of the human ARHGEF9 syndrome beyond IF, further validating Gabra2-1 mice as a useful model to study the ARHGEF9 related X-linked complex neurodevelopmental disorder in humans.",Score,0 (2),"The mouse model variant was generated for a binding domain of a receptor for Cb and not within the ARHGEF9 gene; therefore, the GCEP recommends zero score.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9305fb2c-6cdf-492d-9dd0-8b03dd4fab1c-2024-05-23T160000.000Z,2699,PubMed:35169261 +Atp1a2+/R887 knock-in mice are more prone to CSD,Model Systems Non-human model organism,"Leo L, et al., 2011, PMID: 21731499",Cortical spreading depression (CSD) is the phenomenon hypothesized to underly migraine aura.,Score,1 (2),"Downgraded to one point because CSD is a model for migraine aura, but is not necessarily the same thing.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_fe788a45-b8da-4377-acdb-5dd55fcc3130-2024-01-16T200000.000Z,2702,PubMed:21731499 +ATP6AP1 (a.k.a. Ac45) knockdown,Model Systems Non-human model organism,"Qin A, et al., 2011, PMID: 22087256","siRNA suppression of ATP6AP1 (a.k.a. Ac45) in mouse osteoclasts was shown to affect the function of V-ATPase, causing impaired intracellular acidification and endocytosis. An attempt to generate conditional osteoclast ATP6AP1-KO mice resulted in embryonic lethality, with impaired CNS development.",Review,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c6bfce2b-c20c-40f9-b2f5-d81f76a328f7-2024-05-15T160000.000Z,2703,PubMed:22087256 +V-ATPase interactions,Protein Interaction,"Huttlin EL, et al., 2017, PMID: 28514442",The authors used affinity purification-mass spectrometry methodology to elucidate protein interaction networks and co-complexes.,Score,1 (0.5),Score increased based on the number of genes encoding v-ATPase subunits that are associated with CDG.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c6bfce2b-c20c-40f9-b2f5-d81f76a328f7-2024-05-15T160000.000Z,2703,PubMed:28514442 +Neugebauer_Mouse model,Model Systems Non-human model organism,"Neugebauer KA, et al., 2022, PMID: 36243101","Baat-/- mice were underweight in early life but exhibited catch-up growth. At 3wo, KO animals had increased phospholipid excretion and decreased subcutaneous fat pad mass, liver mass, glycogen staining in hepatocytes, and hepatic vitamin A stores, but they were less marked in adulthood. KO mice had an altered microbiome in early life. Their bile acid pool was highly enriched in cholic acid but not completely devoid of conjugated bile acids. KO animals had 27-fold lower taurine-conjugated bile acids than wild type in their liver but similar concentrations of glycine-conjugated bile acids and higher microbially conjugated bile acids. Furthermore, the bile acid pool in Baat-/- was enriched in a variety of unusual bile acids.",Score,0.5 (2),Minimal points are awarded for the recapitulation of the biochemical phenotype.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9b732497-a853-45af-bf8e-b3ad663159f1-2024-06-21T160000.000Z,2705,PubMed:36243101 +bbs1-1 Chlamydomonas cannot perform phototaxis.,Model Systems Non-human model organism,"Lechtreck KF, et al., 2009, PMID: 20038682","The mutants lack the ability to perform phototaxis, which is common among all BBSome mutants tested (described in text but data not shown). Flagella from the mutant show loss of BBS4 localization (Figure 4C). However, flagellar length was normal (Figure 2B) and flagellar regeneration was normal as well (described in text but data not shown).",Score,0.25 (2),"Minimal scoring has been recommended, as many of the known features of the human patients are not at the cellular level. However, ciliary-mediated phototaxis in the organism may be an approximate match to the function of the BBSome in the human photoreceptor cilia.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ee6e7562-927a-459b-a0f1-ccd849c7e783-2023-12-07T170000.000Z,2706,PubMed:20038682 +BBS1 encodes a BBSome component.,Biochemical Function A,"Seo S, et al., 2011, PMID: 22072986","Other BBSome components have been asserted in connection with various monogenic forms of Bardet-Biedl syndrome, including BBS2 (PMID: 11285252), ARL6 (PMID: 15258860), BBS4 (PMID: 11381270), BBS5 (PMID: 15137946), MKKS (PMID: 10973238, PMID: 10973251), BBS7 (PMID: 12567324), and TTC8 (PMID: 14520415).",Score,1 (0.5),Up-scoring for this evidence has been recommended due to the high number of other BBSome components asserted to harbor variants causing the same disease entity (Bardet-Biedl syndrome).,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ee6e7562-927a-459b-a0f1-ccd849c7e783-2023-12-07T170000.000Z,2706,PubMed:22072986 +BBS1 encodes a component of the BBSome.,Biochemical Function B,"Seo S, et al., 2011, PMID: 22072986","The experiment has been performed in mouse testis, indicating the relevance to the male hypogonadism shown in many forms of BBSome-related ciliopathy. Retinal dysfunction and obesity are also phenotypes shared by many conditions caused by loss-of-function in other BBSome components.",Score,0.5 (0.5),"Default scoring is recommended, as the experiment indicates an involvement in the BBSome complex known to control the formation and maintenance of functionally important cilia in the retina.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ee6e7562-927a-459b-a0f1-ccd849c7e783-2023-12-07T170000.000Z,2706,PubMed:22072986 +Zbbs1 knockdown disrupts ciliary beating frequency.,Model Systems Non-human model organism,"Kim YH, et al., 2013, PMID: 24069149","Morpholino-based knockdown of the zbbs1 gene causes hydrocephalus (Figure 3B), formation of pronephritic cysts (Figure 3G), embyronic body axis abnormalities (Figure 4B), heart looping defects (Figure 5B), longer cilia (Figure 7F), and normal ciliary ultrastructure (Figure 7I), and aberrant ciliary motility in the pronephritic tubule and nasal pit (Supplementary Movies).",Score,0.5 (2),Loss of function in the BBS1 ortholog results in kidney phenotypes that match the human patients as well as cellular phenotypes consistent with ciliopathy underlying the human retinal features.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ee6e7562-927a-459b-a0f1-ccd849c7e783-2023-12-07T170000.000Z,2706,PubMed:24069149 +Ciliary receptors mislocalize in Bbs1 homozygous null mice.,Model Systems Non-human model organism,"Stubbs T, et al., 2023, PMID: 36699005","The model animals do not exhibit ciliary morphology defects, but have many signaling membrane proteins showing defective accumulation in or exclusion from cilia in the brain. These include failure of Sstr3 and Mchr1 to localize to cilia (Figure 1), lower AC3 labeling in cilia of the striatum (Figure 1), higher dopamine receptor 1 staining (Figure 2), higher staining of Gpr161 (Figures 3 and 4), Gpr19 (Figure 5), and beta-arrestin (Figures 6 and 7).",Score,0.5 (2),"These molecular defects do not match well-known human phenotypes, but the study adds to the level of mechanistic detail known about the disease etiology, and is consistent with ciliopathy as the underlying cause of disease.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ee6e7562-927a-459b-a0f1-ccd849c7e783-2023-12-07T170000.000Z,2706,PubMed:36699005 +BBS2 plays a role in BBSome,Biochemical Function A,"Seo S, et al., 2011, PMID: 22072986","Other BBSome components have been asserted in connection with various monogenic forms of Bardet-Biedl syndrome, including BBS2 (PMID: 11285252), ARL6 (PMID: 15258860), BBS4 (PMID: 11381270), BBS5 (PMID: 15137946), MKKS (PMID: 10973238, PMID: 10973251), BBS7 (PMID: 12567324), and TTC8 (PMID: 14520415).",Score,1 (0.5),This piece of evidence has been upscored to 1 point due to the high number of other BBSome genes asserted to contain pathogenic variants also causing Bardet-Biedl syndrome.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_be74a060-cfb3-4180-a107-cfaf0e81bfa3-2024-03-07T170000.000Z,2708,PubMed:22072986 +BBS2_Zebrafish_Retina,Model Systems Non-human model organism,"Song P, et al., 2020, PMID: 33324636",Homozygous KO zebrafish were shown to have retinal degeneration and reduced visual accuity as seen in human BBS patients. However. the authors only studied retina features of BBS instead of other aspects of the syndrome.,Score,0.5 (2),"Downscored due to the use of zebrafish as a model, authors only studied retina features of BBS instead of other aspects of the syndrome.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_be74a060-cfb3-4180-a107-cfaf0e81bfa3-2024-03-07T170000.000Z,2708,PubMed:33324636 +Zebrafish MO rescue,Rescue Non-human model organism,"Wang H, et al., 2011, PMID: 22219648","""Of the morpholino-injected embryos, 59% had a severe phenotype, and 89% exhibited some defect (Figure 4B). Severe phenotypes were seen in only 27% of the embryos (n=80) when the bbs4 morpholino was coinjected with 150 pg of wild-type human BBS4 mRNA and in only 19% of the embryos (n=86) coinjected with 175 pg of wild-type BBS4 mRNA. These results mirror previous reports of approximately 80% of morphants being rescued by human wild-type BBS4 mRNA [50]. Importantly, injection of 200 pg of mRNA from the human BBS4 missense allele did not provide any rescuing effect (n=63)."" and ""When bbs4 morphants were coinjected with 200 ng of human BBS4 mRNA, the trafficking defect was reversed, and no rhodopsin mislocalization was observed. In contrast, rhodopsin remained mislocalized in embryos coinjected with morpholino and 200 ng of the BBS4 missense mRNA.""",Score,1 (2),"Half score as the zebrafish phenotype is suggestive of the human phenotype but not as clear as, for example, the mouse knockout phenotype",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_988d537d-5595-4b8f-bbc4-8e3aefc025fa-2023-12-07T170000.000Z,2709,PubMed:22219648 +Zebrafish MO,Model Systems Non-human model organism,"Wang H, et al., 2011, PMID: 22219648","Zebrafish notochord developes into vertebral column. Kinking of notochord reflects abnormal skeletal system development, which is seen in human disease. In addition, mislocationzation of rhodopsin in the zebrafish retina suggests abnormality of the visual system; retinal dystrophy is classic feature of BBS4 disease in humans.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_988d537d-5595-4b8f-bbc4-8e3aefc025fa-2023-12-07T170000.000Z,2709,PubMed:22219648 +BBS4-deficient renal cells,Functional Alteration Non-patient cells,"Hernandez-Hernandez V, et al., 2013, PMID: 23716571","""We discovered that Bbs4- and Bbs6-deficient renal medullary cells display a characteristic behaviour comprising poor migration, adhesion and division with an inability to form lamellipodial and filopodial extensions. Moreover, fewer mutant cells were ciliated [48%+ 6 for wild-type (WT) cells versus 23%+ 7 for Bbs4 null cells; P < 0.0001] and their cilia were shorter (2.55 mm+ 0.41 for WT cells versus 2.16 mm+ 0.23 for Bbs4 null cells; P < 0.0001). While the microtubular cytoskeleton and cortical actin were intact, actin stress fibre formation was severely disrupted, forming abnormal apical stress fibre aggregates.""",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_988d537d-5595-4b8f-bbc4-8e3aefc025fa-2023-12-07T170000.000Z,2709,PubMed:23716571 +Morpholino knockdown,Model Systems Non-human model organism,"Al-Hamed MH, et al., 2014, PMID: 24559376","Retinal layering defects, abnormal cardiac looping and dilated, cystic pronephric ducts with reduced cilia expression, and reduced renal function seen in the Morphants resemble human patients.",Score,0.5 (2),"Multiple zebrafish model scored, downgraded score to avoid double counting.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_bdb1249e-ab95-4d34-a43f-1dbb09eb3d94-2023-12-07T170000.000Z,2710,PubMed:24559376 +Morpholino knockdown,Model Systems Non-human model organism,"Castro-Sánchez S, et al., 2019, PMID: 31506453","abnormal body axis/length, notochord and somite morphology;",Score,0.5 (2),Multiple morpholino knockdown papers curated. Phenotypes not sufficiently resembling human.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_bdb1249e-ab95-4d34-a43f-1dbb09eb3d94-2023-12-07T170000.000Z,2710,PubMed:31506453 +Exon 11 Skipping in Canine Model System,Model Systems Non-human model organism,"Böhm J, et al., 2013, PMID: 23754947","Inherited Myopathy of Great Danes is similar in phenotype to that reported in association with BIN1-related centronuclear myopathy in human and is characterized by generalized muscle atrophy, exercise intolerance, exercise-induced tremor and muscle wasting. The disease typically starts before 10 months of age, is highly progressive, and most of the affected dogs are euthanized before 18 months of age due to severe debilitating muscle weakness. Similar to the muscle phenotypes found in humans, muscle biopsies in affected dogs revealed internalized or central nuclei without evidence of inflammation, disruption of the sarcomeric architecture with central fiber areas devoid of myofibrils, and central accumulations of mitochondria and glycogen granules.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6d04cc64-0994-4579-99d5-bd2b89710173-2024-06-10T160000.000Z,2712,PubMed:23754947 +Amphiphysin II (BIN1) Expression in Human Skeletal Muscle,Expression A,"Butler MH, et al., 1997, PMID: 9182667",Northern blot analysis of multiple diverse human tissues demonstrated marked enrichment of Amphiphysin II (BIN1) mRNA in skeletal muscle. Immunofluorescence light microscopy and electron microscopy immunocytochemistry localization of Amphiphysin II (BIN1) protein in skeletal muscle suggest the protein localizes around the plasmalemma of T tubules,Score,0.5 (0.5),The Northern blot and in situ localization experiments in human tissue are in agreement with the enriched expression in skeletal muscle reported by HPA and GTEx.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6d04cc64-0994-4579-99d5-bd2b89710173-2024-06-10T160000.000Z,2712,PubMed:9182667 +Lachgar-Ruiz mouse model,Model Systems Non-human model organism,"Lachgar-Ruiz M, et al., 2023, PMID: 37165931","In mature mice aged 14 weeks, they found no difference in auditory brainstem response (ABR) thresholds between homozygous mutants, heterozygotes and wildtype littermates. Ccdc50tm1a homozygous mouse mutant, with only 30% of the normal transcript levels, has normal ABR thresholds. They also generated a more severe allele; Ccdc50tm1b allele in which exon 3 and part of the inserted cassette are deleted. No difference in ABR thresholds was observed between Ccdc50tm1b homozygotes, heterozygotes and control littermate mice at 14 weeks and 6 months of age",Score,0 (2),Mutant mouse showed normal ABR thresholds,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_cf656dcb-6644-41bb-a29a-d7bdf54b28f7-2024-06-25T160000.000Z,2721,PubMed:37165931 +Protein interaction,Protein Interaction,"Nyegaard M, et al., 2015, PMID: 26197441",R192X mutation was shown to not affect disulfide homodimerization of CD164 protein. Also did not have an effect on WT CD164 internalization when mutant and WT were cotransfected and differentially tagged,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e9524ca4-7d17-4691-b650-0d457531c7fd-2024-06-25T160000.000Z,2723,PubMed:26197441 +Expression,Expression A,"Nyegaard M, et al., 2015, PMID: 26197441","Cd164 was expressed in mouse cochlea at P5. The protein localized to cochlear neurons, IHCs, OHCs, Kolliker’s organ, lateral cochlear wall, and stria vascularis",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e9524ca4-7d17-4691-b650-0d457531c7fd-2024-06-25T160000.000Z,2723,PubMed:26197441 +Rouzier Functional Alteration,Functional Alteration Patient cells,"Rouzier C, et al., 2017, PMID: 28335035","Patient fibroblasts also revealed increased contact between ER and mitochondria, which could explain increased Ca2+ flux- ER stress markers were not elevated, so ER stress was discounted as mechanism (ER stress likely causes WFS1). It’s not clear if this is similar or different to effect of complete loss of Cisd2 protein",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0a18d59c-c00c-4bb3-b6d6-1e59b92d1313-2023-06-01T160000.000Z,2729,PubMed:28335035 +Cattaneo RT-PCR,Functional Alteration Patient cells,"Cattaneo M, et al., 2017, PMID: 29237418",RT-PCR coupled with 5′-RACE analyses of patient's PBMCs demonstrated that the c.103 + 1G > A mutation functionally impaired the mRNA processing by generating multiple aberrant splice variants missing all or part of exon 1.,Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0a18d59c-c00c-4bb3-b6d6-1e59b92d1313-2023-06-01T160000.000Z,2729,PubMed:29237418 +Cattaneo expression,Expression B,"Cattaneo M, et al., 2017, PMID: 29237418","Western blot analysis did not reveal the presence of the protein in the patients, whereas a decrease of approximately 50% was observed in the heterozygous parents compared with that observed in the healthy control",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0a18d59c-c00c-4bb3-b6d6-1e59b92d1313-2023-06-01T160000.000Z,2729,PubMed:29237418 +Willer_Rescue in patient cells,Rescue Patient cells,"Willer T, et al., 2012, PMID: 22522420",Expression of WT-CRPPA restored functional α-DG glycosylation,Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6d774637-2d63-48fc-b670-da4d9e57377c-2023-12-12T170000.000Z,2736,PubMed:22522420 +Ispd-cKO mice gene replacement,Rescue Non-human model organism,"Tokuoka H, et al., 2022, PMID: 35422047",,Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6d774637-2d63-48fc-b670-da4d9e57377c-2023-12-12T170000.000Z,2736,PubMed:35422047 +ISPD-deficient mouse,Model Systems Non-human model organism,"Tokuoka H, et al., 2022, PMID: 35422047",The conditional knockout mouse mimics the skeletal muscle phenotype seen in humans with biallelic variants in CRPPA causing autosomal recessive limb girdle muscular dystrophy,Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6d774637-2d63-48fc-b670-da4d9e57377c-2023-12-12T170000.000Z,2736,PubMed:35422047 +Co-immunoprecipitation,Protein Interaction,"Wu M, et al., 2013, PMID: 24349431","Necdin inhibits MYC and MYC overexpression results in cystic phenotype. +CYS1 binds to Necdin",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9b3fd5b2-e89e-409a-9802-35cf6ac26913-2024-03-11T160000.000Z,2740,PubMed:24349431 +Rescue by targeted expression of a cystin-GFP fusion protein,Rescue Non-human model organism,"Yang C, et al., 2021, PMID: 34521872",Probably by downregulating Myc expression in the collecting duct cells,Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9b3fd5b2-e89e-409a-9802-35cf6ac26913-2024-03-11T160000.000Z,2740,PubMed:34521872 +DHDDS siRNA knockdown in HepG2 cells,Functional Alteration Non-patient cells,"Sabry S, et al., 2016, PMID: 27343064","DHDDS activity was reduced by 50% in HepG2 cells transfected with siRNA targetting DHDDS, 4 days post-transfection (Fig 6d). These cells showed reduced radiolabeled mannose incorporation into DLO without significantly affecting the amount of radioactivity associated with N-glycans (Fig 6e). The high ratio of [2-3H]DLO/[2-3H]N-glycan in the siRNA-treated HepG2 cells is similar that seen in fibroblasts from the patient described in the paper (with biallelic variants in DHDDS). Thin layer chromatography revealed various truncated DLOs in the siRNA-treated HepG2 cells (Fig. 6f).",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_748d9424-1f8c-4d72-8e79-2e0b8cc7c445-2023-04-06T160000.000Z,2743,PubMed:27343064 +K42E Dhdds Knock-In Mouse,Model Systems Non-human model organism,"Ramachandra Rao S, et al., 2020, PMID: 32272552","While there was no gross evidence for retinal degeneration in Dhdds-K42E/K42E mice, more detailed evaluation in later studies revealed abnormailities consistent with retinopathy observed in human patients with DHDDS biallelic variants including progressive ERG defects (Chakraborty et al., Invest. Ophthamol. Vis. Sci. 2021, 62, 2958), evidence of ectopic and pykntoic photoreceptor nuclei, apoptotic cells, and disorganized and degenerated RPE cells (Pittler et al, Invest. Ophthalmol. Vis. Sci. 2022, 63, 2377). +Based on these studies, the retinal phenotype of the Dhdds K42E knock-in mouse is less severe than that observed in human patients. However, common features include, major symptoms confined to retina (not known if older mice develop neurological symptoms), and also shorter chain dolichol species in knock-in mouse and humans. in knock in mice, the retinal dysfunction occurs more in the inner retina, rather the outer retina in humans (see Fliesler et al, 2022 review).",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_748d9424-1f8c-4d72-8e79-2e0b8cc7c445-2023-04-06T160000.000Z,2743,PubMed:32272552 +Dhdds rod-specific knockout mouse,Model Systems Non-human model organism,"Ramachandra Rao S, et al., 2020, PMID: 32526701","Rod-specific Dhdds knockout mice share various features with human patients with biallelic variants in DHDDS including photoreceptor degeneration, reduced length of rod outer segments, and progressive reduction of ERG response. Of note, in the mouse model, DHDDS is completely knocked out in rods, whereas by far the most common cause of retinal degenraiton in human related to DHDDS is a missense variant, p.Lys42Gln (K42E). Note that the mouse K42E-knock in model has a less dramatic phenotype that the knockout mouse.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_748d9424-1f8c-4d72-8e79-2e0b8cc7c445-2023-04-06T160000.000Z,2743,PubMed:32526701 +Function of DHDDS in dolichol synthesis,Biochemical Function B,"Bar-El ML, et al., 2020, PMID: 33077723","DHDDS encodes the catalytic subunit of cis-prenyltransferase (cis-PTase). cis-PTase is a heterotetramer composed of two heterodimers of DHDDS (dehydrodolichyl diphosphate synthase) and the Nogo-B receptor (NgBR) that is required for the biosynthesis of dolichol, an essential lipid serving as glycosyl moiety carrier for protein N-glycosylation. The authors showed that purified DHDDS/NgBR complex formed stable heterotetramers in solution, with equimolar stoichiometry of DHDDS and NgBR subunits, and had markedly increased activity compared to purified homodimeric DHDDS. Thefeore, both subunits are required for signficant cis-PTase activity. The proceeded to generate a 2.3 Å crystal structure which revealed that the tetramer assembles via the DHDDS C-termini as a dimer-of-heterodimers. +The role of DHDDS in dolichol biosythesis is consistent with the finding that urine and plasma samples from individuals with biallelic variants in DHDDS have shorter dolichol profiles compared to those of unaffected homozygous normal and heterozygous individuals. In the affected individuals, D18 was the dominant dolichol species, compared to D19 in unaffected individuals and, therefore, D18/D19 ratios of affected individuals were higher than those of unaffected (Wen et al, 2013, PMID: 24078709).",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_748d9424-1f8c-4d72-8e79-2e0b8cc7c445-2023-04-06T160000.000Z,2743,PubMed:33077723 +RNAi knock down in Drosophila,Model Systems Non-human model organism,"Brandwine T, et al., 2021, PMID: 34290587","Targeted expression of CG10778 (ortholog of DHDDS)-RNAi in the Drosophila eye disc and pupal retina at the larval stage resulted in retinal degeneration. Photoreceptors R2 and R5 had a near normal structure of their rhabdomere (photoreceptor outer segments), while all other photoreceptors exhibited retinal degeneration at all regions. Rhodopsin levels were markedly reduced in RNAi-treated flies, and ER membranes accumulated in the photoreceptors. The authors concluded that CG10778 is required for the normal development of the Drosophila retina. +Similarly, humans with biallelic loss of function variants in DHDDS have been reported with retinitis pigmentosa (retinopathy).",Score,1 (2),Reduced due to differences in retinal architecture between flies and humans.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_748d9424-1f8c-4d72-8e79-2e0b8cc7c445-2023-04-06T160000.000Z,2743,PubMed:34290587 +Boumil Rescue,Model Systems Non-human model organism,"Boumil RM, et al., 2010, PMID: 20700442","1st report of ""fitful"" mice with recurrent, non-lethal seizures; phenotype is semidominant; homozygous mice have more severe phenotype",Review,2 (2),"Heterozygotes reportedly suffered seizures following routine handling and did not have spontaneous seizures. Homozygote ""fitful"" mice experienced spontaneous seizures. The Epilepsy GCEP typically does not award points to mouse models without spontaneous seizures and for this reason, I have updated this evidence's status to ""Review.""",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_31f598a3-7efd-4e43-83f3-587e98924260-2024-02-06T080000.000Z,2748,PubMed:20700442 +Asinof Rescue,Model Systems Non-human model organism,"Asinof SK, et al., 2015, PMID: 26125563",Used “fitful” mice with an EE disorder that carry a spontaneous mutation in DNM1. They demonstrated that seizure activity is independent from dev delay.,Review,0.5 (2),Used “fitful” mice with an EE disorder that carry a spontaneous mutation in DNM1. They demonstrated that seizure activity is independent from dev delay.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_31f598a3-7efd-4e43-83f3-587e98924260-2024-02-06T080000.000Z,2748,PubMed:26125563 +FA Nonpatient Cells,Functional Alteration Non-patient cells,"Dhindsa RS, et al., 2015, PMID: 27066543",Expression of mutant proteins decrease endocytosis activity in dominant negative manner. The G359A variant showed disrupted higher-order DNM1 oligomerization. EM of mutation DNM1-transfected HeLa cells and DNM1 mutate mice showed vesicle defects indicating vesicle scission activity,Review,0.5 (0.5),"This is variant-level functional evidence. I have removed it from the experimental evidence total and instead applied it as supporting evidence for the individual with the G359A variant. +Expression of mutant proteins decrease endocytosis activity in dominant negative manner.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_31f598a3-7efd-4e43-83f3-587e98924260-2024-02-06T080000.000Z,2748,PubMed:27066543 +DZIP1L Immunofluorescence on human kidney sections,Expression A,"Hertz JM, et al., 2022, PMID: 35211789",IF shows positive staining for DZIP1L,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_f1e2d1d2-b77c-4f1a-b185-31e3a95aae9b-2024-03-29T160000.000Z,2751,PubMed:35211789 +Megakaryocyte differentiation and proplatelet formation,Functional Alteration Patient cells,"Saultier P, et al., 2017, PMID: 28255014","On day 11, the percentage of mature CD41hi CD42ahi MKs was strikingly reduced, while the percentage of CD41lowCD42- and CD41-CD42- cells was increased in F1-II2 compared with the control. The percentage of high-ploidy cells (≥8n) was reduced among FLI1 variant carriers at day 12 (11.9, 8.2 and 5.8% for the control, the F1-II2 and the F1-III1 affected members, respectively) and day 14 of maturation (11.3, 6.2 and 4.5% for the control, the F1-II2 and the F1-III1 affected members, respectively). At days 12-13, the percentage of PPT-forming MKs was significantly reduced in the affected members F1- II2 and F2-II4 compared with three controls (16% ± 1 vs. 3% ± 1, p<0.05). MKs from patients were smaller and formed very few PPTs, which displayed reduced extensions and branching.",Score,1 (1),"The authors used the peripheral blood CD34+ cells to generated MKs and demonstrated that the mature MK cell number from the FLI1 variant carrier was significantly reduced compared with the WT controls. They also showed that MKs from patients were smaller and formed very few PPTs, which displayed reduced extensions and branching. These results suggested an altered FLI1 function associated with MKs differentiation and maturation.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_dd0eaa15-3ee7-4db7-9920-c380757ece33-2023-09-06T170000.000Z,2761,PubMed:28255014 +Fzd4+/- mice,Model Systems Non-human model organism,"Ngo MH, et al., 2016, PMID: 27489958","Fzd4+/- indicate that haplo-insufficiency results in abnormal retinal vasculature development, seen as early as P12. This is consistent with abnormal retinal vasculature in humans with heterozygous mutations from early in life",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_2da74e15-54c4-405c-aa44-301f4717087d-2024-04-04T160000.000Z,2765,PubMed:27489958 +GAS2L2 stabilizes microtubules and localizes to plus ends.,Biochemical Function B,"Stroud MJ, et al., 2014, PMID: 24706950",These biochemical data link GAS2L2 to a function in regulating microtubule stability in coordination with the plus-end-associated EB1 protein and through cross-talk with actin fibers. Please note that the data linking GAS2L2 to microtubule plus ends and interaction with EB1 are further supported by proteomics findings from PMID: 22885064.,Score,0.5 (0.5),"These data further establish the link between GAS2L2 function and regulation of the interactions between microtubules and actin filaments. While other biochemical evidence have been scored as part of this curation, this study adds detail on the interaction with microtubule plus ends specifically, the physical association with EB1, and the ability of exogenous GAS2L2 to exert a stabilizing effect on microtubule dynamics.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_91afae37-4cfc-4aeb-af0f-26a9596611f3-2023-09-14T160000.000Z,2767,PubMed:24706950 +Xenopus tropicalis embryo with Gas2l2 knockdown,Model Systems Non-human model organism,"Seidl C, et al., 2023, PMID: 36878953",The embryos lacking Gas2l2 expression exhibit less effective ciliary motility (ciliary gliding defect) as well a abnormal ciliary morphology (shortening) relative to control embyros.,Score,0.5 (2),Lower scoring has been recommended as the model is morpholino-based and recapitulates only the cellular level of the human defects.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_91afae37-4cfc-4aeb-af0f-26a9596611f3-2023-09-14T160000.000Z,2767,PubMed:36878953 +Review of glucocerebrosidase function,Biochemical Function B,"Boer DEC, et al., 2020, PMID: 32182893","The lysosomal enzyme acid β-glucosidase (also known as glucocerebrosidase, GCase) degrades the glycosphingolipid glucosylceramide (GlcCer) (glucocerebroside) (Fig 1A). This comprehensive review discusses the multiple roles of glucocerebrosidase both within and outside the lysosome. Lack of GCase activity results in accumulation of GlcCer in the lysosomal of patients with Gaucher disease. This is can be noted by the presence of Gaucher cells, abnormal macrophages caused by the accumulation of GlCSer, seen in bone marrow. The accumulation of GlcCer in body tissues causes the clinical characteristics of Gaucher disease including hepatosplemomegaly, bone abnormalities, thrombocytopenia and, in some cases neurological problems. Furthermore, GCase generates ceramides from GlcCer molecules in the outer part of the skin (the stratum corneum), therefore providing an essential building block for lipid lamellae. This is required for the skin to be able to act as an effective barrier, a property which is essential to survival. Skin abnormalities are commonly reported in individuals with type 2 gaicher disease, including the most severe cases in which babies have a collodion skin phenotype.",Score,2 (0.5),"The score is increased because the function of glucocerebrosidase has been well-characterized since its role in Gaucher disease was reported in 1965, as shown by the detail provided in this review.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_fbc5a876-f97e-4f9c-be99-664e2f6c8470-2020-06-24T160000.000Z,2769,PubMed:32182893 +Rational peptide design,Rescue Patient cells,"Froese DS, et al., 2015, PMID: 26199317",Western showing partial rescue of protein expression with addition of stabilizing peptide.,Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3f01d412-0f6d-4a0f-88db-b55b2af4a0a2-2023-09-21T160000.000Z,2770,PubMed:26199317 +Bianchi - Model and Rescue,Model Systems Non-human model organism,"Bianchi V, et al., 2012, PMID: 22291894","Using electron microscopy and electrophysiology, we now report that lack of aGDI impairs several steps in synaptic vesicle (SV) biogenesis and recycling in the hippocampus",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_8afc42b0-6c5e-460b-87d1-035c051fe7ca-2023-04-27T060000.000Z,2771,PubMed:22291894 +Bianchi - Functional Alteration Non-Patient Cells,Functional Alteration Non-patient cells,"Bianchi V, et al., 2012, PMID: 22291894","Using electron microscopy and electrophysiology, we now report that lack of aGDI impairs several steps in synaptic vesicle (SV) biogenesis and recycling in the hippocampus",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_8afc42b0-6c5e-460b-87d1-035c051fe7ca-2023-04-27T060000.000Z,2771,PubMed:22291894 +Chi Functional Alteration 1,Functional Alteration Non-patient cells,"Chi J, et al., 2012, PMID: 22393412","Hela cells transfected with WT and R42P Cx31. Mutant but not WT caused small nuclei, and TEM showed morphological features of necrosis including translucent cytoplasm, swellign of organelles, disruption of plasma membrane, dilation of nuclear membrane, and condensation of chromatin. No difference in apoptosis, so authors propose cell death is necrotic and not apoptotic. Mutant Cx31 effectively mediated dye transfer indicating functional gap junctions. Mutant Cx31 formed consitutitvely active hemichannels which could be cause of cell death",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1d48c959-31d8-44e2-985c-c48921e8f08a-2023-06-01T160000.000Z,2772,PubMed:22393412 +Chi Functional Alteration 2,Functional Alteration Non-patient cells,"Chi J, et al., 2012, PMID: 22393412","Cx31R42P induces production of reactive oxygen species, and this could be partially rescued by treatment with ROS scavenger butylated hydroxyanisole",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1d48c959-31d8-44e2-985c-c48921e8f08a-2023-06-01T160000.000Z,2772,PubMed:22393412 +Zebrafish embryo manipulation,Rescue Non-human model organism,"Ramachandran H, et al., 2016, PMID: 26374130","They used zebrafish pronephros model. Knockdown of the zebrafish isoform nphp7.2 results in cyst formation, which can be rescued by +zebrafish nphp7.2 mRNA. They generated the corresponding nphp7.2 mutation, and performed the rescue experiments in parallel with wild-type nphp7.2 mRNA. Although wild-type mRNA +ameliorated the phenotype and reduced cyst formation, there was no reduction but even a slight increase in zebrafish embryos micro-injected with the mutant mRNA.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c51be76f-59d3-4884-9df3-4416686848ab-2024-06-27T160000.000Z,2773,PubMed:26374130 +Nuclear fractionation with western blot analysis,Functional Alteration Non-patient cells,"Ramachandran H, et al., 2016, PMID: 26374130",Nuclear fractionation in combination with western blot analysis showed that GLIS2 C175R point mutation abolished the nuclear localization of GLIS2.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c51be76f-59d3-4884-9df3-4416686848ab-2024-06-27T160000.000Z,2773,PubMed:26374130 +"Hemizygous OA1 disruption in mouse, continued",Model Systems Non-human model organism,"Palmisano I, et al., 2008, PMID: 18697795","The mice match the human patients in that they exhibit congenital onset of cytological abnormalities (PMID: 16303920), These were previously shown in the RPE and are here shown in the melanocytes as well (Figure 3). Most importantly, this study shows a defect in microtubule-based melanosome motility (Figure 7), indicating an underlying mechanism for the disease.",Score,1.5 (2),This study complements earlier characterization of the same model by finding additional phenotypes and characterizing an underlying cellular defect in microtubule-based melanosome motility that helps clarify the underlying mechanism of disease in the human patients.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_41096b60-bbfb-469e-9695-8a23986f467c-2022-10-06T160000.000Z,2779,PubMed:18697795 +Zebrafish knockdown of the GPR143 ortholog OA1,Model Systems Non-human model organism,"Burgoyne T, et al., 2015, PMID: 25690007","The zebrafish match one feature of the human patients in that they exhibit abnormalities of retinal pigmentation consistent with the ability of GPR143 loss-of-function to trigger defects in melanosome regulation (Figure 1). This is only an approximate match, as patients also exhibit giant melanosomes in the RPE that are not observed here.",Score,0.25 (2),"Reduced scoring is recommended because the match to a human phenotype is only approximate, yet provides some evidence of a similar function in humans and zebrafish.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_41096b60-bbfb-469e-9695-8a23986f467c-2022-10-06T160000.000Z,2779,PubMed:25690007 +IMPDH activity assay and enzyme kinetics,Biochemical Function B,"Buey RM, et al., 2015, PMID: 26558346","Mutations associated with human retinopathies map into the guanine nucleotide-binding sites including a previously undescribed non-canonical site and disrupt allosteric inhibition. Together, the results shed light on the mechanisms of the allosteric regulation of enzymes mediated by Bateman domains and provide a molecular basis for certain retinopathies.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_04d85991-25a4-4da6-8090-65b8cfb771cd-2024-02-01T170000.000Z,2793,PubMed:26558346 +IMPDH expression in zebrafish retina,Expression A,"Cleghorn WM, et al., 2022, PMID: 34813793","We demonstrate biochemical and structural similarity between the zebrafish and human retinal variant of IMPDH1, uncover dynamic changes in photoreceptor filaments throughout the day, and use metabolomics to elucidate an important role for Impdh1 in purine nucleotide homeostasis in photoreceptors. In zebrafish, gene subfunctionalization due to ancestral duplication resulted in a predominant retinal variant expressed exclusively in rod and cone photoreceptors. This variant is structurally and functionally similar to the human IMPDH1 retinal variant and shares a reduced sensitivity to GTP-mediated inhibition. We also demonstrated that Impdh1a forms prominent protein filaments in vitro and in vivo in both rod and cone photoreceptor cell bodies, synapses, and to a lesser degree, in outer segments",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_04d85991-25a4-4da6-8090-65b8cfb771cd-2024-02-01T170000.000Z,2793,PubMed:34813793 +Knockout mouse model of Impg1,Model Systems Non-human model organism,"Olivier G, et al., 2022, PMID: 36140676","The model exhibits phenotypes consistent with a critical role of Impg1 in photoreceptor maintenance. Phenotypes included hyperpigmented and sometimes autofluorescent subretinal deposits that were present at 9 months of age (Figure 2B) and increased by 14 months of age (Figure 2C) that were localized between the photoreceptor outer segment and the RPE (Figure 2D). Some images showed nummular pigmentation of the fundus (Figure 2E). Interestingly, attenuation of ERG response was first noted at 9 months and pronounced at 14 months (Figure 3A), which is consistent with the findings from an independent mouse model that showed less dramatic findings at earlier 5 month and 8 month time points (PMID: 32265257). Scotopic ERG was more affected than photopic ERG (Figure 3B). Retinal thickness was also reduced in the outer layer relative to the inner layer (Figure 3C). Retinoid generation was also progressively abnormal (Figure 4), indicating that photoreceptors might be lost. The IPM was also disorganized at 14 months (Figure 5), with cellular material accumulating in the IPM consistent with cell death (Figure 6).",Score,0.5 (2),"Reduced scoring is considered appropriate, despite the extent of match to the human patient phenotypes, due to the phenotype appearing in older homozygous animals rather than in the heterozygous animals. Some scoring was considered appropriate given the information provided about photoreceptor loss and IPM degeneration as underlying the mechanism of disease.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c6816122-6b22-4ac8-bc20-f1cc68b3b7ed-2023-09-07T160000.000Z,2794,PubMed:36140676 +Knockout mouse model of Impg1,Model Systems Non-human model organism,"Olivier G, et al., 2022, PMID: 36140676","The model exhibits phenotypes consistent with a critical role of Impg1 in photoreceptor maintenance. Phenotypes included hyperpigmented and sometimes autofluorescent subretinal deposits that were present at 9 months of age (Figure 2B) and increased by 14 months of age (Figure 2C) that were localized between the photoreceptor outer segment and the RPE (Figure 2D). Some images showed nummular pigmentation of the fundus (Figure 2E). Interestingly, attenuation of ERG response was first noted at 9 months and pronounced at 14 months (Figure 3A), which is consistent with the findings from an independent mouse model that showed less dramatic findings at earlier 5 month and 8 month time points (PMID: 32265257). Scotopic ERG was more affected than photopic ERG (Figure 3B). Retinal thickness was also reduced in the outer layer relative to the inner layer (Figure 3C). Retinoid generation was also progressively abnormal (Figure 4), indicating that photoreceptors might be lost. The IPM was also disorganized at 14 months (Figure 5), with cellular material accumulating in the IPM consistent with cell death (Figure 6).",Score,2 (2),"Default scoring is considered appropriate, given the extent of match to the human patient phenotypes, as well as the information provided about photoreceptor loss and IPM degeneration as underlying the mechanism of disease. The difference in time points analyzed from a previous study (PMID: 32265257) was considered the most likely explanation for the drastic differences in severity.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d638e88c-feaa-4d84-a4e7-9b83481bfb0c-2023-09-07T160000.000Z,2795,PubMed:36140676 +Strunnikova_Expression,Expression A,"Strunnikova NV, et al., 2010, PMID: 20360305","Therefore, we performed a global expression profiling of native and cultured human fetal and adult RPE and determined a set of highly expressed ‘signature’ genes by comparing the observed RPE gene profiles to the Novartis expression database (SymAtlas: http://wombat.gnf.org/index.html) of 78 tissues. Using stringent selection criteria of at least 10-fold higher expression in three distinct preparations, we identified 154 RPE signature genes, which were validated by qRT-PCR analysis in RPE and in an independent set of 11 tissues. Gene expression levels were determined by microarray and subsequently confirmed via RT-PCR.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_f0705bfe-f3fa-495f-8a5d-77561d0afe91-2023-02-02T170000.000Z,2798,PubMed:20360305 +ElShamieh_ExpressionA,Expression A,"El Shamieh S, et al., 2017, PMID: 29057815","To validate if transcript 1 ( NM 018474.4) is present in blood, fibroblasts and human +retina, reverse transcription‐PCR (RT‐PCR) experiments were performed. Indeed major bands could be detected in amplicons covering exons 1–4, exons 4–6 and exons 6–13 in all tissues tested, studies that were confirmed by Sanger sequencing in control and patient whole blood, fibroblast cells and control retina (Figure 3).",Score,0.25 (0.5),"Expression is present in tissues not relevant to disease, as well as in an RP-affected patient who carries a KIZ mutation.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_f0705bfe-f3fa-495f-8a5d-77561d0afe91-2023-02-02T170000.000Z,2798,PubMed:29057815 +ElShamieh_BiochemicalA,Biochemical Function A,"El Shamieh S, et al., 2017, PMID: 29057815",Each gene has been reported to function in cilia by previous biocurators.,Score,0 (0.5),Retina GCEP decided that this evidence did not clearly show that KIZ plays a role in RP.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_f0705bfe-f3fa-495f-8a5d-77561d0afe91-2023-02-02T170000.000Z,2798,PubMed:29057815 +Knock Out Mouse-T Cells,Model Systems Non-human model organism,"Placek K, et al., 2017, PMID: 28759003",The following model system shows the reduction in T cells and Reduction of T regulatory cells that could explain the autoimmune phenotype shown in some of the human cases.,Score,2 (2),The following example explains the T cell and autoimmune phenotypes found in some of these kabuki patients.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_15029985-0c1a-4835-95fe-eb05dedaf85c-2021-10-21T160000.000Z,2800,PubMed:28759003 +Targeted disruption of Lrp5 in mice,Model Systems Non-human model organism,"Kato M, et al., 2002, PMID: 11956231","Model animals subjected to targeted disruption of Lrp5 resembled human patients in that they exhibited reduced bone mineral density in the post-natal stage (Figs. S2, 3A), decreased osteoblast proliferation (Fig. 4), delayed ossification (Fig. 5), and remnants of the hyaloid vascular system due to failure of macrophage-mediated endothelial cell apoptosis (Fig. 8).",Score,2.5 (2),"The model animals recapitulate ocular, bone, and molecular characteristics of the human patients, as well as the mode of inheritance and loss-of-function mechanism.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c46e0508-399f-48d0-9dbc-55f10cf8460d-2023-03-02T170000.000Z,2803,PubMed:11956231 +Gil-Krzewska_Function,Biochemical Function B,"Gil-Krzewska A, et al., 2018, PMID: 29241728",Patients with CHS also display a similar cellular phenotype with giant granules in leukocytes.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5d752f7c-43d2-4ba9-910f-f286f5443012-2020-05-27T160000.000Z,2804,PubMed:29241728 +LZTFL1 interacts with the BBSome,Biochemical Function B,"Seo S, et al., 2011, PMID: 22072986","This study describes the identification of LZTFL1 (Leucine-zipper transcription factor-like 1) as a protein that interacts with the BBSome and negatively regulates its trafficking activity to the cilia. As such, LZTLF1 is important to the function of the cilia. This function is consistent with the phenotypic characteristics of BBS, a condition known to be caused by ciliary dysfunction. Variants in the genes encoding the components of the BBSome, with which LZTFL1 interacts, cause BBS, providing further support for a role of LZTLF1 in BBS. Finally, the authors also provide evidence that the BBSome and LZTFL1 are part of the transport mechanism of Sonic Hedgehog (SHH) signal transducer, Smoothened (SMO) that localizes to cilia. As the SHH pathway is known to be important in limb development, and perturbation of the pathway has been associated with polydactyly (PMID: 34884862), these results are consistent with the function of LZTFL1 in the BBS phenotype, one of the characteristics of which is polydactyly.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e352868c-b5d8-451d-89ef-61a147ea7b4f-2024-01-04T170000.000Z,2805,PubMed:22072986 +Rescue of cilia defect in patient-derived fibroblasts,Rescue Patient cells,"Tucker BA, et al., 2022, PMID: 34518651",Viral delivery of the retinal MAK significantly reduced cilia length under Ef1alpha and CMV promotors. canonical isoform under CMV promotor resulted in rescue as well. These results indicate that delivery of especially retinal MAK can restore the cell's ability to regulate cilia length.,Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ee785a8d-420d-4c3a-a585-c963d06df52e-2023-03-02T170000.000Z,2808,PubMed:34518651 +Zebrafish KO,Model Systems Non-human model organism,"Tucker BA, et al., 2022, PMID: 34518651",The mak KO zebrafish had a significantly reduced startle response as compared to WT fish. Note: the KO zebrafish also had elongated cilia length (as shown in patient-derived fibroblasts),Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ee785a8d-420d-4c3a-a585-c963d06df52e-2023-03-02T170000.000Z,2808,PubMed:34518651 +Zebrafish rescue,Rescue Non-human model organism,"Tucker BA, et al., 2022, PMID: 34518651","All fish injected with rescue mRNA showed significant increase in response to visual stimuli, indicating partial recovery of visual function. In addition, injection of human MAK mRNA was able to rescue aberrant cilia lengths (significant reduction in cilia length was seen in rescue experiment)",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ee785a8d-420d-4c3a-a585-c963d06df52e-2023-03-02T170000.000Z,2808,PubMed:34518651 +Cilia defect in patient-derived fibroblasts,Functional Alteration Patient cells,"Tucker BA, et al., 2022, PMID: 34518651","Dermal fibroblasts from patients homozygous for MAK 353 bp Alu insertion were evaluated for cilia length. As compared to an unaffected control, the patient-derived fibroblasts has longer primary cilia",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ee785a8d-420d-4c3a-a585-c963d06df52e-2023-03-02T170000.000Z,2808,PubMed:34518651 +Tissue Specific MEIS2 knockout,Model Systems Non-human model organism,"Machon O, et al., 2015, PMID: 26545946","The tissue specific deletion of meis2 resulted in cardiac defects and abnormalities of the head bones and cartilage. These findings are representative of the heart defects, dysmorphic facies, and cleft palate observed in humans with MEIS2 variants.",Score,0.5 (2),"Downgraded to 0.5 point because the authors studied knockout mice (-/-) or tissue specific mutants, rather than heterozygous mice and no neurodevelopmental phenotypes were explored.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_fe156246-6e64-4096-a4c5-a83a3e70dbb9-2022-04-22T060000.000Z,2814,PubMed:26545946 +Restoration of peroxisome morphology,Rescue Patient cells,"Costello JL, et al., 2017, PMID: 28108524","Reintroduction of MFF resulted in formation of numerous spherical peroxisomes, restoring the normal phenotype",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_021d15d7-dbf0-4b71-bbb5-48dc4a4b5ee6-2024-06-21T160000.000Z,2815,PubMed:28108524 +Peroxisomal elongation in MFF-deficient fibroblasts,Functional Alteration Patient cells,"Passmore JB, et al., 2020, PMID: 32224193","Fibroblasts from all MFF-deficient patients showed highly elongated peroxisomes (>30 μm) whereas in controls peroxisomes showed a punctate staining pattern typical for human fibroblasts (Fig. 1A). Authors transfected MFF-deficient fibroblasts with Myc-MFF using microporation, which resulted in MFF being observed to localize in spots on elongated peroxisomes (and elongated mitochondria) supporting a role in the assembly of the division machinery and the formation of division sites. Many MFF-expressing cells showed short, dividing peroxisomes or fully divided, spherical peroxisomes. The highly elongated peroxisomes in MFF-deficient cells may be subject to autophagic processes and capable of being degraded. No notable abnormalities were found in all three MFF-deficient cell lines relating to the metabolism of VLCFAs or branched-chain fatty acids in peroxisomes.",Score,1 (1),The evidence suggests that MFF plays a role in peroxisomal and mitochondrial fission.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_021d15d7-dbf0-4b71-bbb5-48dc4a4b5ee6-2024-06-21T160000.000Z,2815,PubMed:32224193 +MKKS_Biochemical,Biochemical Function A,"Álvarez-Satta M, et al., 2017, PMID: 28824921",PMID: 19190184,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c054871f-bcf0-48c1-a252-5c02d05adc97-2024-05-02T160000.000Z,2816,PubMed:28824921 +KO Mouse,Model Systems Non-human model organism,"Dickinson ME, et al., 2016, PMID: 27626380",The embryonic lethality in knockout mice is consistent with the death in infancy observed in several of the MOGS-CDG patients.,Score,0 (2),Due to the embryonic lethality the degree of disease recapitulation could not be studied. Alteration of N-linked glycosylation was not investigated. This mouse is reported by the International Mouse Phenotyping Consortium.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5a628248-c2f9-4d31-b614-e082e3f83416-2021-07-20T130742.194Z,2818,PubMed:27626380 +Han 2014 Experimental 1,Functional Alteration Patient cells,"Han L, et al., 2014, PMID: 25209314",Arg442Gly Mutant iPSC-induced CMs showed marked increase in action potential duration (APD) versus wt iPSC CMs (Figure 4A) and increased arrythmogenic events in Arg442Gly iPSC-induced CMs versus WT iPSC-induced CMs (Figure 4F),Score,1 (1),"iPSCs from HCM patient with a single missense mutation (Arginine442Glycine) in the MYH7 gene. A widespread increase of genes responsible for 'Cell Proliferation' was observed in HCM iPSC-CMs when compared with control iPSC-CMs. Additionally, HCM iPSC-CMs exhibited disorganized sarcomeres and electrophysiological irregularities. Furthermore, disease phenotypes of HCM iPSC-CMs were attenuated with pharmaceutical treatments.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_31325c90-05cb-4db0-9372-e4f705cd5c82-2023-07-12T160000.000Z,2822,PubMed:25209314 +Lelli 2016 Mouse Model,Model Systems Non-human model organism,"Lelli A, et al., 2016, PMID: 26754646","Auditory brainstem responses at 1 month showed no hearing impairment, but between 2 and 4 months the Myo3a-/- ABR thresholds were much higher than heterozygous Myo3a+/- and wild-type mice. DPOEA thresholds and amplitudes did not differe between variant and control mice of 2-4 months. This is consistent with late-onset hearing loss, where OHC function is not impaired.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a8fa3d7b-73a2-43a3-8f13-7dac3fd27737-2023-06-01T160000.000Z,2824,PubMed:26754646 +Lelli 2016 Functional Alteration,Functional Alteration Non-patient cells,"Lelli A, et al., 2016, PMID: 26754646","Immuno staining for myosin IIIa in mouse model cochlea showed weak signal at tips of IHC and OHC stereocilia at day P8, and entire disappearance of signal by P13.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a8fa3d7b-73a2-43a3-8f13-7dac3fd27737-2023-06-01T160000.000Z,2824,PubMed:26754646 +Rescue using exogenous NEK10,Rescue Cell culture model,"Porpora M, et al., 2018, PMID: 29581457",Re-introduction of exogenous NEK10 that cannot be targeted by siRNA rescued cilia in NEK10-depleted cells.,Score,0 (1),Rescue assay of cell culture and zebrafish scored under other entry as lumped category.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_72a2f8fa-ee83-48cc-93fa-22a8990c8d13-2023-07-13T160000.000Z,2827,PubMed:29581457 +Zebrafish Rescue,Rescue Non-human model organism,"Porpora M, et al., 2018, PMID: 29581457",Co-injection of human WT NEK10 induced statistically significant rescue of cilia length,Score,2 (2),Rescue of cell culture and zebrafish combined into same scoring category.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_72a2f8fa-ee83-48cc-93fa-22a8990c8d13-2023-07-13T160000.000Z,2827,PubMed:29581457 +Immunostaining analysis,Expression A,"Porpora M, et al., 2018, PMID: 29581457",Immunostaining analysis confirmed significant fraction of NEK10 is localized at cilia. Serum deprived HEK293 cells were immunostained and acetylated tubulin and analyzed by confocal microscope.,Score,0.1 (0.5),Recognize as independent assay but showing same datapoint as Chivukula 2020 paper.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_72a2f8fa-ee83-48cc-93fa-22a8990c8d13-2023-07-13T160000.000Z,2827,PubMed:29581457 +CRISPR/CAS-9 NEK10 ALI LOF Culture,Model Systems Cell culture model,"Chivukula RR, et al., 2020, PMID: 31959991",Altered or non functional cilia is phenotype for primary ciliary dyskinesia in humans.,Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_72a2f8fa-ee83-48cc-93fa-22a8990c8d13-2023-07-13T160000.000Z,2827,PubMed:31959991 +ALI-GFP Cilia Cell Expression,Expression A,"Chivukula RR, et al., 2020, PMID: 31959991","Generated ALI cultures in which eGFP is expressed under control of NEK10 promoter. Found 149-fold enrichment of FOXJ1 with reciprocal depletion of secretory and basal cell marker transcripts, while confocal imaging confirmed GFP positivity restricted to cells harboring apical cilia.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_72a2f8fa-ee83-48cc-93fa-22a8990c8d13-2023-07-13T160000.000Z,2827,PubMed:31959991 +NEK10 Proteomic Study,Protein Interaction,"Chivukula RR, et al., 2020, PMID: 31959991",Examined effects of NEK10 deletion on proteins previously proteomically identified in airway cilia. Peptides form all classes of motile ciliary genes were depleted in NEK10 KO ALI,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_72a2f8fa-ee83-48cc-93fa-22a8990c8d13-2023-07-13T160000.000Z,2827,PubMed:31959991 +Nipbl+/- mouse model,Model Systems Non-human model organism,"Kawauchi S, et al., 2009, PMID: 19763162","Mice heterozygous for a gene-trap mutation upstream of the first coding exon of Nipbl displayed many features of human CdLS, including pre- and postnatal growth retardation, +cardiac septal defects, delayed bone development, lean body habitus, microbrachycephaly with characteristic craniofacial changes, behavioral disturbances, ophthalmological abnormalities, cerebellar hypoplasia, and hearing deficits.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d4ecc430-6562-4d58-9118-c5253dc95ae9-2023-06-28T060000.000Z,2828,PubMed:19763162 +Zebrafish model,Model Systems Non-human model organism,"Muto A, et al., 2014, PMID: 25255084","Early limb development is highly conserved from fish to +mammals. Each fin/limb bud possesses an apical +ectodermal ridge (AER) and zone of polarizing activity (ZPA), which play important roles in growth and patterning. Nipbl levels are critical for limb development (Figure 1), and that Nipbl regulates expression of specific sets of genes in the embryonic limb, including many key +developmental regulators that are conserved between fish and mice. The idea that the strength of limb phenotypes is related to the +degree of nipbl depletion is further supported by the observation, in +zebrafish, that fin reductions are more severe when larger amounts +of nipbla-MO are injected, or when both nipbla and nipblb are +knocked-down, as opposed to either one alone (Figure S3).",Score,1 (2),Downgraded as CdLS is a syndrome encompassing numerous organ systems of which Zebrafish does not always have an equivalent so direct comparison of the phenotypes is limited.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d4ecc430-6562-4d58-9118-c5253dc95ae9-2023-06-28T060000.000Z,2828,PubMed:25255084 +Nipped-B407 Drosophila mutant,Model Systems Non-human model organism,"Wu Y, et al., 2015, PMID: 26544867","Fly Nipped-B mutants demonstrate a strikingly analogous growth +and neurocognitive/behavioral phenotype between heterozygous Nipped-B mutants and +human CdLS individuals, including small body size, learning and memory deficits, disruptive +sleep patterns and circadian rhythm defects.",Score,1 (2),Downgrading as CdLS is a syndrome encompassing numerous organ systems of which Drosophila does not always have an equivalent so direct comparison of the phenotypes is limited.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d4ecc430-6562-4d58-9118-c5253dc95ae9-2023-06-28T060000.000Z,2828,PubMed:26544867 +Gene therapy in Npc1-/- mice,Rescue Non-human model organism,"Kurokawa Y, et al., 2021, PMID: 33256498","AAV-hNPC1 was injected into both the left lateral ventricle and cisterna magna in Npc1-/- mice at 4 to 5 days after birth. In mice sacrificed at 10 weeks of age, RT-PCR revealed expression of hNPC1 in AAV-treated Npc1-/- , but not in untreated Npc1+/+ and Npc1-/- in the brain (Fig. 2C). In addition, hNPC1 was also detected in the liver, lung, and heart of treated mice but not untreated mice. +NPC1-/- mice treated with AAV-hNPC1 showed improvement of life span, body weight loss, and rotarod performance (see Fig 3). Untreated Npc1-/- mice developed difficulty in moving and eating. They had an ataxic gait and progressed to inability to stand. They were unable to eat solid food and died at 10 to 12 weeks. In comparison, AAV-treated Npc1-/- mice continued walking without problems until week 20 and as late as week 35 for some. However, they gradually developed a spastic gait and ataxia with a wide base, and symptoms progressed to death. In the cerebellum, histological analysis showed presence of more Purkinje cells, granular cells and fibers, and neuronal cells in treated Npc1-/- compared to untreated Npc-/- mice (Fig 4). Filipin staining showed the accumulation of unesterified cholesterol in the liver of untreated Npc1-/- mice. Livers of AAV-treated Npc1-/- mice showed weaker staining than untreated Npc1-/- mice (Fig 5).",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e8459873-2577-43ff-966c-e5180683d4f4-2022-03-01T170000.000Z,2830,PubMed:33256498 +Rescue of phenotype on NPC2 mice by NPC2 protein,Rescue Non-human model organism,"Nielsen GK, et al., 2011, PMID: 22073306","Three-week-old NPC2 −/− mice received twice weekly intravenous injections of 5 mg/kg NPC2 until trial termination 66 days later. +NPC2-treated NPC2−/− mice had significant reductions in cholesterol storage in liver, spleen and lung when compared to saline-treated NPC2-/- animals, exhibiting partial correction in storage by NPC2 treatment. +In contrast to the accumulation of lipid-laden foam cells observed on histological analyses of visceral organs in saline-treated NPC2-/- mice, the appearance of liver and spleen from NPC2-treated NPC2−/− mice was similar to those of wild type mice (Fig. 5, 6). In lung, saline-treated NPC2−/− mice had findings consistent with alveolar lipoproteinosis while NPC2 treatment led to a reduction in macrophage infiltration and PAS-positive material, and improvement in alveolar architecture (Fig 7). +Weight gain was slightly improved as a result of the NPC2 treatment but significant motor coordination deficits were still observed. Ultrastructural cerebellar abnormalities were detected in both saline treated and NPC2 treated NPC2 −/− animals at 87 days of age. The data suggest that protein replacement may be beneficial in the treatment of the visceral manifestations in NPC2 disease and further suggest that neurodegeneration is not secondary to visceral dysfunction.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_82bb23dd-d3bc-478d-bb3d-d1928e810029-2022-04-05T160000.000Z,2831,PubMed:22073306 +Nsun2 knockout mouse model,Model Systems Non-human model organism,"Blanco S, et al., 2011, PMID: 22144916",Nsun2-/- mice exhibited small size and infertility.,Score,0.5 (2),This mouse model recapitulates two features observed in affected individuals. They also had reduced brain size due to excessive cell death in the prenatal brain. The score was downgraded due to the lack of characterization of nervous system deficits.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c6878f90-f485-4c44-95d3-a33b0ec9f66f-2023-10-18T160000.000Z,2832,PubMed:22144916 +NSun2 deletion causes neurodevelopmental defects in mice,Model Systems Non-human model organism,"Blanco S, et al., 2014, PMID: 25063673","NSun2-/- mice showed a reduction of spontaneous alternations in the Y maxe test, which suggests deficient spatial working memory.",Score,1.5 (2),This same mouse model was reported in Blanco et al. (2011) as exhibiting small size and infertility and awarded 0.5 points (see below). We are awarding 1.5 points to these new findings so overall the knockout model gets the default 2 points.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c6878f90-f485-4c44-95d3-a33b0ec9f66f-2023-10-18T160000.000Z,2832,PubMed:25063673 +Neuronal Nsun2 deficiency in mice,Model Systems Non-human model organism,"Blaze J, et al., 2021, PMID: 34389722","Mice with conditional ablation of Nsun2 in excitatory neurons (CamK-Cre+,Nsun22lox/2lox mutant mice) exhibited a decrease in tRNA cytosine methylation in the adult cortex and glycine codon-specific defects in translational efficiency. This caused decreased expression of glycine-rich synaptic proteins critical for glutamatergic neurotransmission, associated with impaired synaptic signaling at prefrontal cortex pyramidal neurons and defective contextual fear memory. Changes in the neuronal translatome were also associated with an increase in glycine biosynthesis in the mutant cortex.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c6878f90-f485-4c44-95d3-a33b0ec9f66f-2023-10-18T160000.000Z,2832,PubMed:34389722 +Rescue of Pde6a-mutant dogs with canine Pde6a,Rescue Non-human model organism,"Mowat FM, et al., 2017, PMID: 28676737","Rod ERG response shows improvement from undetectable to detectable following AAV-Pde6a injection (Fig. 1). Visual impairment also improved according to visual navigation ability (Fig. 2). Attenuation of retinal blood vessels was prevented as well (Fig. 3). Photoreceptor outer nuclear layer thickness was preserved (Fig. 4). Finally, treatment promoted rod photoreceptor survival (Fig. 5).",Score,2 (2),Default points have been awarded as the number of phenotypes rescued and the degree of rescue make a convincing case that biallelic variants in Pde6a are the underlying cause of disease in this animal model.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_165bc0fc-d0ce-4a74-a953-8d4687fbaa96-2022-12-01T170000.000Z,2836,PubMed:28676737 +The macaque model harbors a homozygous LOF variant in PDE6C.,Model Systems Non-human model organism,"Moshiri A, et al., 2019, PMID: 30667376","This is a naturally occurring macaque model that matches the autosomal recessive mode of inheritance from the human patients (Figure 7) and exhibits reduced visual acuity (Supplemental Video 1), lack of light-adapted ERG responses and normal dark-adapted ERG responses (Figures 1A-1E, Figure 2). The affected animals also exhibit progressive macular atrophy consistent with achromatopsia (Figure 3). Reduced foveal thickness was also observed (Figures 4A, 4B), as well as thinning of the outer nuclear layer and photoreceptor outer segments (Figures 5A, 5B).",Score,3 (2),The model has been up-scored as its phenotypes are comprehensive and represent a nearly complete match to the human patient clinical features.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_73ed48ac-bdd6-4608-953d-773da6ade759-2023-11-02T160000.000Z,2837,PubMed:30667376 +Jentzsch_2023: Pde6g-/- mouse,Model Systems Non-human model organism,"Jentzsch MC, et al., 2023, PMID: 37363133","This Pde6g-/- mouse model recapitulates the findings in human retinopathy. Specifically, with its early onset and rapid time course, these mice mimic the early and severe onset in patients with biallelic variants in PDE6G.",Score,1 (2),"Score reduced because, although detailed histology was provided, there were no additional analyses such as ERG.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b5b69965-33e0-4a8c-b5dd-faede6c39912-2024-06-06T160000.000Z,2838,PubMed:37363133 +Castillon_PGAP3/2 Protein Interaction,Protein Interaction,"Castillon GA, et al., 2013, PMID: 23615438","C-terminally tagged PGAP3 constructs, PGAP3-EGFP and PGAP3-HA, can be specifically co-precipitated by FLAG-tagged PGAP2. Since the amount of tagged PGAP3 that co-precipitated was low, it was not excluded that endogenous, nontagged PGAP3, interacts with PGAP2 more efficiently than C-terminally tagged PGAP3.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c63978db-fe31-489a-985c-6b353f0d5243-2023-09-05T060000.000Z,2840,PubMed:23615438 +Da'as _ Zebrafish Model Organism,Model Systems Non-human model organism,", , PMID: 32726939","Pgap3 morphants displayed defective neural tube formation during the early stages of nervous system development, affecting brain morphogenesis. The significant abnormal midbrain and hindbrain formation demonstrated by separation of the left and right tectal ventricles, defects in the cerebellar corpus, and caudal hindbrain formation disrupted oligodendrocytes expression leading to shorter motor neurons axons. Assessment of zebrafish neuromuscular responses revealed epileptic-like movements at early development, followed by seizure-like behavior, loss of touch response, and hypotonia, mimicking the clinical phenotype human patients. These are the clinical hallmarks and developmental defects seen in HPMRS4 patients, suggesting a novel and essential role of PGAP3 at the early stages of brain development and morphogenesis.",Score,1 (2),Downgraded for being a non-mammalian organism.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c63978db-fe31-489a-985c-6b353f0d5243-2023-09-05T060000.000Z,2840,PubMed:32726939 +KO Mouse,Model Systems Non-human model organism,"Dickinson ME, et al., 2016, PMID: 27626380",Both mice and humans had abnormal metabolic profiles with phosphohydroxylysinuria in humans and decreased circulating creatinine in the mice.,Score,0 (2),"The homozygous knockout mouse, from the International Mouse Phenotyping Consortium, was not tested for phosphohydroxylysinuria so recapitulation of patient phenotypes is unkown.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_82ba1358-e58c-4187-bbe7-0f1bf41267d0-2023-11-17T170000.000Z,2841,PubMed:27626380 +PIGA iPSCs,Model Systems Cell culture model,"Yuan X, et al., 2017, PMID: 28441409","The model demonstrates alterations in characteristics of neurons, the relevant substrate for the human neurological phenotype.",Score,0 (1),"While an effect is demonstrated, the relationship of this effect to epilepsy and neurodevelopmental disability is speculative.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1fbb591b-eb34-4b73-a741-2f101886c896-2024-04-16T170000.000Z,2842,PubMed:28441409 +Drosophila models of PIGA-CDG,Model Systems Non-human model organism,", , PMID: 37961693","While evaluating climbing ability as a general measure of neurological function, a subset of flies were noted to have seizure-like activity preventing climbing activity. Performed the bang-sensitive assay (commonly used measure of seizure susceptibility in flies) which showed 35% of PIG-A+/− flies have seizure activity compared with zero seizures in the WT flies. Neuron-specific knockdown resulted in reduced lifespan and neurological phenotypes but no seizures while glia-knockdown reduced lifespan and resulted in a seizure phenotype in 70%. The human phenotype includes seizures in nearly all patients reported so far (PMID 25326635 reports a patient not noted to have seizures) whereas only a subset of flies have seizures.",Score,0.5 (2),Downgrading since drosophila are not a well established model for human seizures (non-vertebrate).,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1fbb591b-eb34-4b73-a741-2f101886c896-2024-04-16T170000.000Z,2842,PubMed:37961693 +R749H mouse model,Model Systems Non-human model organism,"Maslon MM, et al., 2019, PMID: 30988016",Early embryonic death of zygotes carrying a CRISPR/Cas9 p.R749H mutation (hom or het) supports the pathogenicity of missense variants in POLR2A but does not align with the phenotypes seen in humans with similar missense variants (i.e. p.Thr736Met and p.Ser755del),Score,0 (2),Embryonic lethality is not similar to the phenotype observed in humans.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_45cab675-1ca5-4c25-97a9-bfeeeb1e112a-2024-03-15T160000.000Z,2851,PubMed:30988016 +R749H mESCs and neurons,Model Systems Cell culture model,"Maslon MM, et al., 2019, PMID: 30988016",Several genes shown misregulated in R749H mouse neurons have a human ortholog linked to phenotypes similar to those seen in individuals carrying de novo POLR2A missense mutations. Examples include: CNTNAP2(OMIM604569) NRXN1(OMIM600565) KIAA0442(OMIM607270) and SYN1(OMIM313440),Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_45cab675-1ca5-4c25-97a9-bfeeeb1e112a-2024-03-15T160000.000Z,2851,PubMed:30988016 +CRIPSR/CAS9 generated sheep,Model Systems Non-human model organism,"Eaton SL, et al., 2019, PMID: 31289301","Vision loss, early death in infancy, and reduced PPT1 activity is observed in human patients as well as in the model organism.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ae7ebc05-9401-4932-afe2-a80e0d31e12f-2024-06-10T190000.000Z,2858,PubMed:31289301 +PRPF8 mutations impact BRR2 interaction,Functional Alteration Non-patient cells,"Maeder C, et al., 2009, PMID: 19098916",reduced yeast growth,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b9efbbc3-6ce1-4f92-8472-627c2060dd88-2023-04-06T160000.000Z,2861,PubMed:19098916 +Structural modeling of Brr2 and PRPF8 interaction,Protein Interaction,"Nguyen TH, et al., 2013, PMID: 23727230",Both cause AD RP and physically interact.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b9efbbc3-6ce1-4f92-8472-627c2060dd88-2023-04-06T160000.000Z,2861,PubMed:23727230 +Sliceosome iCLIP,Biochemical Function A,"Wickramasinghe VO, et al., 2015, PMID: 26392272",depletion of BRR2/SNRNP200 strongly phenocopies splicing deficits seen in PRPF8 depletion,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b9efbbc3-6ce1-4f92-8472-627c2060dd88-2023-04-06T160000.000Z,2861,PubMed:26392272 +drosophila model of RP using PRPF8 RP mutations from human,Model Systems Non-human model organism,"Stanković D, et al., 2020, PMID: 32424050",tissue specific impact of PRPF8 mutations,Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b9efbbc3-6ce1-4f92-8472-627c2060dd88-2023-04-06T160000.000Z,2861,PubMed:32424050 +Gene expression/splicing: Fibroblasts vs. PRPF8 patients,Functional Alteration Patient cells,"Arzalluz-Luque Á, et al., 2021, PMID: 33994920",splicing differences between control and patient cell line,Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b9efbbc3-6ce1-4f92-8472-627c2060dd88-2023-04-06T160000.000Z,2861,PubMed:33994920 +PRPF8 expression in iPSC-RPEs from RP patient and control,Expression A,"Arzalluz-Luque Á, et al., 2021, PMID: 33994920",immunohistochemistry in iPSC-RPEs shows PRPF8 in control and RP patients,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b9efbbc3-6ce1-4f92-8472-627c2060dd88-2023-04-06T160000.000Z,2861,PubMed:33994920 +Immunoprecipitation,Protein Interaction,"Hume AN, et al., 2001, PMID: 11266470","myosinVa coimmunoprecipitates with anti-Rab27a antibodies from melanocytes and mouse tissues. Immunofluorescence microscopy showed that Rab27a and myosinVa colocalize in wild-type melanocytes, but absent from melanosomes in Rab27a mutant ashen melanocytes.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_85b7d8d2-1d22-44f3-9b24-580b42d69300-2023-10-31T040000.000Z,2864,PubMed:11266470 +Cytotoxicity and secretion assay,Model Systems Non-human model organism,"Stinchcombe JC, et al., 2001, PMID: 11266472",Immunoblot of cell lysates from ashen mice exhibits no detectable endogenous Rab27a. Cytotoxicity and secretion assays show that ash/ash cytotoxic T lymphocytes CTLs are unable to kill target cells or secrete granzyme A and hexosaminidase.,Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_85b7d8d2-1d22-44f3-9b24-580b42d69300-2023-10-31T040000.000Z,2864,PubMed:11266472 +Construction of Expression Plasmids and Transfection,Rescue Patient cells,"Bahadoran P, et al., 2001, PMID: 11266474","Re-expression of Rab27a in GS melanocytes restored melanosome transport to dendrite tips, leading to a phenotypic reversion of the diseased cells.",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_85b7d8d2-1d22-44f3-9b24-580b42d69300-2023-10-31T040000.000Z,2864,PubMed:11266474 +Immunofluorescence study,Expression B,"Bahadoran P, et al., 2001, PMID: 11266474","Immunofluorescence studies with an anti–TRP-1 antibody confirmed the biased distribution of melanosomes in GS melanocytes and evidenced the absence of accumulation of melanosomes at their dendrite tips. Immunofluorescence study failed to detect Rab27a in GS melanocytes. The results show that these GS melanocytes have an abnormal distribution of melanosomes and a normal expression of myosin-V, but no expression of Rab27a.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_85b7d8d2-1d22-44f3-9b24-580b42d69300-2023-10-31T040000.000Z,2864,PubMed:11266474 +Altered prefrontal cortex dev. in heterozygous reeler mice,Model Systems Non-human model organism,"Iafrati J, et al., 2014, PMID: 23752244",This study showed that fear memory erasure persists until adolescence in heterozygous reeler mice. This behavioral abnormality is concomitant to reduced dendritic spine density and anomalous long-term potentiation in the prefrontal cortex. A single injection of ketamine during the juvenile period reinstates normal fear memory in adolescent mice and restores normal spine density and synaptic plasticity.,Score,0 (2),This model is another demonstration of changes in fear based learning in heterozygous reeler mice. This evidence is not scored because the significance of heterozygous LoF variants in humans is unclear.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c654081c-5abd-4f86-a3f7-90d7f117b93d-2023-07-19T060000.000Z,2866,PubMed:23752244 +Differential methylation at RELN gene promoter in autism,Functional Alteration Patient cells,"Lintas C, et al., 2016, PMID: 27134686",The upstream promoter region was methylated specifically in ASD brains wile a downstream region is methylated only in controls,Score,0 (1),This study shows that there may be some epigenetic link between the RELN gene and ASD based on an increase in methylation at the promoter region in ASD-patient derived brain tissues. Not scored because epigenetic factors are not part of this assessment of mendelian inheritance.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c654081c-5abd-4f86-a3f7-90d7f117b93d-2023-07-19T060000.000Z,2866,PubMed:27134686 +iPSCs with RELN deletion CNV altered neuronal migration,Functional Alteration Patient cells,"Arioka Y, et al., 2018, PMID: 30022058","iPSC-derived neurons from a patient with schizophrenia with a heterozygous intragenic deletion in RELN, maternally-inherited. Used a single cell tracking assay to look at the movement of neuronal migration of iPSc neurons with a rare deletion variant identified in a patient with schizophrenia. They found that neurons heterozygous for the RELN deletion had impaired directionality of dopaminergic neuronal migration. RELN-del triggered an impaired reelin signal and decreased the expression levels of genes relevant for cell movement in human neurons. Single-cell trajectory analysis revealed that control neurons possessed directional migration even in vitro, while RELN-del neurons demonstrated a wandering type of migration.",Score,0 (1),iPSC-derived neurons from a patient with a RELN intragenic deletion were found to have impaired migration that may be indicative of its role in complex neurodevelopmental disorders. These findings should be counted for the autosomal recessive lissencephaly curation as they pertain to neuronal migration.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c654081c-5abd-4f86-a3f7-90d7f117b93d-2023-07-19T060000.000Z,2866,PubMed:30022058 +Mouse model,Model Systems Non-human model organism,"Zhao B, et al., 2016, PMID: 27269051",Hearing loss in the homozygous mutant reflected that of humans with the condition.,Score,3 (2),There are multiple pieces of evidence in this article (multiple pieces of mechanotransduction/signal evidence).,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ed7e0813-4e94-40a9-b3ef-ef90d5c4dce4-2024-05-15T160000.000Z,2867,PubMed:27269051 +Guinea Pig Models,Model Systems Non-human model organism,"Zhang J, et al., 2020, PMID: 34008309","Ectopic expression of ROR1 prevents cochlear hair cell loss in guinea pigs with noise-induced hearing loss. Overexpression of ROR1 could up‐regulate Wnt5a, which in turn led to activation of the NF‐κB signalling pathway, thus acting to inhibit the apoptosis of cochlear hair cells.",Score,0 (2),Noise-induced hearing loss is not synonymous with sensorineural hearing loss,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_fdee1ffc-d8bd-4188-acb6-5fad8f5902a6-2022-06-15T040000.000Z,2870,PubMed:34008309 +Dickinson et al. 2016,Model Systems Non-human model organism,"Dickinson ME, et al., 2016, PMID: 27626380","Hydrocephalus (in the mouse model), the build up of fluid is similar to Bronchiectasis (respiratory/mucus build up in humans). Likewise, sinusitis in the mouse model matches with the sinusitis and other respiratory conditions typical of human PCD patients.",Score,1 (2),The mice are unable to produce the lower respiratory phenotypes that humans have.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_25b8ea38-8de2-45b7-95a1-51b33affb747-2023-10-12T160000.000Z,2874,PubMed:27626380 +Sedykh et al. 2016,Biochemical Function B,"Sedykh I, et al., 2016, PMID: 27687975",Supplemental Figure 8 shows the localization of RSPH9 in hair cell kinocilia.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_25b8ea38-8de2-45b7-95a1-51b33affb747-2023-10-12T160000.000Z,2874,PubMed:27687975 +Zou et al. 2020,Model Systems Non-human model organism,"Zou W, et al., 2020, PMID: 32709945","Hydrocephalus (in the mouse model), the build up of fluid is similar to Bronchiectasis (respiratory/mucus build up in humans). Likewise, sinusitis in the mouse model matches with the sinusitis and other respiratory conditions typical of human PCD patients.",Score,1 (2),The mice are unable to produce the lower respiratory phenotypes that humans have.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_25b8ea38-8de2-45b7-95a1-51b33affb747-2023-10-12T160000.000Z,2874,PubMed:32709945 +Aprea et al. 2023,Biochemical Function A,"Aprea I, et al., 2023, PMID: 36873931","PMID: 24518672 documents how RSPH1 and RSPH9, which encode homologs of components of the ‘head’ structure of ciliary radial spoke complexes identified in Chlamydomonas, cause clinical phenotypes that appear to be indistinguishable except at the gene level. They both also have a relationship with PCD.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_25b8ea38-8de2-45b7-95a1-51b33affb747-2023-10-12T160000.000Z,2874,PubMed:36873931 +Aprea et al. 2023,Biochemical Function B,"Aprea I, et al., 2023, PMID: 36873931",???,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_25b8ea38-8de2-45b7-95a1-51b33affb747-2023-10-12T160000.000Z,2874,PubMed:36873931 +Mouse model,Model Systems Non-human model organism,"Pang B, et al., 2022, PMID: 35887274","In the mouse model, the seizures were triggered (not spontaneous)",Score,0 (2),No spontaneous seizures were detected.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_cd76888e-9502-48f3-af06-56f1ae5ed975-2024-05-07T170000.000Z,2885,PubMed:35887274 +Yoshimura Expression,Expression A,"Yoshimura H, et al., 2014, PMID: 24676347","This study investigated the expression patterns of deafness gene in mouse cochlea using a microarray. The study found that SLC17A8 is expressed throughout the cochlea but it is not expressed evenly. The gene is expressed 3x more in the apex than in the base according to microarray analysis. If ADSNHL is caused by haploinsufficiency in this gene, the patient would theoretically begin to lose high frequency hearing abilities before lower frequency abilities. The reports in the literature have so far been consistent with this prediction.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_8c399400-090a-4b2e-93ff-0c4915ce81c7-2023-06-01T160000.000Z,2887,PubMed:24676347 +Mk adherence,Functional Alteration Patient cells,"Barozzi S, et al., 2021, PMID: 33054137","Differently from previous findings,3 proplatelet formation (PPF) of mutant Mk in suspension liquid cultures was comparable to controls (Figure 1D-E). However, when Mk were let adhere to fibrinogen or type I collagen, two components of the BM ECM that regulate platelet formation, mutant Mk exhibited a markedly increased adhesion and spreading, often with aberrant morphology. This prominent adhesion phenotype was associated with an increased number and density of podosomes, i.e., the actin-based focal adhesion structures that mediate Mk contact with ECM proteins. Importantly, in adhesion to fibrinogen, an ECM substrate that promotes PPF,8,9 the increased spreading of the patient’s Mk was associated with a significantly reduced extension of typical proplatelets. Finally, using a modified transwell assay, we found that patient Mk presented a significantly impaired SDF1-driven migration both in adhesion to fibrinogen and type I collagen.",Score,1 (1),"Provided evidence that thrombocytopenia derives from an altered interaction of Mk with the ECM components. Since actin cytoskeleton reorganization after Mk interaction with the ECM is crucial for proplatelet extension, an altered cytoskeletal rearrangement upon Mk adhesion to fibrinogen, due to SRC constitutive activation, likely underlies the impaired PPF.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3420133d-7a37-4f76-a3e7-6b9a0bc3803e-2024-06-03T160000.000Z,2893,PubMed:33054137 +Synapsin knockout mice,Model Systems Non-human model organism,"Greco B, et al., 2013, PMID: 23280234",Both knock-out mice and human patients have ASD-related phenotypes,Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ca5a3e64-5daa-4a2f-876d-4e7648c53ff8-2023-04-05T180000.000Z,2898,PubMed:23280234 +Function study of p.W356* variant,Functional Alteration Non-patient cells,"Giannandrea M, et al., 2013, PMID: 23818987","In cells positive for expression of the EYFP-tagged W3566* Syn I, the mutant protein was uniformly dispersed throughout the neuronal cytoplasm, in the absence of any polarized distribution toward the axonal domains.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ca5a3e64-5daa-4a2f-876d-4e7648c53ff8-2023-04-05T180000.000Z,2898,PubMed:23818987 +Expression in hair cells,Expression A,"Tona R, et al., 2020, PMID: 32987832","In hair cells, TBC1D24 expression is detected only in human temporal bone sections from deceased presumably normal hearing individuals, while it was undetectable in mouse hair cells.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_cd496a45-5ae0-4e56-8a3d-2c410a5bd0c8-2024-06-25T160000.000Z,2899,PubMed:32987832 +KO Mouse,Model Systems Non-human model organism,"Kanai M, et al., 2009, PMID: 19323847","Trp levels in plasma were 9.3-fold higher in Tdo-/- than Tdo+/+ mice. Additionally 5-HIAA (the catabolic product of Trp via the serotonin pathway) was much higher in the knockout. This is consistent with the increased levels of tryptophan and serotonin observed in the human patient. Tryptophan levels in knockout mice were also higher in the hippocampus and midbrain. TDO was also shown to modulate anxiety-related behaviors, as revealed by two classical behavioral tests, in the mice which has not been shown in humans.",Score,2 (2),"Knockout mice recapitulated increased plasma levels of tryptophan and serotonin. Increased tryptophan levels have also been reported in knockout mice in the brain, liver (PMID: 27392942), and urine (PMID: 25035993).",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b20a4b6d-c43c-4397-bbd2-3d4c6ea6f0e0-2023-11-17T170000.000Z,2901,PubMed:19323847 +TECR mutation alters activity of Ca2+ pump,Protein Interaction,"Uchida Y, et al., 2021, PMID: 33482198","TECR interacts with ATP2A2 (SERC2A) which encodes a Calcium pump in the ER that regulates myelin function and impacts neural function, learning, and memory",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_8c7adee2-6a14-4348-a018-9097954bd39d-2022-03-10T070000.000Z,2902,PubMed:33482198 +Rescue of Complex Abnormalities in TIMMDC1 Patient cells,Rescue Cell culture model,"Kremer LS, et al., 2017, PMID: 28604674","Western Blot with TIMMDC1 absence (and reduction in NDUFB8, NDUFB3, NDUFA13), which was rescued with re-expression of WT TMMDC1 in patient fibroblasts +Patient #96687 also had rescue on BN PAGE of complex I with re-expression of TIMMDC1",Score,2 (1),"0.5 Patient #35791 rescue by western blot of TIMMDC1 and other complex I subunits +0.5 - Patient #66744 rescue by western blot of TIMMDC1 and other complex I subunits +1 - Patient #96687 rescue by western blot of TIMMDC1 and other complex I subunits + rescue of BN PAGE abnormalities",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d27e1ad8-d7b4-466e-bd70-9363abd2f31c-2024-02-22T050000.000Z,2907,PubMed:28604674 +"TP53 Nutlin, Etoposide Domainant Negative / LOF Screen",Functional Alteration Non-patient cells,"Giacomelli AO, et al., 2018, PMID: 30224644","Giacomelli et al created a massive library of all possible missense and nonsense mutations in TP53 (8258). The authors created isogenic TP53-WT (p53WT) and -null (p53NULL) A549 human lung carcinoma cell populations using CRISPR-Cas9-mediated gene editing. The authors added two p53-activating agents, nutlin-3 and etoposide, as well as WT TP53, and performed pooled positive-selection screens designed to enrich for dominant-negative (DN), loss-of-function (LOF), or WT-like alleles.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_78494aba-bb52-4b33-bf1d-ebbb5374df4b-2024-03-22T170000.000Z,2913,PubMed:30224644 +Pleines - Mouse,Model Systems Non-human model organism,"Pleines I, et al., 2017, PMID: 28134622","Humans harboring a heterozygous TPM4 variant and Tpm4+/- mice both exhibit decreased platelet counts with large platelet volumes. Western blots of both human and mice demonstrated decreased expression of Tpm4 protein. Transmission electron microscopy of mice platelets demonstrated large platelets with large vacuoles, which is noted in humans harboring variants in this gene. Both humans and mice demonstrated reduced thrombus formation under flow. Proplatelet formation was decreased in mice in a dose dependent manner. Tail bleeding times of mice were increased in mice with homozygous trunctation.",Score,2 (2),"The mouse model recapitulated the phenotype seen in humans with heterozygous variants in TPM4 including decreased platelet size, increased platelet volume, bleeding tendency, decreased thrombus formation on collagen under flow and impaired proplatelet formation.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0b8bb90f-f190-4e20-8f65-27d236cb7d79-2024-05-01T160000.000Z,2914,PubMed:28134622 +Pleines - Expression,Expression B,"Pleines I, et al., 2017, PMID: 28134622","Western blot analysis measured protein level of controls as well as individuals harboring the R105* (R69*) variant in TPM4. A 50% reduction of expression is noted in individuals with the nonsense variant in TMP4 as compared to controls. Additionally, mRNA levels were measured using RT-PCR and were reduced to 59%-78% of the control.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0b8bb90f-f190-4e20-8f65-27d236cb7d79-2024-05-01T160000.000Z,2914,PubMed:28134622 +MuRF1 relationship to hypertrophic response,Biochemical Function B,"Arya R, et al., 2004, PMID: 15596539","Overexpression of the MuRF1 gene results in reduced hypertrophic response to phenylephrine, which is what you would expect as the reverse of loss-of-function mutations in this gene (which have been associated with the development of hypertrophic cardiomyopathy).",Score,0 (0.5),Scored 0 points as max scoring for functional evidence has already been reached.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9e8365b8-3238-4844-8392-58f66be7f318-2024-06-06T160000.000Z,2919,PubMed:15596539 +conditional mouse model,Model Systems Non-human model organism,"Zhang C, et al., 2018, PMID: 30354230","Early loss of TSPAN12 in endothelial cells causes lack of intraretinal capillaries and increased VE-cadherin (CDH5 [cadherin5 aka VE-cadherin]) expression, consistent with premature vascular quiescence.",Review,2 (2),Not scored because a previous mouse model has been scored.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9c7915a6-c4eb-47c7-9c51-a81279b6e6a4-2022-01-06T170000.000Z,2921,PubMed:30354230 +Retinal Organoid expression,Expression A,"Cowan CS, et al., 2020, PMID: 32946783","Figure S7 shows TTLL5 is expressed most highly in cones of peripheral retina, foveal retina and developed organoids",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_db2083b7-fe3d-459e-8874-35ed9ebb0785-2023-10-05T160000.000Z,2924,PubMed:32946783 +Fetal-specific expression of exons 213-217,Expression A,"Savarese M, et al., 2018, PMID: 29598826",Total mRNA sequencing data from the ENCODE project indicates expression of TTN exons 213 and 217 is increased in fetal skeletal and cardiac muscle tissue compared to adult skeletal and cardiac muscle tissue.,Score,0.5 (0.5),Multiple individuals with variants affecting TTN exons 213-217 have been reported in the literature with metatranscript-only TTN variants and prenatal muscle phenotypes that do not progress or progress only minimally in childhood. The enhanced expression of these exons in fetal muscle tissue suggests these variants may alter TTN function in fetal development.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_41ead80d-f134-43e5-9373-ac55bdcfc0a1-2022-01-11T170000.000Z,2925,PubMed:29598826 +UROC1 Unique Liver Expression,Expression A,"Glinton KE, et al., 2019, PMID: 30619714","According to a global classification of RNA-Seq data, the family of urocanases is almost exclusively expressed in the liver (PMID:24309898). Likewise, the Human Protein atlas indicates that UROC1 protein and RNA expression is unique to the liver in the human body. Since the proposed pathogenic mechanism of urocanic aciduria is the inability to metabolize urocanic acid produced via metabolism, this unique expression is directly related to the potential mechanism and phenotypes observed.",Score,0.5 (0.5),"As urocanase is expressed solely in the liver, a tissue directly relevant to the pathogenic mechansim and resulting biochemical abnormality, this evidence recieves default points.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_af2ff293-39ce-46b7-af58-01e3685f4334-2024-04-26T160000.000Z,2926,PubMed:30619714 +UROC1 in Histidine Metabolism,Biochemical Function B,"Glinton KE, et al., 2019, PMID: 30619714","Defects in this section of histidine metabolism would certainly cause the biochemical abnormality characteristic of this disorder, urocanic aciduria, due to the buildup of the metabolite directly before this step in the pathway.",Score,2 (0.5),"As the function of urocanase in histidine metabolism is very well-characterized, and the biochemical abnormality characteristic of the disorder is a direct result of the loss-of-function in this enzyme, this evidence scores maximum points.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_af2ff293-39ce-46b7-af58-01e3685f4334-2024-04-26T160000.000Z,2926,PubMed:30619714 +Mouse model,Model Systems Non-human model organism,"Cui C, et al., 2013, PMID: 24302887",Similar to BBS/MKS1 syndromes seen in patients.,Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_2569ec01-fad8-47ee-ba7b-4ad4fb534c9a-2024-03-07T170000.000Z,2929,PubMed:24302887 +Mouse knockout,Model Systems Non-human model organism,"Toriyama M, et al., 2016, PMID: 27158779",Phenotypes seen in mice are features of ciliopathy symptoms seen in patients.,Review,2 (2),The other mouse model (PMID: 24302887) was scored to avoid duplication.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_2569ec01-fad8-47ee-ba7b-4ad4fb534c9a-2024-03-07T170000.000Z,2929,PubMed:27158779 +Cochlear and Vestibular Expression,Expression A,"Ebrahim S, et al., 2016, PMID: 27117407","The long transcript is expressed in the retina, vestibule and cochlea, whereas the C-terminal transcript is expressed exclusively in the cochlea and vestibule and the N-terminal transcript is expressed exclusively in the retina (Ebrahim et al. 2016, PMID: 27117407).",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3188ec93-954a-4daa-b99d-7c5fccad8e1a-2024-01-17T170000.000Z,2931,PubMed:27117407 +Ebrahim Whrn(tm1b/tm1b) Model,Model Systems Non-human model organism,"Ebrahim S, et al., 2016, PMID: 27117407","Exon 4 of Whrn is deleted and a cassette including a β-galactosidase reporter (lacZ) is inserted into intron 3. The C-terminal transcript of WHRN is predicted to be affected. 14 week-old mice showed profound impairment only at higher frequencies (24-30 kHz), and only moderate impairment at lower frequencies. Mice do not have vestibular abnormalities. Hearing loss is not progressive between 4 and 14 weeks. OHC stereocilia bundles are affected but IHCs appear normal. .",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3188ec93-954a-4daa-b99d-7c5fccad8e1a-2024-01-17T170000.000Z,2931,PubMed:27117407 +Ebrahim Animal Model,Model Systems Non-human model organism,"Ebrahim S, et al., 2016, PMID: 27117407",Whrn(w/wi) mice are profoundly deaf and exhibit headbobbing and circling characteristic of vestibular dysfunction. Heterozygous mice had AR thresholds comparable to wildtype suggesting disease is entirely recessive.,Score,2 (2),The Whrn(wi/wi) mouse model is consistent in variant location and phenotype with patients. This mouse model is scored for the ARNSHL gene-disease pair. All other Whrn mouse models were assessed and concluded not to be scored for this curation due to phenotyping and variant location/impact.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3188ec93-954a-4daa-b99d-7c5fccad8e1a-2024-01-17T170000.000Z,2931,PubMed:27117407 +Ebrahim Non-patient cells,Functional Alteration Non-patient cells,"Ebrahim S, et al., 2016, PMID: 27117407","In Whrn(wi/wi) mice, the IHC stereocilia were abnormally short and OHCs were rounded with irregular spacing between stereocilia rows. Whrn(tm1b/tm1b) OHC stereocilia bundles were similar to Whrn(wi/wi) mice, but the IHC stereocilia bundles appeared normal. WHRN-S (short C-terminal isoform) is necessary for normal IHC stereocilia length, but both WHRN-S and WHRN-L (long isoform) are required for normal OHC stereocilia bundle morphology.",Score,0 (0.5),Scoring as part of the animal model.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3188ec93-954a-4daa-b99d-7c5fccad8e1a-2024-01-17T170000.000Z,2931,PubMed:27117407 +Wnt5a in canonical and non-canonical signaling,Biochemical Function A,"Mikels AJ, et al., 2006, PMID: 16602827","The impact of Wnt5a ligand on Wnt signaling was studied in mouse cells and HEK293 cells. STF-luciferase assay was used as a readout of beta-catenin activity. Wnt3a expression activaed the canonical pathway. However, over-expression of Wnt5a inhibited canonical Wnt signaling by Wnt3a in mouse cells (Fig 1). Frizzled 4 receptor was exogenously expressed in 293 cells (293Fz4), and were treated with Wnt proteins, followed by assay for cytosolic beta-catenin protein accumulation via Western blot analysis. Wnt5a treatment led to beta-catenin stabilization specifically in cells expressing mFz4 (Fig 4a). Wnt5a at different dosage concentrations did not inhibit Wnt3a-mediated reporter activation in 293Fz4 cells (Fig 4c). TheWnt5a treatment also activated the STF reporter when LRP5 was coexpressed, but not when LRP6 was co-expressed (Fig 4b). Exogenous expression of mRor2 in HEK293 cells, followed by immunoprecipitation and STF-luciferase assay demonstrated that signaling through the Wnt5a-Ror2 interaction is required for inhibition of canonical Wnt signaling (Fig 5 and 6).ROR2 is the receptor for WNT5A (PMID 12839624).",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0fb2940f-f0e0-442c-beb8-72fc959d5a43-2024-04-25T160000.000Z,2932,PubMed:16602827 +Xpnpep3-KO mice,Model Systems Non-human model organism,"Tong L, et al., 2023, PMID: 37599822",KO of Xpnpep3−/− in vivo recapitulated the NPHPL-like phenotype with mitochondrial dysfunction and ciliary defects.,Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c1fd65c6-6010-4ee7-bb1c-e347c539127c-2024-06-10T160000.000Z,2933,PubMed:37599822 +Complementation of MRPS25 Patient FCL,Rescue Cell culture model,"Bugiardini E, et al., 2019, PMID: 31039582","In patient cells, transgenic MRPS25 was well tolerated and restored +MRPS gene levels (0.5) +Rescues 28S subunit (0.5) +Partial restoration of OXPHOS protein levels (0.5)",Score,1.5 (1),"In patient cells, transgenic MRPS25 was well tolerated and restored +MRPS gene levels (0.5) +Rescues 28S subunit (0.5) +Partial restoration of OXPHOS protein levels (0.5)",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9c0105a1-52a1-4674-b0d2-61bba99d1d9a-2024-06-20T040000.000Z,2935,PubMed:31039582 +RNA processing disorder impact on mitochondrial,Biochemical Function A,"Karasik A, et al., 2019, PMID: 31455609","All genes are associated with PMD +TRMT10C binds with PRORP +SLC25A46 is the SAM transporter (and this is a SAM dependent enzyme) +ELAC2 processes 3' end of RNAs +tRNAs",Score,2 (0.5),>10 genes interacting with mt-RNA processing,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3745add8-6f0f-4385-9422-afe1f3a80097-2024-04-15T040000.000Z,2936,PubMed:31455609 +"Rescue of PRORP in F3, II-1 Cells",Rescue Patient cells,"Hochberg I, et al., 2021, PMID: 34715011","Transduction with WT PRORP in F3, II-1 FCL increased PRORP and MT-CO1 on immunoblot +Transduction did not increase SDHA nor TRMT10C +Did not see increase with MT-CO1 or PRORP with transduction of TRMT10C or empty vector",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3745add8-6f0f-4385-9422-afe1f3a80097-2024-04-15T040000.000Z,2936,PubMed:34715011 +Mouse model TRMU knockout,Model Systems Non-human model organism,"Wu Y, et al., 2016, PMID: 27689697","0.5 - Laboratory examinations of 3-week-old mice revealed significantly elevated plasma levels of lactate, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in Mtu1LKO mice +0.5 – Markedly reduced translation in hepatocytes from Mtu1LKO (decrease in steady state levels of NDUFB8, MTCO1). +0.5 - Decreased activities of respiratory chain I (70%), III (67%), IV (52%), but not II (Statistically significant, and raw values don’t account for upregulated CS) +0.5 – In the livers of Mtu1LKO mice, the s2 modification was nearly absent in the three mt-tRNA +There was a trace of τm5s2-containing mt-tRNAs, but this result was most likely derived from non-hepatic cell +Note: Interestingly, these mt-tRNAs were partially s2-modified even in the livers of Mtu1Flox mice; 40~70% of the mt-tRNAGlu, mt-tRNAGln and mt-tRNALys contained τm5s2U and s2U modifications +Mitochondrial histology is abnormal with swollen or complete loss of cristae +16-week-old liver Mtu1 KO mice were alive and exhibited sustained liver function. Similar LFTs to 3-week-old liver KO, much higher than 16-week-old floxed mice",Score,2.5 (2),"Constitutive KO +Score 0.5 points from embryonic lethality +liver conditional KO +0.5 - Laboratory examinations of 3-week-old mice revealed significantly elevated plasma levels of lactate, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in Mtu1LKO mice +0.5 – Markedly reduced translation in hepatocytes from Mtu1LKO (decrease in steady state levels of NDUFB8, MTCO1). +0.5 - Decreased activities of respiratory chain I (70%), III (67%), IV (52%), but not II (Statistically significant, and raw values don’t account for upregulated CS) +0.5 – In the livers of Mtu1LKO mice, the s2 modification was nearly absent in the three mt-tRNA",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d025dc5a-fd47-4418-bd20-e2dca69e3308-2024-05-23T040000.000Z,2937,PubMed:27689697 +mttu-1 c. elegans studies,Model Systems Non-human model organism,"Navarro-González C, et al., 2017, PMID: 28732077","Complex I deficiency, slow growth",Score,0.5 (2),"Score 0.5 for c. elegans model, note that mttu-1 thiolates different mt-tRNAs than human TRMU",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d025dc5a-fd47-4418-bd20-e2dca69e3308-2024-05-23T040000.000Z,2937,PubMed:28732077 +D. rerio CRSIPR knockout of TRMU,Model Systems Non-human model organism,"Zhang Q, et al., 2018, PMID: 30137487","Saw thiouridylation in MT-TK, MT-TE, MT-TQ, but not MT-TL1 in WT +Similar to human +mtu1−/− mutant zebrafish exhibited the complete loss of 2-thiouridylation of mitochondrial tRNAGln, tRNAGlu, and tRNALys. +mtu1+/− mutant fish were 63%, 66% and 85% +Score 0.5 pt +loss of mtu1 caused the decreases in the steady-state levels of all seven mitochondrial tRNAs but not those of three cytoplasmic tRNA +Indicating a global effect on mt-tRNA metabolism +Also saw reduction in MT-ND1, MT-ND6, MT-CO2, ATP5A compared to control +Modest reduction in Sdhb as well. MT-CYB highest at 75% compared to control +Score 0.5: RC deficiency Complex I (39%), II (55%), III (83%), IV (41.4%), V (47%) +42% of -/- had abnormal swimming behavior or weak startle response +hair bundle densities in utricle, saccule and lagena +Eyes, muscle and brain did not show defects 5 dpf (days post fertilization)",Score,1 (2),score 0.5 points for abnormal thiouridylation and 0.5 points for respiratory chain defect,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d025dc5a-fd47-4418-bd20-e2dca69e3308-2024-05-23T040000.000Z,2937,PubMed:30137487 +Numerous Complex I subunits and Assembly Factors,Biochemical Function A,"Zhu J, et al., 2016, PMID: 27509854",All complex I subunits and assembly factors,Score,2 (0.5),>10 complex I subunits and assembly factors,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_64c32007-a9f5-4bf4-8694-8aba531341bf-2024-04-15T040000.000Z,2938,PubMed:27509854 +Embryonic lethal mouse model,Model Systems Non-human model organism,"Dickinson ME, et al., 2016, PMID: 27626380","Early lethality +NDUFS7 knockout is lethal by E9.5 in mice",Score,0.5 (2),Score 0.5 points for embryonic lethality,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_64c32007-a9f5-4bf4-8694-8aba531341bf-2024-04-15T040000.000Z,2938,PubMed:27626380 +V122M growth on galactose studies,Functional Alteration Patient cells,"Iannetti EF, et al., 2018, PMID: 30429455","FCL of patient cells proliferates in glucose but significantly reduced cell viability in galactose of NDUFS7 patient cells +Rescued cell death by pyruvate and exogenous NAD+ +Cellular ATP content decreased in galactose medium (but was averaged for all three patients – so not included in scoring)",Score,0.5 (1),Likely patient cells from PMID: 10360771; score 0.5 for reduced viability in galactose,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_64c32007-a9f5-4bf4-8694-8aba531341bf-2024-04-15T040000.000Z,2938,PubMed:30429455 +Drosophila RNAi knockdown of NDUFS7 (ND-20),Model Systems Non-human model organism,"Foriel S, et al., 2019, PMID: 30972103","Complex I deficiency in flies along with early lethality +Fifteen days after the transfer to the experimental vials, the total number of pupae and empty pupae were counted manually with a cell counter for each vial to evaluate the percentage of eclosion. +Significant Reductions in Complex I (rotenone sensitive ~40% of control) with upregulation of II, III, and IV at 25 °C +Pupal lethality 28°C +Percent of eclosed pupae minimal in NDUFs7 KD lines (<20% at 25 °C; and virtually 0% at 28°C)",Score,0.5 (2),Only score 0.5 for drosophila study,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_64c32007-a9f5-4bf4-8694-8aba531341bf-2024-04-15T040000.000Z,2938,PubMed:30972103 +Canis familiaris model,Model Systems Non-human model organism,"Christen M, et al., 2024, PMID: 38316835","Human patients have Leigh +Jack Russel Terrier x Chihuahua mixed breed littermates with ataxia dystonia, elevated lactate (6.8-9.5 mM) within first week of life, Leigh Syndrome +MRI: The lesions affected the caudate nuclei, cingulate gyri, rostral and caudal colliculi, lateral lemniscus, cerebellar cortex, cerebellar white matter, cerebellar nuclei, and multiple brainstem nuclei (olivary nuclei and pontine nuclei) +Brain histopathology: Histopathological investigations revealed the lesions on MRI to correspond to bilaterally symmetrical regions of subacute to chronic necrosis",Score,1 (2),Strong phenotypic overlap with human cases - score 1 point,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_64c32007-a9f5-4bf4-8694-8aba531341bf-2024-04-15T040000.000Z,2938,PubMed:38316835 +Drosophila with V179M,Model Systems Non-human model organism,"Christen M, et al., 2024, PMID: 38316835","No effect on survival and no adult flies seen (overexpression of WT unable to rescue lethality) +Analyzed impact on development (dark = more developed) +Analyzed dark pupae vs light pupae and saw a significantly reduced in % of dark pupae was seen with knockdown lines that were overexpressed with the V179M variant (~5%) compared to baseline knockdown (~50%). +Significantly increased number of dark pupae seen with overexpression of wild type (~85%), improvement compared to baseline KD",Score,0.5 (2),Score 0.5 points for drosophila study,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_64c32007-a9f5-4bf4-8694-8aba531341bf-2024-04-15T040000.000Z,2938,PubMed:38316835 +K78R knock-in mouse model,Model Systems Non-human model organism,"Colombo S, et al., 2023, PMID: 37275776",Variant-specific mouse model demonstrates features associated with developmental and motor delay (figure 1) and recapitulates a seizure phenotype that is often reported in individuals with GNB1-related neurodevelopmental disorders (figure 2). The seizure phenotype was demonstrated by EEG (figure 2) and further studied using P0 ex vivo cortical neurons (figure 3). The seizure phenotype of this mouse model was independently confirmed by a second group (PMID: 36405774).,Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_f83c8548-99d7-489d-8582-ac4ad5abd0ec-2023-08-16T040000.000Z,2939,PubMed:37275776 +Mouse Model of Cox6a2-/- phenotype,Model Systems Non-human model organism,"Quintens R, et al., 2013, PMID: 23460811","Isolated skeletal muscles of Cox6a2 −/− mice are more resistance to fatigue +The switch in muscle fiber composition towards a more oxidative profile in Cox6a2 −/− mice was also reflected by the mechanical properties of these muscles. The specific force production (force/cross-sectional area) of soleus and extensor digitorum longus (EDL) muscles (Fig. 7A), as well as the grip strength (Fig. 7B) were similar between WT and Cox6a2 −/− mice. However, in a fatiguing protocol, isolated soleus muscle of Cox6a2 −/− mice was more resistant to fatigue and recovered much faster as compared to WT muscle (Fig. 7D), which is consistent with an increase in oxidative muscle fibers. However, this was not reflected at the level of the whole animal since we observed that in an endurance experiment Cox6a2 −/− mice had decreased exercise capacity as compared to WT mice when running uphill. When mice were forced to run downhill there was no significant difference in performance, although there was again a tendency towards reduced performance in Cox6a2 −/− mice (Fig. 7C). We ascribe this discrepancy between the in vitro and in vivo muscle performance to the cardiac phenotype of these mice (i.e. diastolic dysfunction), which is only observed under high workloads [30]. Finally, despite the loss of COX6A2 expression, ATP levels within the skeletal muscles of Cox6a2 −/− and WT mice were similar (Fig. 7E), which is consistent with previous observations in the heart [30]. Thus, Cox6a2 −/− mice have developed compensatory mechanisms that allow production of sufficient amounts of ATP to perform mechanical work.",Score,0 (2),Conflicting exercise capacity results between Wt and homozygous deletion mice so not scored,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c09fbc40-dc5e-4cbd-80d1-1f918fffdceb-2024-03-18T040000.000Z,2943,PubMed:23460811 +Double knockout and subsequent Knock In of COX4I2 HEK293,Functional Alteration Non-patient cells,"Pajuelo Reguera D, et al., 2020, PMID: 32075102","MT-CO2 ~50% of parental cells line, similar results for COX5A and COX6C +In accordance with the quantification of the COX subunit contents (Figure 1C), the amount of the native COX complexes in the 4i1 and 4i2 KI cell lines corresponded to 54% and 61% of the COX level in parental HEK293, respectively. +In terms of maximal activity rates at 30 µM concentration of cytochrome c, 4i1 and 4i2 KI cell lines displayed equal values, corresponding to 55% and 52% of control HEK293 values, respectively (Figure 2A). But when normalized to COX2 content is comparable to parent cells",Score,0.5 (0.5),Score 0.5 for reduced COX subunits and decreased amount of COX,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_18fa1fc5-ce1b-4fec-9cc0-c94dd5c040c7-2024-03-18T040000.000Z,2945,PubMed:32075102 +HEK293 Cells COX4I1 Knockout,Functional Alteration Non-patient cells,"Čunátová K, et al., 2021, PMID: 33578848","COX4I1 and MT-CO2 were undetectable, COX5A and COX6C only barely detectable, and MT-CO1 significantly decreased in COX4I1 KO on western blot +Importantly, COX4I1 KO in HEK293 cells did not trigger expression of the alternative isoform COX4I2 +(As we showed previously [15], HEK293 cells (wt) do not show detectable levels COX4I2 protein) +Analysis of two technical replicates of two representative clones for each COX4I2 KO, COX4I1 KO, and COX4I1/4I2 KO yielded reliable data for nine cIV subunits (Figure 1d). These confirmed our previous findings of generalized cIV subunit deficiency in COX4I1 KO +Consistent with the profound decrease in cIV subunit levels, COX4I1 and COX4I1/4I2 KO clones showed complete absence of OXPHOS activity (OCR) or response to additions of uncoupler and inhibitors (Figure 2a). +Importantly, the respiratory OXPHOS impairment can be complemented by knock-in (KI) of either COX4I1 or COX4I2 isoforms of cIV subunit 4. +These pulse-chase experiments revealed that apart from the MT-ATP6 and MT-ATP8 components of cV, the majority of mtDNA-encoded OXPHOS subunits were synthesized less in COX4I1 KO and COX4I1/4I2 KO clones than in the wt HEK293 cells in the “pulse” samples",Score,1 (0.5),"Score 0.5 points for western blot data showing absence of COX4I1 and numerous other subunits / with complementation restoration +Score 0.5 points for OCR deficiency and absence of response to uncoupler and inhibitors +Potential impact on global mitochondrial proteostasis is noted but not scored",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_18fa1fc5-ce1b-4fec-9cc0-c94dd5c040c7-2024-03-18T040000.000Z,2945,PubMed:33578848 +Non-patient fibroblasts shRNA knockdown,Functional Alteration Non-patient cells,"Douiev L, et al., 2021, PMID: 33672589","Showed knockdown of COX4I1 with shRNA in HFF line +Showed COX deficiency in HFF shRNA COX4I1 line compared to HFF with control vector +basal and maximal OCRs and ATP-dependent OCRs in the HFF-shCOX4I1 cells were +decreased by 30–40%, but to a lesser extent than expected from the COX4I1 transcripts",Score,0.5 (0.5),"COX Deficiency (20% of control) in HFF shRNA line +OCR deficiency relatively mild so not scored",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_18fa1fc5-ce1b-4fec-9cc0-c94dd5c040c7-2024-03-18T040000.000Z,2945,PubMed:33672589 +HEK293 Cells COX4I2 Knock-in,Functional Alteration Non-patient cells,"Pajuelo Reguera D, et al., 2020, PMID: 32075102","In accordance with the quantification of the COX subunit contents (Figure 1C), the amount of the native COX complexes in the 4i1 and 4i2 KI cell lines corresponded to 54% and 61% of the COX level in parental HEK293, respectively. +In both knock-in cell lines, COX activity displayed a hyperbolic response to increasing substrate concentrations. In terms of maximal activity rates at 30 µM concentration of cytochrome c, 4i1 and 4i2 KI cell lines displayed equal values, corresponding to 55% and 52% of control HEK293 values, respectively (Figure 2A). But when normalized to COX2 content is ,comparable to parent cells",Score,0.5 (0.5),Score 0.5 for reduced COX subunits and decreased amount of COX,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a77de2a3-bc6f-47fc-a56c-edee31e11dcb-2024-03-18T040000.000Z,2946,PubMed:32075102 +ESCO2 knockout mouse,Model Systems Non-human model organism,"Whelan G, et al., 2012, PMID: 22101327","Major diagnostic marker for RBS and SC: premature centromere separation (PCS) and heterochromatin repulsion (HR) (Schule et al., 2005 PMID 16380922)",Score,1 (2),"Due to the difference in Esco2 requirement for pre-implantation +development between mouse and human, most of the disease phenotypes could not be observed in the mouse model.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_4020105e-bc43-4365-9540-9a8f77b37fae-2021-03-19T160000.000Z,2971,PubMed:22101327 +SCC disfunction in esco2 mutant zebrafish,Model Systems Non-human model organism,"Percival SM, et al., 2015, PMID: 26044958","Similar to Roberts-SC phocomelia syndrome, zebrafish embryos had small head size, growth retardation and pectoral fins were either absent or only a small nub was present. Chromosome cohesion loss, extensive chromosome scattering, imprecise chromosome segregation, an increased mitotic index and various forms of genomic instability was observed. Some cells divided with normal mitotic progression and lack genomic instability in the esco2 mutant, which suggests that compensatory cohesion establishment mechanisms are in place to allow for normal mitotic progression and division in these cells. Although not a hallmark of RBS, heart defects are prevalent in 25-75% of patients. Esco2 mutant embryos seemed to undergo proper morphogenesis but did not undergo proper heart looping and often had variable heartbeat rates and lack of blood flow. Esco2 mutant embryos also showed head necrosis and by 4 days post-fertilization, all were almost completely degraded.",Score,1 (2),"Mutating esco2 in zebrafish proved lethal and therefore, not all phenotypes (e.g. craniofacial abnormalities) could be observed",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_4020105e-bc43-4365-9540-9a8f77b37fae-2021-03-19T160000.000Z,2971,PubMed:26044958 +Comparison of smc3 and esco2 knockdown phenotypes,Biochemical Function B,"Banerji R, et al., 2017, PMID: 29084713","RBS is characterized by growth retardation, craniofacial deformities and limb malformation, consistent with impairment of normal bone growth. +Authors compared knockdown smc3 and esco2 phenotypes in a zebrafish regenerating fin model. +SMC3 has been definitely associated with Cornelia de Lange syndrome (CdLS), a cohesinopathy with many disease phenotypes in common with Roberts-SC phocomelia syndrome including craniofacial deformities, limb malformation, organ defects and mental retardation. +Similar to esco2 knockdown, morpholino-mediated knockdown of smc3 reduces cx43 expression and perturbs zebrafish bone and tissue regeneration. And similar to esco2 knockdown, overexpression of cx43 rescues the smc3-dependent skeletal phenotypes. (Cx43 encodes connexin-43, important in cell-to-cell communication, the most abundang connexin in bone cells and important to skeletal development) +Synergy experiments demonstrate that both esco2 and smc3 act in a common pathway with cx43. +NOTE: other genes that have been definitively associated with CdLS include RAD21, NIPBL and HDAC8",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_4020105e-bc43-4365-9540-9a8f77b37fae-2021-03-19T160000.000Z,2971,PubMed:29084713 +Mouse model,Model Systems Non-human model organism,"Filatova A, et al., 2019, PMID: 31273213","Mice with heterozygous Smarcb1 disruption in the nervous system (Smarcb1+/inv NesCre+/-) were smaller and had smaller brains compared to controls. Mutant mice demonstrate brain midline abnormalities like those seen individuals with Coffin-Siris Syndrome, including agenesis of the corpus callosum and vermis hypoplasia. Smarcb1 transcript levels were significantly reduced in mutant brain tissue to about 70% of control levels.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ea554e80-81d2-4100-8d0e-b762ea38fe23-2023-08-15T160000.000Z,2978,PubMed:31273213 +Multiple Complex V subunits and assembly factors,Biochemical Function A,"Jonckheere AI, et al., 2012, PMID: 21874297",Biochemical function shared with 2-5 other gene products = 1 point per Mito GCEP (same as TMEM70),Score,1 (0.5),Score 1 point for Biochemical function shared with 2-5 other gene products (3 genes),https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1b48db69-0e48-47b6-bbd3-4c09ade82a73-2024-04-15T040000.000Z,2979,PubMed:21874297 +Zebrafish morpholino knockdown,Model Systems Non-human model organism,"Nagata Y, et al., 2017, PMID: 29234032","significantly higher percentage with swollen pericardial sac +Larger pericardial sac area and atrial area +Ventricular fractional shortening significantly reduced in z-usmg5 knockdown +No different in heart rate +Importantly no differences in cardiac morphology and function, such as pericardial area, atrial area, ventricular diameter, and ventricular fractional shortening between the wild-type embryos and control MO group +Rescued with co-injection of WT z-usmg5 mRNA with morphilino (MO) resulted in significant reduction in pericardial sac and atrial areas and improvement in ventricular fractional shortening compared to just z-usmg5 MO",Score,0.5 (2),Score 0.5 points due to limited human phenotype overlap to date,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1b48db69-0e48-47b6-bbd3-4c09ade82a73-2024-04-15T040000.000Z,2979,PubMed:29234032 +Baggio - Drosophila,Model Systems Non-human model organism,"Baggio F, et al., 2014, PMID: 25428350","Ubiquitous downregulation of DmLrpprc2 expression causes respiratory chain dysfunction (0.5 points), developmental delay and shortened lifespan (0.5 points). Decreased DmLRPPRC2 expression does not globally affect steady-state levels or polyadenylation of mitochondrial transcripts, but some mitochondrial transcripts abnormally associate with the mitochondrial ribosomes and some products are dramatically overproduced and other ones decreased, which, in turn, results in severe deficiency of respiratory chain complexes.",Score,1 (2),"Ubiquitous downregulation of DmLrpprc2 expression causes respiratory chain dysfunction (0.5 points), developmental delay and shortened lifespan (0.5 points). Decreased DmLRPPRC2 expression does not globally affect steady-state levels or polyadenylation of mitochondrial transcripts, but some mitochondrial transcripts abnormally associate with the mitochondrial ribosomes and some products are dramatically overproduced and other ones decreased, which, in turn, results in severe deficiency of respiratory chain complexes.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_72f89e4d-6a21-4556-b601-ce87f4ab60d4-2024-06-20T040000.000Z,2984,PubMed:25428350 +Burelle - Functional alteration in patient cells,Functional Alteration Patient cells,"Burelle Y, et al., 2015, PMID: 25835550","Despite maintaining normal ATP levels, patient fibroblast showed impaired COX enzyme activity, mitochondrial network fragmentation, impaired oxidative phosphorylation capacity, and lower membrane potential. Increased sensitivity to Ca2+-induced permeability transition but no changes in reactive oxygen species production were also observed. Patient fibroblasts also display enhanced susceptibility to cell death when exposed to palmitate, an effect that is potentiated by high lactate, while high glucose or acidosis alone or in combination were neutral.",Score,0.5 (1),"Despite maintaining normal ATP levels, patient fibroblast showed impaired COX enzyme activity, mitochondrial network fragmentation, impaired oxidative phosphorylation capacity, and lower membrane potential. Increased sensitivity to Ca2+-induced permeability transition but no changes in reactive oxygen species production were also observed. Patient fibroblasts also display enhanced susceptibility to cell death when exposed to palmitate, an effect that is potentiated by high lactate, while high glucose or acidosis alone or in combination were neutral.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_72f89e4d-6a21-4556-b601-ce87f4ab60d4-2024-06-20T040000.000Z,2984,PubMed:25835550 +Olahava - Functional alteration in patient cells,Functional Alteration Patient cells,"Oláhová M, et al., 2015, PMID: 26510951","There was a marked decrease in the steady-state levels of LRPPRC protein in patient muscle and fibroblast compared to age-matched controls, a significant decrease in basal oxygen consumption rate in patient fibroblasts; steady-state protein levels of subunits of mitochondrial respiratory chain complexes in patient fibroblasts and muscle (analyzed SDS-PAGE and immunoblotting) showed an almost complete loss of mitochondrial (COXI and COXII) and nuclear-encoded (COXIV) subunits of Complex IV; steady-state levels of Complex I subunit proteins NDUFB8, NDUFA9 and NDUFA13 were also decreased in Patient 2 fibroblasts and muscle (levels of Complex V and Complex III subunits remained unchanged); there was a slight decrease of fully assembled Complex IV in Patient 1 and 2 fibroblasts, almost complete lack of Complex IV in the muscle of Patient 2 (analyzed by blue native PAGE); and patient muscle homogenates displayed decreased levels of Complex I. Fibroblast and muscle samples from patients also showed decreased steady-state levels of mitochondrial mRNA transcripts (MTCO1, MTCO2, MTND1 and RNA14) and pulse labelling experiments showed a mild decrease in synthesis of COX1 in patients 1 and 2.",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_72f89e4d-6a21-4556-b601-ce87f4ab60d4-2024-06-20T040000.000Z,2984,PubMed:26510951 +Richman - Mice,Model Systems Non-human model organism,"Richman TR, et al., 2016, PMID: 27319982","Complex IV deficiency, motor coordination impairment, and visual impairment are seen in patients.",Score,3 (2),The phenotype is recapitulated in mice.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c1e50ae4-9de7-4e26-a97d-6f2a77186955-2024-04-29T040000.000Z,2985,PubMed:27319982 +Sferruzza - functional alteration in patient cells,Functional Alteration Patient cells,"Sferruzza G, et al., 2021, PMID: 33709035","In SDS-PAGE, there was a striking reduction of MT-CO1 in patient fibroblasts compared with the heterozygous daughter and a healthy control. In BN-PAGE, there was fully compromised assembly of COX.",Score,0.5 (1),"In SDS-PAGE, there was a striking reduction of MT-CO1 in patient fibroblasts compared with the heterozygous daughter and a healthy control. In BN-PAGE, there was fully compromised assembly of COX.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c1e50ae4-9de7-4e26-a97d-6f2a77186955-2024-04-29T040000.000Z,2985,PubMed:33709035 +DDOST variants affect LOX N-glycosylation,Functional Alteration Non-patient cells,"Kas SM, et al., 2023, PMID: 37848450","LOX N-glycosylation was also restored by DDOST p.G200D, p.S206P and p.R379Q, but not by p.L364Ffs11 or p.I405Tfs7.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e0605b51-70c5-42ee-81b5-d45bb0b1fdab-2023-11-15T170000.000Z,2987,PubMed:37848450 +Kas 2023 Biochemical function,Biochemical Function B,"Kas SM, et al., 2023, PMID: 37848450","OST48 is a non-catalytic component of the oligosaccharyltransferase (OST) complex, which transfers glycans to substrate proteins. CDGs have a spectrum of clinical phenotypes caused by abnormal N-glycosylation.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e0605b51-70c5-42ee-81b5-d45bb0b1fdab-2023-11-15T170000.000Z,2987,PubMed:37848450 +Navarro-Gonzales - C. Elegans,Model Systems Non-human model organism,"Navarro-González C, et al., 2017, PMID: 28732077","mtcu-1 deletion showed slight decrease in steady state level of cI subunit, mild OXPHOS dysfunction (reduced maximal OCR), moderate increase in ROS (upregulation in genes involved in antioxidant response), reduced fertility",Score,0.5 (2),"mtcu-1 deletion showed slight decrease in steady state level of cI subunit, mild OXPHOS dysfunction (reduced maximal OCR), moderate increase in ROS (upregulation in genes involved in antioxidant response), reduced fertility",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_393ee652-756b-4b54-9e0a-916bbae9d9eb-2024-05-23T040000.000Z,2988,PubMed:28732077 +Asano - Functional alteration in non-patient cells,Functional Alteration Non-patient cells,"Asano K, et al., 2018, PMID: 29390138","GTPBP3 KO in HEK293T cells; severely reduced oxygen consumption rate, reduced complex I and IV activity but increased complex II activity, reduced levels of complex I proteins (ND2 and NDUFB8). Pulse labeling of mt protein synthesis showed a reduced rate.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_393ee652-756b-4b54-9e0a-916bbae9d9eb-2024-05-23T040000.000Z,2988,PubMed:29390138 +Chen - Zebrafish,Model Systems Non-human model organism,"Chen D, et al., 2019, PMID: 30916346","gtpbp3 knockout zebrafish generated by CRISPR/Cas9; showed impaired mitochondrial translation, increased proteostasis stress and altered activities of respiratory chain complexes; resulted in alterations in the embryonic heart development and reduced fractional shortening of ventricles in mutant zebrafish, gtpbp3 knock-out zebrafish exhibited hypertrophy of cardiomyocytes and myocardial fiber disarray in ventricles.",Score,1 (2),"gtpbp3 knockout zebrafish generated by CRISPR/Cas9; showed impaired mitochondrial translation, increased proteostasis stress and altered activities of respiratory chain complexes; resulted in alterations in the embryonic heart development and reduced fractional shortening of ventricles in mutant zebrafish, gtpbp3 knock-out zebrafish exhibited hypertrophy of cardiomyocytes and myocardial fiber disarray in ventricles.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_393ee652-756b-4b54-9e0a-916bbae9d9eb-2024-05-23T040000.000Z,2988,PubMed:30916346 +Loss of IFT121(WDR35) negatively influenced IFT43,Protein Interaction,"Duran I, et al., 2017, PMID: 28400947","The IFT-A complex, together with the dynein 2 motor complex, mediates retrograde transport in cilia. IFT43 is a satellite component of IFT-A complex of intraflagellar retrograde transport, alongside 2 other satellite components, IFT121(WDR35) and IFT139. Patients with IFT43 mutations exhibited short rib polydactyly syndrome (SRPS) phenotype, as reported by Duran et al. Cilia formation was disrupted in IFT43 mutant cells. Analysis of cultured chondrocytes from the SRPS cases with IFT121(WDR35) mutations found decreased IFT43 levels (Fig. 6c, d) and normal levels of IFT-A core complex member IFT144 (Fig. 6c, e), indicating that while the IFT121 mutations caused instability of the satellite component IFT43, they did not affect overall IFT-A core stability.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9e3f8578-6df2-4503-9e38-c110a9f00924-2022-02-23T170000.000Z,2990,PubMed:28400947 +Defect in cilium assembly (patient cells),Functional Alteration Patient cells,"Duran I, et al., 2017, PMID: 28400947","Studies of the cilia in chondrocyte cell lines from both cases showed a reduction in the percentage of cilia present on the cells, indicating defective ciliogenesis (Fig. 6f). The average cilia lengths were reduced on the cells that had cilia and the cilia shapes were abnormal (Fig. 6g, h). Ciliogenesis in the IFT121(WDR35) cases was impaired but not absent.",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9e3f8578-6df2-4503-9e38-c110a9f00924-2022-02-23T170000.000Z,2990,PubMed:28400947 +Hong functional alteration,Functional Alteration Non-patient cells,"Hong CJ, et al., 2016, PMID: 27727273","Zfp423-deficient precursors have abnormal distribution of cilium morphology. Cerebellum sections from E18.5 mice showed both structures intact among cells in the external germinal layer (EGL) and with comparable frequency per cell between Zfp423nur12-homozygous and littermate controls. Volume measurements extracted from optical sections, however, showed a significant increase in cilium volume in Zfp423nur12 EGL compared to controls. Among co-processed sections from eight littermate pairs, typical volumes were larger in the mutant than in the control animal for all eight comparisons. Structured illumination microscopy also showed altered cilium dimensions in Zfp423nur12 EGL. Mutant GCPs showed significant increases in both cilia length and base width.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c61623dd-07b1-41c5-b445-3f9f8575cc06-2024-06-26T160000.000Z,2996,PubMed:27727273 +Hong biochemical function,Biochemical Function B,"Hong CJ, et al., 2016, PMID: 27727273","Zfp423 Regulates Sonic Hedgehog Signaling via Primary Cilium Function. Zfp423 is expressed by cerebellar granule cell precursors and loss of Zfp423 in these precursors leads to cell-intrinsic reduction in proliferation, loss of response to Shh, and primary cilia abnormalities including diminished frequency of both Smoothened and IFT88 localization which are required for normal signal processing and specifically for expansion of GCPs. Loss of Zfp423 also alters expression of several genes encoding key cilium components, including increased expression of Tulp3. Tulp3 is a direct binding target of Zfp423 and reducing the overexpression of Tulp3 in Zfp423-deficient cells suppresses Smoothened translocation defects. These results suggest a a signaling mechanistic connection, complementary to the DNA damage response (DDR) shown by Chaki et al. 2012, between ZNF423/Zfp423 ciliopathy-related phenotypes and function of the primary cilium",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c61623dd-07b1-41c5-b445-3f9f8575cc06-2024-06-26T160000.000Z,2996,PubMed:27727273 +Ferret Model,Model Systems Cell culture model,"Johnson MB, et al., 2018, PMID: 29643508",The microcephaly and brain anomalies seen in mice reflect the anomalies seen in humans.,Score,1 (1),"This is actually a ferret model (the ferret was not an option for a model organism in the GCI). However, it is supposed to be scored at 1 pt. (downgraded from 2 pts. due to not being as specific of a model as the mouse model, which was upgraded to 3 pts.).",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_41e82e1a-528f-48ee-9e07-22865077f61d-2024-03-14T170000.000Z,3000,PubMed:29643508 +Zhang - Drosophila,Model Systems Non-human model organism,"Zhang K, et al., 2013, PMID: 23509070","Loss of sicily is associated with neurodegeneration (retinal degeneration) and enlarged and vacuolated mitochondria with dissociated cristae (0.5 for phenotype, 0.5 for mitochondrial abnormalities). In the absence of Sicily, CI activity is severely impaired, and ROS production is elevated (0.5). Ubiquitous expression of human C8ORF38 cDNA also rescues the lethality and ERG defect (1).",Score,2.5 (2),"Loss of sicily is associated with neurodegeneration (retinal degeneration) and enlarged and vacuolated mitochondria with dissociated cristae (0.5 for phenotype, 0.5 for mitochondrial abnormalities). In the absence of Sicily, CI activity is severely impaired, and ROS production is elevated (0.5). Ubiquitous expression of human C8ORF38 cDNA also rescues the lethality and ERG defect (1).",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a9f5bc35-3a3e-481c-86f4-8dd909642f7e-2024-06-20T160000.000Z,3022,PubMed:23509070 +Kohda - Rescue in patient cells,Rescue Patient cells,"Kohda M, et al., 2016, PMID: 26741492",,Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a9f5bc35-3a3e-481c-86f4-8dd909642f7e-2024-06-20T160000.000Z,3022,PubMed:26741492 +Nozawa - Drosophila,Model Systems Non-human model organism,"Nozawa N, et al., 2023, PMID: 37364055","Larvae expressing sicily RNAi developed without gross morphological defects, but muscles of third instar larvae with sicily knockdown were thinner, more fragile and less innervated than those of third instar larvae expressing control RNAi +Although control pupae were distributed all over the wall of the vial, pupae with sicily knockdown were found closer to the medium, suggesting that sicily-knockdown larvae could not climb far from the medium. Many males with sicily knockdown died before eclosion. In contrast, females with sicily knockdown matured normally and survived to the adult stage +Adult males with sicily knockdown had severely impaired locomotor functions (0.5 point) and died prematurely. Adult females with sicily knockdown also exhibited locomotor defects and premature death, and they developed bang sensitivity (amount of time to recover from mechanical stress) when they aged. +Sicily knockdown dramatically reduced CI levels in both males and females +Sicily knockdown caused lactate accumulation in males and females (0.5 point). Pyruvate also accumulated in males and females with sicily knockdown.",Score,1 (2),"Larvae expressing sicily RNAi developed without gross morphological defects, but muscles of third instar larvae with sicily knockdown were thinner, more fragile and less innervated than those of third instar larvae expressing control RNAi +Although control pupae were distributed all over the wall of the vial, pupae with sicily knockdown were found closer to the medium, suggesting that sicily-knockdown larvae could not climb far from the medium. Many males with sicily knockdown died before eclosion. In contrast, females with sicily knockdown matured normally and survived to the adult stage +Adult males with sicily knockdown had severely impaired locomotor functions (0.5 point) and died prematurely. Adult females with sicily knockdown also exhibited locomotor defects and premature death, and they developed bang sensitivity (amount of time to recover from mechanical stress) when they aged. +Sicily knockdown dramatically reduced CI levels in both males and females +Sicily knockdown caused lactate accumulation in males and females (0.5 point). Pyruvate also accumulated in males and females with sicily knockdown.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a9f5bc35-3a3e-481c-86f4-8dd909642f7e-2024-06-20T160000.000Z,3022,PubMed:37364055 +Pyle - Functional alteration in patient cells,Functional Alteration Patient cells,"Pyle A, et al., 2014, PMID: 26380172","Authors measured oxygen consumption as a marker of the electron transport chain (ETC) capacity. As shown in Fig. 3, the patient cell lines showed a decrease in OCR when compared to controls. This difference is notably bigger after treating the cells with FCCP, an ETC accelerator which acts as an uncoupling agent transporting hydrogen ions the inner mitochondrial membrane, showing a clear ETC defect in the patient cell lines.",Score,0.5 (1),"Authors measured oxygen consumption as a marker of the electron transport chain (ETC) capacity. As shown in Fig. 3, the patient cell lines showed a decrease in OCR when compared to controls. This difference is notably bigger after treating the cells with FCCP, an ETC accelerator which acts as an uncoupling agent transporting hydrogen ions the inner mitochondrial membrane, showing a clear ETC defect in the patient cell lines.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_27e53978-d972-44e0-8605-0b2c9e35eb51-2024-05-23T040000.000Z,3023,PubMed:26380172 +Wesolowska - Functional alteration in patient cells,Functional Alteration Patient cells,"Wesolowska M, et al., 2015, PMID: 27858754","De novo mitochondrial translation was assessed in patient fibroblasts and indicated a global decrease in protein synthesis (Fig. 4A), as seen in previously reported patients. This reduction in mt-protein synthesis is not a consequence of a reduction in mt-RNA levels, which are modestly elevated (Fig. 4B), again as seen in other C12orf65 patients. When cells are artificially depleted of C12orf65 protein using siRNA, the elevation in mt-RNA levels is more striking (Fig. 4C). A mitoribosome defect is unlikely to be responsible in this patient, as no global differences were observed in the steady state levels of mitoribosomal protein levels (Fig. 4D). To identify if the synthesised polypeptides are stable, steady state levels of RC proteins were assessed by western blotting following SDS-PAGE. This confirmed decreased levels of complex IV (COX2 expression), consistent with our biochemical assays but also revealed reduced levels of CI and modest changes in CIII subunits (Fig. 4E). To determine if synthesised polypeptides were incorporated into fully assembled oxidative phosphorylation complexes, western blots of mitochondrial fractions separated by 1D BN-PAGE were performed. A reduction in the amount of fully assembled complexes I, IV and V was observed in the patient compared to controls, together with a minor complex III defect, visible in the I+III supercomplex (Fig. 4F). These data are consistent with C12orf65 playing a ubiquitous role in mt-translation but with a more severe effect on CIV activity. This translation defect caused by loss of C12orf65 does not appear to trigger an unfolded protein response as no increase was seen in relevant proteases (Fig. 4G, LONP and CLPX).",Score,0.5 (1),"De novo mitochondrial translation was assessed in patient fibroblasts and indicated a global decrease in protein synthesis (Fig. 4A), as seen in previously reported patients. This reduction in mt-protein synthesis is not a consequence of a reduction in mt-RNA levels, which are modestly elevated (Fig. 4B), again as seen in other C12orf65 patients. When cells are artificially depleted of C12orf65 protein using siRNA, the elevation in mt-RNA levels is more striking (Fig. 4C). A mitoribosome defect is unlikely to be responsible in this patient, as no global differences were observed in the steady state levels of mitoribosomal protein levels (Fig. 4D). To identify if the synthesised polypeptides are stable, steady state levels of RC proteins were assessed by western blotting following SDS-PAGE. This confirmed decreased levels of complex IV (COX2 expression), consistent with our biochemical assays but also revealed reduced levels of CI and modest changes in CIII subunits (Fig. 4E). To determine if synthesised polypeptides were incorporated into fully assembled oxidative phosphorylation complexes, western blots of mitochondrial fractions separated by 1D BN-PAGE were performed. A reduction in the amount of fully assembled complexes I, IV and V was observed in the patient compared to controls, together with a minor complex III defect, visible in the I+III supercomplex (Fig. 4F). These data are consistent with C12orf65 playing a ubiquitous role in mt-translation but with a more severe effect on CIV activity. This translation defect caused by loss of C12orf65 does not appear to trigger an unfolded protein response as no increase was seen in relevant proteases (Fig. 4G, LONP and CLPX).",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_27e53978-d972-44e0-8605-0b2c9e35eb51-2024-05-23T040000.000Z,3023,PubMed:27858754 +Emperador - Rescue,Rescue Patient cells,"Emperador S, et al., 2020, PMID: 31969900",,Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b211e7b2-d93b-4995-ad30-1f4d962867b0-2024-05-23T160000.000Z,3037,PubMed:31969900 +Alsina - mice,Model Systems Non-human model organism,"Alsina D, et al., 2020, PMID: 32525278","Homozygous KO mice were predominantly perinatal lethal, but the few surviving animals were apparently normal until the age of 8–12 months when they gradually develop signs of mitochondrial dysfunction and weight loss.​ One-year-old Fbxl4 knockouts show a global reduction in a variety of mitochondrial proteins and mtDNA depletion, whereas lysosomal proteins are upregulated.",Score,1 (2),"Homozygous KO mice were predominantly perinatal lethal, but the few surviving animals were apparently normal until the age of 8–12 months when they gradually develop signs of mitochondrial dysfunction and weight loss.​ One-year-old Fbxl4 knockouts show a global reduction in a variety of mitochondrial proteins and mtDNA depletion, whereas lysosomal proteins are upregulated.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b211e7b2-d93b-4995-ad30-1f4d962867b0-2024-05-23T160000.000Z,3037,PubMed:32525278 +Lavorato - zebrafish,Model Systems Non-human model organism,"Lavorato M, et al., 2022, PMID: 35881484",fbxl4sa12470 zebrafish larvae showed liver stenosis and mitochondria ultrastructural damage.,Score,0.5 (2),fbxl4sa12470 zebrafish larvae showed liver stenosis and mitochondria ultrastructural damage.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b211e7b2-d93b-4995-ad30-1f4d962867b0-2024-05-23T160000.000Z,3037,PubMed:35881484 +Lavorato - worms,Model Systems Non-human model organism,"Lavorato M, et al., 2022, PMID: 35881484","fbxl-1(ok3741) C. elegans displayed developmental delay (delayed larval development), abnormal growth, reduced fecundity, and globally impaired neurologic and/or muscular activity involving their pharyngeal pump rate, body-bend locomotion, and swimming activity​. DCA treatment rescued fecundity, pharyngeal pumping function, and biochemical deficiencies at the level of RC enzyme activity and intracellular lactate.",Score,1 (2),"fbxl-1(ok3741) C. elegans displayed developmental delay (delayed larval development), abnormal growth, reduced fecundity, and globally impaired neurologic and/or muscular activity involving their pharyngeal pump rate, body-bend locomotion, and swimming activity​. DCA treatment rescued fecundity, pharyngeal pumping function, and biochemical deficiencies at the level of RC enzyme activity and intracellular lactate.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b211e7b2-d93b-4995-ad30-1f4d962867b0-2024-05-23T160000.000Z,3037,PubMed:35881484 +electron microscopy,Expression A,"Graser S, et al., 2007, PMID: 17954613","Using electron microscopy, CEP164 has been shown to be localized to the distal appendages of mature centrioles",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_961b81f6-7ad1-49e2-b675-c035b4d8d35d-2021-10-27T160000.000Z,3062,PubMed:17954613 +Global and tissue specific (multiciliated) CEP164 KO mouse,Model Systems Non-human model organism,"Siller SS, et al., 2017, PMID: 29244804","At E9.5 and E10.5, CEP164-KO embryos exhibited holoprosencephaly, cardiac looping defects, an edematous pericardial sac, and a truncated posterior trunk. These phenotypes are similar to those reported for mouse mutants for KIF3A and KIF3B, which are major components of the kinesin-II ciliary anterograde motor, providing evidence for the essential role of CEP164 in primary ciliogenesis and for mammalian embryogenesis. +Specific ablation of CEP164 in multiciliated cells (CEP164fl/fl with Cre under FOXJ1 promoter) from the the airways, brain ventricles, oviducts and testis showed: + +approx. 20% that succumbed to death due to severe hydrocephalus around weaning and another approx. 20% that exhibited mild hydrocephalus, which resolved itself later +substantial ventricular enlargement +A clear reduction in the number of ependymal multicilia +A marked decrease in the number of airway multicilia +Impaired mucociliary clearance +This is consistent with the primary ciliary dyskinesia/bronchiectasis phenotypes seen in patients",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_961b81f6-7ad1-49e2-b675-c035b4d8d35d-2021-10-27T160000.000Z,3062,PubMed:29244804 +Human embryonic and foetal expression,Expression A,"Devlin LA, et al., 2020, PMID: 31990917",MRC-Wellcome Trust Human Developmental Biology Resource (HDBR) to perform immunohistochemistry studies on human embryonic and foetal tissues to determine the expression patterns of CEP164 during development,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_961b81f6-7ad1-49e2-b675-c035b4d8d35d-2021-10-27T160000.000Z,3062,PubMed:31990917