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+Label,Experimental Category,Reference,Explanation,Score Status,Points (default points),Reason for Changed Score,url,primary_index,pmid
+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
+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
+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
+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
+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
+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
+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
+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
+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
+Munis Cell Culture Rescue,Rescue Cell culture model,"Munis AM, et al., 2021, PMID: 33426150","Following the rescue, immunoblotting showed SFTPB knockout cells with expression of mature SPB homodimer and transepithelial electrical resistance (TEER) levels increased to be comparable with wild type SALI cultures. Treatment with a control vector expressing EGFP failed to generate SPB homodimers and did not correct the TEER.",Score,0.5 (1),Score reduced as cell culture model evidence from the same paper is scored.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_4bfa265f-3b7a-4091-8e97-b13a7f4f2de7-2024-10-17T190000.000Z,1966,PubMed:33426150
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+POMGNT2 knockout in HAP1 cells,Functional Alteration Non-patient cells,"Endo Y, et al., 2015, PMID: 27066570","HAP1 POMGNT2 knockout cells exhibited defects in their reactivity to the anti-α-dystroglycan antibody IIH6, which detects the glycosylated form of α-dystroglycan, when observed by fluorescent microscopy. Furthermore, no glycosylated α-dystroglycan was visible in western blot of protein from HAP1 POMGNT2 knockout cells.",Score,1 (0.5),The score for this functional alteration evidence was upgraded to 1 point from a default of 0.5 points given the ability of the wild type POMGNT2 cDNA to rescue the α-dystroglycan glycosylation defects in HAP1 POMGNT2 knockout cells.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_522f3d3f-8026-439f-9318-2e4df6097a2e-2024-08-14T190000.000Z,2853,PubMed:27066570
+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
+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
+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 knockout mice exhibit defects in left–right axis patterning (including heart defects) and short cilia (PMIDs: 25722189, 27320864). IFT46 and ODA16 are thought to interact to transport ODAs via the IFT.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_999c6072-d9c6-4339-aea7-8247941748a6-2024-07-11T160000.000Z,575,PubMed:18852297
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+Mdm4 TM/TM MEFs,Model Systems Cell culture model,"Toufektchan E, et al., 2020, PMID: 32300648","MDM4 is a negative regulator of p53. This culture model demonstrated that loss of function of MDM4 results in an increased activity of p53 and short telomeres, features observed in humans with germ line mutations.",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5c4e0701-22d0-4e73-bf76-a23e9472fe3d-2024-12-10T170000.000Z,2969,PubMed:32300648
+Le Coz_in vitro,Model Systems Cell culture model,"Le Coz C, et al., 2021, PMID: 33951726","The authors demonstrate that biallelic PU.1 ETS expression is important for human B and myeloid cell development in vitro, similar to that seen in humans. Following the gene alteration to model PU.MA patient haematopoiesis (as described above), surviving myeloid (CD33+) or B cell precursors (CD19intIgM−, CD19hiIgM−, or CD19hiIgM+) did not possess SPI1 exon five (PEST domain) mutations of any kind despite very high initial editing efficiency at that genomic site. In-frame exon four edits that preserved the ETS were tolerated in B cell precursors, whereas ETS-altering frameshift edits of exon four were not.",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_76a93861-b7d3-4d08-8882-6a7a1456b51a-2024-12-12T170000.000Z,2966,PubMed:33951726
+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
+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
+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
+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
+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
+Mouse in situ hybridization,Expression A,"Mommersteeg MT, et al., 2015, PMID: 25691540",Mouse ISH at E16.5,Score,0 (0.5),Already scored for this expression in another study,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a0d0c93c-abf7-4bf2-8b0f-e47cfce87656-2024-09-03T160000.000Z,1876,PubMed:25691540
+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
+Lentiviral Vector Rescue,Rescue Patient cells,"Izawa K, et al., 2017, PMID: 28011863",The lentivirus induced surface expression of CD70 to levels comparable with those seen on LCLs from control donors,Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_69aa819c-1f25-42fe-8469-4641fc088a57-2025-02-05T170000.000Z,2989,PubMed:28011863
+Zhang patient cells,Functional Alteration Patient cells,"Zhang S, et al., 2023, PMID: 36579833","Quantitative analysis of the number, total area, average length and total signal intensity per visual field (0.143 mm2) of AChR clusters in C2C12 cells expressing WT-DOK7 or p.G64R-DOK7/p.G64R-DOK7 markedly reduced AChR clustering.",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b40a6c0a-1152-4d29-8ba3-1136600085b9-2025-02-24T170000.000Z,3017,PubMed:36579833
+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
+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
+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
+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
+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
+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
+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
+Expression of CCDC65 during ciliogenesis,Expression A,"Horani A, et al., 2013, PMID: 23991085",,Score,1 (0.5),Two separate experiments validated the expression of CCDC65 in PCD relevant tissues and during ciliogenesis,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_662ab516-ba5f-46aa-97b2-ef4c8f3201a5-2024-08-08T160000.000Z,327,PubMed:23991085
+Yan_Mouse Model,Model Systems Non-human model organism,"Yan L, et al., 2023, PMID: 37228654","The Wdr60 PB/PB embryos had much less cilia than WT embryos. The human phenotype is a skeletal ciliopathy, which is caused by defects in the function of cilia.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ad85ec94-69a9-4e67-a366-5ec2d574f1e4-2024-09-04T160000.000Z,669,PubMed:37228654
+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
+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
+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
+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
+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
+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
+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
+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
+Rnaseh2c-/- mice,Model Systems Non-human model organism,"Hiller B, et al., 2012, PMID: 22802351","Although mouse phenotype was limited for knock-out model due to early embryonic lethality, cells obtained from knock-out mouse embryos demonstrated increased genomic ribonucleotide load consistent with underlying disease mechanism.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9f65b554-f11e-41ff-8a6f-dcb5d8484122-2024-08-26T160000.000Z,1871,PubMed:22802351
+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
+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
+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
+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
+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
+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
+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
+Abkevich Expression,Expression B,"Abkevich V, et al., 2012, PMID: 23047548","RAD51C promoter methylation was observed consistently in cohorts and the high homologous recombination deficiency (HRD) score showed a significant association with RAD51C deficiency in two data sets and was consistent with scores for BRCA1/2 defects also found in the data sets.
+Ovarian tumors with LOH show increased homologous recombination rates.
+Supplementary Table S4, Supplementary Figure S6,",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_31cb27be-dd32-4bb7-86bd-43c4b1eabaf5-2024-08-29T170000.000Z,1814,PubMed:23047548
+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
+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
+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
+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
+LRRC56 is part of mouse LRO transcriptome,Expression A,"Bellchambers HM, et al., 2023, PMID: 37393374","Single cell RNA sequencing (scRNA-seq) was done to generate a transcriptomic profile list of LRO genes from precisely staged 0–1 somite mouse embryos, when the LRO fluid flow is first detected.  LRRC56 was one of 196  transcripts described as the LRO transcriptome. LRO cells have motile cilia and are involved in determining embryo laterality. The expression of LRRC56 in the LRO is consistent with LRRC56 playing a role in determining human left right patterning.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ceef14a8-34d2-41ac-8c03-47c5eaff8986-2024-11-19T200000.000Z,1227,PubMed:37393374
+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
+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
+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
+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
+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
+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
+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
+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
+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
+"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
+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
+POPDC1 and PODPC2 at the sarcolemma in muscle of patients,Expression B,"De Ridder W, et al., 2019, PMID: 31119192","IHC  staining in patient and control muscle samples was performed to examine POPDC1 and POPDC2 at the plasma membrane. Both POPDC1 and POPDC2 were abundantly present at the plasma membrane of control skeletal muscle. In all patient samples, however, both POPDC1 and
+POPDC2 were drastically diminished at the sarcolemma. Levels of SGCA, used as a control marker for sarcolemmal proteins, remained normal in the patient samples with similar staining patterns and intensities as for control samples.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_31a0db34-cad3-4746-a40f-2912318dfbd2-2024-08-29T190000.000Z,2713,PubMed:31119192
+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
+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
+"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
+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
+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
+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
+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
+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
+Lrp2KO mice between embryonic day 10.5 (E10.5) and E15.5,Model Systems Non-human model organism,"Baardman ME, et al., 2016, PMID: 26822476",Similar congenital heart disease phenotypes and specifically that related to aortic arch anomalies  have been seen in a human report.,Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_291857b3-399a-42fa-86f7-d4077f97accd-2024-09-09T160000.000Z,1222,PubMed:26822476
+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
+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
+Ocbina_Rescue,Rescue Non-human model organism,"Ocbina PJ, et al., 2011, PMID: 21552265","Found that Dync2h1lln/lln mutants die by E13.5, but ∼30% of Dync2h1lln/lln Ift172avc1/+ embryos survived to at least E16.5. At E16.5, some Dync2h1lln/lln Ift172avc1/+ mutants (n=2/5) did not exhibit polydactyly in either forelimbs or hindlimbs. Authors state the modest reduction of IFT-B proteins rescued the early lethality and polydactyly caused by the absence of IFT-dynein function.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_27b3d450-9f9a-4ca4-aef0-23a99ce79773-2024-11-06T170000.000Z,2749,PubMed:21552265
+Fujiwara mouse model,Model Systems Non-human model organism,"Fujiwara K, et al., 2016, PMID: 27023172","Defects in KDM4B lead to alteration in dendritic spines within the hippocampi, hyperactivity, memory loss, and epilepsy features in the mouse. They found a decreased number of mature spines and increased number of immature spines, resulting in increased total number of spines in JMJD2B mutant mice. Open-field test suggest that JMJD2B-deficient mice are hyperactive at baseline and have trouble in becoming accustomed to a novel environment. Mutant mice display working memory deficits as determined by assessment of correct entry number in the Y-maze test. The mutants sometimes displayed epileptiform-like seizures following stressful events.",Score,1 (2),Downgraded since the mode of inheritance does not match human cases,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_703aa9ae-30ab-48c2-bb38-05be24558879-2024-11-06T170000.000Z,2797,PubMed:27023172
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+HARTNER 2009,Biochemical Function A,"Hartner JC, et al., 2009, PMID: 19060901","PMID: 38489753: TREX1: deficiency compromised in vivo tumor growth in mice. This delay depended on a functional immune system, systemic type I IFN signaling, and tumor-intrinsic cGAS expression.
+PMID: 19525956: SAMHD1: Performing the identical experiment in macrophages from MyD88/Ifnar1 double knockout mice showed this expression to be interferon dependent",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c6e83262-29db-4535-a41b-8cb8549009bf-2024-10-21T160000.000Z,56,PubMed:19060901
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+Sarcoglycans are associated with LGMD,Biochemical Function A,"Sandonà D, et al., 2009, PMID: 19781108",Both SGCA and SGCB are components of the sarcoglycan complex that is part of the larger dystrophin-glycoprotein complex that functions in the contraction of muscle.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e60e8b70-857e-4dae-bc45-da7db0dd5bf1-2024-11-14T170000.000Z,2880,PubMed:19781108
+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
+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
+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
+AKR1D1 KNOCKOUT MICE MODEL,Model Systems Non-human model organism,"Gathercole LL, et al., 2022, PMID: 35318963","The study of the AKR1D1 gene in mice is similar to human phenotypes because it highlights the role of this gene in regulating bile acid synthesis and glucocorticoid clearance, both of which are crucial for metabolism. In humans, defects in bile acid synthesis can lead to metabolic disorders, similar to the findings in Akr1d1-/- mice. The sex-specific metabolic responses observed in the mice, such as differences in insulin tolerance and fat accumulation, may also reflect similar variations seen in human populations. Understanding these mechanisms in mice can provide insights into how alterations in the AKR1D1 gene might affect human health, particularly regarding metabolic diseases and conditions related to bile acid metabolism.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_236a7baf-2425-4882-a6de-130dfb5117ac-2024-09-27T160000.000Z,85,PubMed:35318963
+Structural defects in respiratory cilia from DNAAF6 patients,Functional Alteration Patient cells,"Paff T, et al., 2017, PMID: 28041644","Loss-of-function PIH1D3 mutations result in structural defects in respiratory cilia of two PCD patients, each carrying a different hemizygous DNAAF6 mutation. TEM microscopy shows an absence of inner and outer dynein arms in respiratory cells of both patients. Immunofluorescent studies of these cells shows an absence or reduction in some of the dynein arm structural proteins (Heavy chains DNAH5 and DNAH9 and intermediate chains DNAI1 and DNAI2 from ODAs and DNALI1 from IDAs), suggesting a defect in the assembly of the dynein arms.  Similar results were seen in immunofluorescent studies of patient sperm flagella where DNAI1 and DNAI2  were absent from patient flagellar axonemes.",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5de9de15-2c09-48f5-bcaf-08c42b97700e-2024-08-17T190000.000Z,619,PubMed:28041644
+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
+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
+Role of AGPAT2 in adipose tissue dynamics,Functional Alteration Non-patient cells,"Cautivo KM, et al., 2016, PMID: 27408775","This study were aimed to characterize morphological, ultrastructural, and molecular changes of Adipose tissue(AT) from Agpat2-/- mice and to assess adipogenic differentiation in Agpat2-/-mouse embryonic fibroblasts (MEFs).
+AGPAT2 deficient adult mice are completely devoid of all white adipose tissue (WAT) and brown adipose tissue(BAT) depots. In contrast, fetuses and newborn Agpat2-/- mice have preserved adipose tissue. However, lipodystrophy results from massive adipocyte death and inflammatory infiltration of the adipose tissue during the first week of life was observed.  At the ultrastructural level, white adipocytes in newborn Agpat2-/- were smaller and had a marked reduction of plasma membrane caveolae, abnormally structured mitochondria and irregular LDs. In addition, enhanced accumulation of autophagic structures observed in Agpat2-/-adipocytes. In vitro studies showed that Agpat2-/- MEF cells display impaired adipogenesis, characterized by a reduced number of adipocytes and ultrastructural abnormalities in lipid droplets, mitochondria, and plasma membrane. Overexpression of PPARg increase the number of Agpat2-/- MEFs that differentiated into adipocyte-like cells but did not prevent morphological abnormalities and cell death.
+This study concludes that lipodystrophy in Agpat2 -/- mice results from postnatal cell death of adipose tissue in combination with acute local inflammation AGPAT2 deficient adipocytes may have altered fat deposition or reduced ability to remodel massive fat availability associated with postnatal feeding.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_dfa30e7e-e750-4b65-bcd5-9421cc34fc43-2024-11-13T170000.000Z,73,PubMed:27408775
+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
+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
+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
+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
+Yme1l1 loss in the CNS causes microphthalmia and cataracts.,Model Systems Non-human model organism,"Sprenger HG, et al., 2019, PMID: 30389680","Newborn homozygous knockout mice had dramatic microphthalmia and developed cataracts (Fig. 1A). The outer plexiform layer of the retina looked disorganized and contained nuclei that were absent from the WT control (Figs. 1B and 1C). Accumulating markers such as Gfap, Tnfα, Il‐1β, Asc, Myd88, and Fgf21 indicated neuroinflammation. mtDNA levels were unaffected (different from Opa1 model). Also brain atrophy was not present. Aberrant positioning of hind limbs and progressive locomotor impairment starting at 17 weeks of age (restricted to hind limbs) were observed. Progressive axonal degeneration of dorso‐lateral tracts and neuroinflammation in the spinal cord (Fig. 4, alternative explanation following absence of brain atrophy evidence in Fig. 3). The mitochondrial network was characterized by fragmented and clumped mitochondria (Fig. 5A)
+respiratory defects that appear in aged mice
+axons of retinal ganglion cells mostly unaffected despite impaired eye development and microphthalmia",Score,0.5 (2),"Microphthalmia and cataracts are more severe and not really what is expected for optic atrophy, but clearly the Yme1l1 protein is more important in mouse development.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1a187bfd-89e8-49f1-82a2-b5312960c722-2025-01-16T170000.000Z,3074,PubMed:30389680
+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
+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
+Mouse Model,Model Systems Non-human model organism,"Wei W, et al., 2022, PMID: 34954140",The anemia and low hemoglobin levels seen in the mice are similar to the phenotypes in humans.,Score,2.5 (2),The score was slightly upgraded due to analyzing a specific variant (p.Glu109Lys) that was seen in humans.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b6093e90-7ec2-4cdb-9323-b67df78930a3-2024-11-20T170000.000Z,1943,PubMed:34954140
+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
+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
+DRC1 loss-of function mouse model,Model Systems Non-human model organism,"Zhang J, et al., 2021, PMID: 34169321","Both human patients and mice carrying loss-of-function DRC1 mutations show signs of male infertility due to severe sperm tail defects. In addition to sperm with abnormal morphology, both human patients and mutant mice have defective respiratory cilia, lacking the N-DRC and exhibiting altered ciliary motility.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ef37e7a5-e14e-4c71-8231-b01bd636b2b9-2025-03-13T160000.000Z,3077,PubMed:34169321
+Beal et al. 2021,Model Systems Non-human model organism,"Beal R, et al., 2021, PMID: 33842485","Picture shows cross-section of a placenta with and without the presence of ARHGEF18 (p.114RhoGEF) - shows slight similarities to retinal layer defects
+Figure 2 shows that polarity is not functioning correctly.",Score,0 (2),Model focused on Cell-Cell Fusion During Placenta Morphogenesis. Not particularly similar to human retinal phenotypes and therefore not particularly strong evidence.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_96382044-7790-49d1-848c-01d699df9550-2024-11-07T170000.000Z,154,PubMed:33842485
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+CRISPR/Cas9 Cell KO Model,Model Systems Cell culture model,"Fazelzadeh Haghighi M, et al., 2024, PMID: 38722107","Both patients cells (Ng, 2018) and model cells showed no significant changes in cell surface fucosylation.",Score,0 (1),"Awarding 0 points because it is unclear if fucosylation is the reason for decreased NOTCH3 mRNA expression (while this is likely, fucosylation of NOTCH3 was not measured). Both human patients and the KO cell line showed no change in cell surface fucosylation, but that does not contribute to our understanding of this disease.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ebb05334-995a-4e93-ab33-16c35929296b-2024-09-18T170000.000Z,781,PubMed:38722107
+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
+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 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
+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
+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
+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
+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
+Chandra2019_RescuePatientCells,Rescue Patient cells,"Chandra G, et al., 2019, PMID: 31341644","ANO5-GFP expression ameliorated the poor repair phenotype of MMD3 patient myoblasts, since dye entry exclusion following focal injury became similar to that of healthy cells. Dysferlin expression did not rescue the phenotype.",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_cecfa828-c192-44ae-9f3f-9dd5a99a5e5a-2024-11-14T170000.000Z,2697,PubMed:31341644
+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
+Zebrafish morpholino knockdown - gata 1/2,Biochemical Function A,", , PMID: 34234691",Both GATA1 and GATA2 have phenotypes consistent with defective erythropoiesis,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c9465f7d-4fc8-49b6-aa2c-4b92eb5f8c32-2025-01-07T170000.000Z,2725,PubMed:34234691
+ZIP13 mutant failed as zinc transporter,Functional Alteration Non-patient cells,"Bin BH, et al., 2014, PMID: 25007800","Overexpression of G74D in 293T cells led to decreased transcription of metallothionein MT1 and zinc level comparing to the WT.  Zinc level was reduced in the presence of G74D or delFLA mutant in transfected 293T cells or Hela cells, suggesting loss of normal ZIP13 function in the presence of the mutants.
+Transfection of G74D mutant in 293T cells didn't affect the transcript of the ZIP13 but the ZIp13 protein level was greatly reduced. Decreased protein change was observed in the delFLA mutant cells, suggesting the loss of normal ZIP function is potentially due to reduced protein expression
+caused by the variants.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_50b48dba-c9ab-4377-b3a2-348c93426aa4-2024-10-25T040000.000Z,2384,PubMed:25007800
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+KO Mouse,Model Systems Non-human model organism,"Wong DA, et al., 2002, PMID: 12163563","In mice, as in humans, there is a significant decrease in the amount of thromboxane B2 production. While, in mice there is only a slight difference in platelet degranulation and aggregation as compared to humans, the mice do still have a significantly increased bleeding time as seen in some humans.",Score,2 (2),"The knockout mouse model recapitulated certain aspects of human disease, namely decreased thromboxane B2 with associated bleeding tendency. However, the authors did not indicate any gastrointestinal phenotypes of these mice.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ff7f6f85-cca7-4eb2-9957-9023c94402f0-2024-11-04T170000.000Z,2846,PubMed:12163563
+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
+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
+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 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
+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
+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
+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 #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
+proteoliposome-based transport assay,Functional Alteration Non-patient cells,"Rautengarten C, et al., 2019, PMID: 31423530","P133L variant retained low activity of 2 to 4% compared to wildtype
+T65P mutation results in a complete loss-of transport activity",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_4ee94dfc-b68e-4a26-ab68-7af456b9d826-2024-12-23T170000.000Z,2495,PubMed:31423530
+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
+Hypermethylation,Functional Alteration Patient cells,"Motzek A, et al., 2016, PMID: 26974671","Global DNA methylation was increased in two of three analysed patients; using the MethylFlash Methylated DNA Quantification Kit (Epigentek). Patients A and B (Try143Cys/Trp112Ter) showed methylation levels that were 5.6 ± 3.0 times (patient A, p = 0,001) and 6.5 ± 3.1 times (patient B, p = 0,011) as high as those of the controls (n = 3). In contrast, patient F (Arg49Cys/Asp86Gly) displayed a methylation level similar to that of controls (1.3 ± 0.7 times, Fig 1). In addition, DNA methylation levels we analyzed at differentially methylated regions (DMRs) of six imprinted genes (MEST, SNRPN, LIT1, H19, GTL2 and PEG3). Three of seven patients showed a hypermethylation in up to five imprinted gene DMRs. DNA hypermethylation seems to be a frequent but not a constant feature associated with AHCY deficiency.",Review,1 (1),"The massive and simultaneous accumulation of SAH and SAM typically associated with AHCY deficiency may reduce or abolish product inhibition of SAM-dependent DNA methyltransferases but not SAM-dependent non-DNA methyltransferases and thus increase DNA methylation in patients. These abnormal DNA methylation reactions may have occurred only in patients that exceeded a critical threshold of elevated SAH levels at the embryonic stage and thus underwent fetal programming during early to mid-gestation. A global DNA methylation analysis of the patients which, owing to lack of sufficient genomic DNA, were up to now only studied for imprinted gene methylation, would be necessary to further corroborate the hypothesis of fetal programming dependent on SAH levels present around implantation. In addition, the fact that only some patients with AHCY deficiency display DNA hypermethylation and these patients are even not all affected at the global or gene-specific level may reflect the involvement of the AHCY protein in a multitude of cellular pathways and complex protein interaction networks including more than 200 SAM-dependent MTs and thereby adjusting the metabolic machinery of the cell and individual. This is further mirrored by the large variety of clinical disease presentations such as potential lethality in early life and association with hepatocellular carcinoma.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d9b3a56b-b188-44d1-9983-a059895c0ba1-2024-12-13T170000.000Z,2692,PubMed:26974671
+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
+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
+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
+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
+li,Model Systems Non-human model organism,"Li W, et al., 2021, PMID: 33623049","MCF7 derived tumor mass within the local mammary gland and were marked by prominent nucleoli with scant cytoplasm and high proliferation. Tumour had cells with genomic instability,",Score,1 (2),"Changed score to allocate 2 points across 2 non-human model systems, PMID 18443292 also reports a mouse model with LOF BARD1 variant resulting in a breast cancer like phenotype.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_09113d8c-ba63-40f1-9c8f-08b67c6c867c-2024-09-03T170000.000Z,211,PubMed:33623049
+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
+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
+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
+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
+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
+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
+Mouse in situ hybridization,Expression A,"Mommersteeg MT, et al., 2015, PMID: 25691540",Mouse ISH,Score,0 (0.5),Type of evidence already scored with other publications,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ef3f81f4-4b3b-40ee-af2c-8235e92e7cfb-2024-09-03T160000.000Z,1877,PubMed:25691540
+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
+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
+transient transfection in vitro,Functional Alteration Non-patient cells,"Stremenova Spegarova J, et al., 2024, PMID: 38753439","equivalent protein expression, but significantly higher dose-dependent NFkB signalling than WT in response to TLR7 agonists",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6ad2864d-9d38-46ad-9bb0-5020b87cbe55-2024-10-11T190000.000Z,3041,PubMed:38753439
+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
+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
+Taniguchi-Ikeda_Rescue in patient cells,Rescue Patient cells,"Taniguchi-Ikeda M, et al., 2011, PMID: 21979053","Corrected fukutin mRNA was restored to 50% or more of the levels seen in normal controls. In addition, recovery of normally glycosylated α-DG in AED-treated myotubes and increased laminin clustering ability were also observed.",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_54e23f1a-3b1b-49ef-aa02-6b46374b1546-2024-08-13T190000.000Z,2760,PubMed:21979053
+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
+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
+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
+Functional Testing for Family 1 Variant,Functional Alteration Patient cells,"Abolhassani H, et al., 2017, PMID: 28011864","Flow cytometric analysis showed that CD70 was absent from B cells from P1 or P2, and expression was reduced to ∼50% of the normal value in the heterozygous father (Fig. 2 A). Western blotting of HEK293 cells transfected with WT or mutant (p.S84Pfs27X) CD70 was performed using two different antibodies recognizing distinct epitopes of CD70 (Ab1 and Ab2; Fig. 1 E and Fig. 2 B). Neither full-length nor truncated forms of mutant CD70 were detected, confirming that the patients’ CD70 allele is a loss-of-expression variant.",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_69aa819c-1f25-42fe-8469-4641fc088a57-2025-02-05T170000.000Z,2989,PubMed:28011864
+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
+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
+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
+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
+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
+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
+"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
+COG3 siRNA in HeLa cells - function in Golgi,Biochemical Function B,"Zolov SN, et al., 2005, PMID: 15728195","siRNA knock down of COG3 in HeLa cells results in:
+reduction of COG1, COG2, and COG4 protein
+fragmentation of the Golgi into three to four stacked cisternae
+accumulation of Golgi proteins (Golgi v-SNAREs GS15, GS28 and GPP130) in nontethered vesicles named “COG complex-dependent” (CCD) vesicles.
+Used GFP-tagged vesicular stomatitis virus G protein (VSVG) as a cargo marker for anterograde protein trafficking and Cy3-labeled subunit B of the Shiga toxin (STB-Cy3) as a marker for the retrograde trafficking.
+Showed that fragmented Golgi membranes are competent for the anterograde trafficking, but COG3 KD resulted in inhibition of retrograde trafficking.
+Abnormality of retrograde trafficking has also been noted in cells from patients (Duan et al)",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6d2120a6-1287-4cba-9f94-f071f0b1abd4-2024-09-19T160000.000Z,451,PubMed:15728195
+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
+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
+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
+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
+Gao hypomorphic mouse,Model Systems Non-human model organism,"Gao R, et al., 2019, PMID: 31024170","Hypomorphic mouse line, a model of decreased ISL1 expression, had VSDs and atrial septal defects. Isl1-f;neo/f;neo mice died shortly after birth with severe cardiac malformations. Whole-mount and histological analyses of Isl1 hypomorphic embryos at E12.5 and E17.5 revealed various degrees of cardiac OFT septation abnormalities, including partial OFT septal defects with aortic stenosis and misalignment and PTA. Nearly all Isl1 hypomorphic mice presented VSDs and ASDs. The results are consistent with human studies which identified ISL1 variants with decreased expression contributing to VSD",Score,1.5 (2),Downgraded 0.5 pt for being a hypomorphic model,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ad4a2c95-f9fb-45a3-84e4-2e1d0d71c779-2024-08-06T160000.000Z,1085,PubMed:31024170
+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
+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
+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
+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
+ciliary beat of airway epithelial cells.,Functional Alteration Patient cells,"Horani A, et al., 2013, PMID: 23991085","Examining the cilia beat pattern of ciliated cell clusters revealed stiff and hyperkinetic cilia, with a limited cilia stroke compared to cilia from non-PCD controls",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_662ab516-ba5f-46aa-97b2-ef4c8f3201a5-2024-08-08T160000.000Z,327,PubMed:23991085
+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
+FKRP and Glycosyltransferase Activity,Functional Alteration Non-patient cells,"Kuwabara N, et al., 2020, PMID: 31949166","Three variants, Tyr88Phe, Ser221Arg, and Leu276Ile, were produced and the oligomerization states and glycosyltransferase activity were analyzed compared to the wild-type. All of the mutated proteins had a lower weight than the WT, suggesting altered structure and subunit dissociation. Activity analysis showed approximately 20%, 5%, and 50% of the wild-type enzyme activity, respectively correlating with the phenotypic severity of probands that have these variants.",Score,0.5 (0.5),"Because FKRP mutants cause a confirmational change in the FKRP protein, resulting in lower glycosyltransferase activity, this evidence supports variants being responsible for the phenotypes observed in muscular dystrophy-dystroglycanopathy. Therefore, this evidence earns default points.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6cb46400-ca4b-48cd-aaf7-dd493f0d2971-2024-08-13T190000.000Z,2759,PubMed:31949166
+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
+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
+Mock Zebrafish,Model Systems Non-human model organism,"Mock AF, et al., 2010, PMID: 20712895","SCA13 variants have similar effects on human and zebrafish Kv3.3 channels. Similarly to R420H, the corresponding mutation R335H was not functional when expressed alone but exerted a dominant negative effect on the activity of the zebrafish wild type subunit. F363L corresponds to the human mutation F448L, which generated functional channels in oocytes. Voltage dependence of pore opening was shifted in the hyperpolarized direction by -7.6 mV compared to wild type Kv3.3 and dramatically slowed channel deactivation.",Score,1 (2),Downgraded by half of default points since this is a Zebrafish model,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_18613a4a-5124-499a-b224-1c4aae4b1c55-2024-11-07T050000.000Z,2983,PubMed:20712895
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+"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
+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
+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
+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
+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
+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
+Hartmann - Functional alteration (patient cells),Functional Alteration Patient cells,"Hartmann B, et al., 2016, PMID: 27495975",Patient cells were shown to have increased mitochondrial fragmentation and impaired cell proliferation evidenced by increase in shortened and fragmented mitochondrial networks in fibroblasts of patient II.5 relative to a control and reduced cell culture growth in patient II.5 fibroblasts.,Score,0.5 (1),Patient cells were shown to have increased mitochondrial fragmentation and impaired cell proliferation evidenced by increase in shortened and fragmented mitochondrial networks in fibroblasts of patient II.5 relative to a control and reduced cell culture growth in patient II.5 fibroblasts.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b403159f-e5ae-446c-bb17-222dc8eebded-2024-07-15T040000.000Z,2951,PubMed:27495975
+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
+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
+Kanagawa_insertion knock-in mouse,Model Systems Non-human model organism,"Kanagawa M, et al., 2009, PMID: 19017726","To recapitulate human phenotype, mice homozygous for the 3-kb insertion (Hp/Hp) and compound heterozygous mice containing 1 insertion allele and a null allele (Hp/-) were generated. In human FCMD patients homozygous insertion allele patients show a milder phneotype compared to those compound heterozygous with a null allele.
+Other than hypoglycosylation of α-DG (more severe in Hp/- than Hp/Hp), no other features of FCMD were recapitulated in the mice. Histopathological features of muscular dystrophy, such as centrally located nuclei, tissue fibrosis and fatty infiltration were not observed in 10-week-old FCMD models Hp/− and Hp/Hp mice. Levels of hypoglycosylation and laminin-binding activity varied among tissues. Gene transfer of a recombinant WT fukutin adenovirus resulted in partial restoration of α-DG glycosylation, which might be beneficial in reducing severity in dystroglycanopathy.",Score,0.5 (2),The evidence is scored minimal points since the model does not recapitulate the FCMD phenotype.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_54e23f1a-3b1b-49ef-aa02-6b46374b1546-2024-08-13T190000.000Z,2760,PubMed:19017726
+Paganini_mouse model,Model Systems Non-human model organism,"Paganini C, et al., 2019, PMID: 30439444","Like the human phenotype, homozygous mice showed short stature, kyphosis, and digit abnormalities.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_30c64852-60e0-44ce-bf10-cf7af11b1fa9-2024-11-20T170000.000Z,296,PubMed:30439444
+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
+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
+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
+Treating Rankl −/− mice with subcutaneous injections of RANK,Rescue Non-human model organism,"Lo Iacono N, et al., 2013, PMID: 23762088","The 1 mg/kg dose proved to be able to almost completely rescue the bone defect, by restoring osteoclast differentiation and resorption. The 1 mg/kg dose importantly improved the hematolymphoid compartment of the treated Rankl −/− mice, with a restoration of the hematopoietic function within the bone marrow and an improvement of splenic and thymic architecture.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_90e426a0-23df-43d0-951c-ab6d7eb41158-2024-12-02T170000.000Z,2910,PubMed:23762088
+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
+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
+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
+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
+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
+CRISPR-mediated myoediting,Rescue Cell culture model,"Long C, et al., 2018, PMID: 29404407","The myoediting procedure corrected a large deletion (Ex48-50del) by destroying the splice acceptor in exon 51, which enables splicing of exon 47 to exon 52 due to reframing by NHEJ. This wass confirmed by sequencing and RT-PCR, and the authors note that this could potentially correct the alteration in ~13% of DMD mutations. Similar rescue of other DMD mutations are described. The authors show restoration of dystrophin protein expression in iCMs as well as rescue of contractile dysfunction in the 3D-EHMs.
+PMID: 30379597 provides a good review of other CRISPR-mediated correction of DMD mutations",Score,1 (1),The evidence is scored default points for restoration of DMD expression in patient-derived cells.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b528435f-dc16-45e0-9f0f-2da3f293ab4c-2024-11-14T170000.000Z,2745,PubMed:29404407
+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
+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
+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
+CEP104 silencing in zebrafish,Model Systems Non-human model organism,"Frikstad KM, et al., 2019, PMID: 31412255","cilia-related manifestations observed in the zebrafish included shortened cilia in Kupffer’s vesicle, heart laterality, and cranial nerve development defects. Joubert syndrome is known as a ciliopathy and patients primarily present with abnormal brain development.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_be550486-4da7-4de4-9db4-6f5cdb98ff39-2025-01-28T170000.000Z,2976,PubMed:31412255
+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
+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
+Gregorio_Expression,Expression A,"Gregorio CC, et al., 1998, PMID: 9817758","At day 9.5 pc, telethonin transcripts were detected in the developing heart and in the somites and otic vesicle. The transcription pattern of telethonin was noted to be similar to that of titin. In a survey of adult tissues by RT-PCR, telethonin transcripts were found in striated muscles, including human fetal heart, adult heart and skeletal muscles, but were absent in normal and pregnant uterus, fetal brain, liver and spleen.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_f3c6c72e-7c2b-42d4-963b-aeddbbe0e4fc-2024-08-14T190000.000Z,2900,PubMed:9817758
+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
+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
+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
+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
+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
+Cacciottolo_65patients_expression,Expression B,"Cacciottolo M, et al., 2011, PMID: 21522182",This study describes a cohort of 65 LGMD/MM patients with ≤20% Dysferlin on Western Blot performed on muscle biopsies from these patients.,Score,0.5 (0.5),"Absent or severely decrease levels of dysferlin protein in muscle tissue is a typical feature of Autosomal recessive limb-girdle muscular dystrophy. This study describes a cohort of 65 LGMD/MM patients with ≤20% Dysferlin on Western Blot performed on muscle biopsies from these patients. Different pathogenic DYSF variants were reported as causal in this study. Since altered protein level is shown repeatedly in multiple patients with the disease regardless of the causative variant, this evidence is scored default points.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_94042756-2e7a-4cfa-812c-1b88b703eeea-2024-11-14T170000.000Z,2750,PubMed:21522182
+Gating for ILC's in DIAPH1 deficient patient cells,Functional Alteration Patient cells,"Azizoglu ZB, et al., 2024, PMID: 39120629","All subsets of helper ILCs were dramatically reduced in the peripheral blood of all four patients
+tested (Fig. 6b, c). Both the frequency of ILC3 among all helper ILCs and their absolute numbers were reduced indicating a major negative impact of DIAPH1 deficiency on ILC3s (or ILC precursors). Additionally, helper ILC1 and ILC2 numbers are significantly reduced as well. There was also reduced cytotoxic activity of DIAPH1-deficient PBMCs, suggesting a functional defect in NK cell cytotoxicity function and a significantly reduced CD69, NKp44 surface and Granzyme B and IFN-γ production by DIAPH1-deficient NK cells, collectively arguing for an impaired NK cell function in the absence of functional cellular DIAPH1.",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1a6bb748-bda5-4d57-ab9c-00882cbefdf6-2024-11-21T170000.000Z,2744,PubMed:39120629
+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
+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
+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
+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
+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
+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
+Cheng_Mouse,Model Systems Non-human model organism,"Cheng C, et al., 2022, PMID: 36280881",Knock-in mouse with c.311T>C; p. L104P was lethal at embryonic day E10.5t.,Score,0.5 (2),Knock-in mouse with c.311T>C; p. L104P was lethal at embryonic day E10.5t.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_940d64cb-da20-4608-961d-345d6c8b437c-2024-09-19T040000.000Z,2941,PubMed:36280881
+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
+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
+A pig model with YME1L1 silencing by dsRNA microinjection,Model Systems Non-human model organism,"Zhou D, et al., 2023, PMID: 37123411","The model shows; mitochondrial fragmentation, mitochondrial dysfunction (ROS production, lower membrane potential, lower ATP levels), apoptosis in embryo, inhibition of proliferation, and reduced blastocyst quality.",Score,0.5 (2),"The model compares silencing of Yme1l1 to a GFP silencing control, with a match to the human patients at the cellular level at least.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1a187bfd-89e8-49f1-82a2-b5312960c722-2025-01-16T170000.000Z,3074,PubMed:37123411
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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 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
+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
+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
+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
+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
+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
+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
+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
+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
+increased sensitivity in transfected cells,Functional Alteration Non-patient cells,"López-Gálvez R, et al., 2021, PMID: 33725261","Activation of the plasma contact system was assessed by western blot and amidolytic assay in basal conditions or after treatment with either artificial or physiological activators.
+Neither wild-type nor FXIILys309 recombinant FXII variants generated by S2 insect (Drosophila) cells were activated by incubation with silica or DXS, even at high concentrations. However, when supplemented to plasma from a patient with congenital deficiency of FXII due to the homozygous c.919delG pathogenic variant, spontaneous activation of the mutated FXIILys309 variant was observed with consequent generation of PKa.",Score,0.5 (0.5),"The results of this study, confirmed the sensitivity of the FXIIThr309Lys variant to become proteolytically cleaved by thrombin, thereby priming FXII for fluid-phase activation of the contact system. This observation and the fact that angioedema episodes in some of the carriers of this variant are triggered during hypercoagulable situations (i.e. contraceptives or pregnancy) in which an increased thrombin generation has been reported, suggest a key role for thrombin as trigger of angioedema in these patients.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_f40992c9-1172-4528-ab53-95108094d4b6-2024-09-04T160000.000Z,2757,PubMed:33725261
+Adhesion to collagen,Functional Alteration Patient cells,"Kirkby NS, et al., 2015, PMID: 26183771",Platelet adhesion to a collagen-coated surface in flowing blood was abolished by cPLA2 inhibition by pyrophenone and absent in blood from cPLA2α-deficient patients.,Score,1 (1),These data are in agreement with reports of the importance of cPLA2α and TXA2 generation in platelet adhesion.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ff7f6f85-cca7-4eb2-9957-9023c94402f0-2024-11-04T170000.000Z,2846,PubMed:26183771
+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
+Rescue of Cargo Delivery Defect in Patient Cells,Rescue Patient cells,"Van Bergen NJ, et al., 2020, PMID: 32639540","Temperature sensitive VSVG-GFP were used to measure cargo delivery efficiency. Prior to transduction, patient derived fibroblasts with homozygous loss-of-function variants exhibited a defect in cargo delivery. Expression of wild type EXOC2 restored wild type cargo delivery. Of note, the defect was also evident in patient fibroblasts with biallelic missense variants in EXOC2. Rescue experiments failed to rescue the phenotype in these cells.",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_8813a496-aad3-4854-83de-8c935d07ad44-2024-08-01T170000.000Z,2756,PubMed:32639540
+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
+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
+Gazzerro_expression_study,Expression A,"Gazzerro E, et al., 2012, PMID: 22461884","LacZ regulatory elements were integrated into the HYCC1 locus of heterozygous Hyccin mice, allowing the tissue location of Hyccin to be studied by LacZ staining. Hyccin gene expression was then found in olfactory nuclei, distinct layers of the neocortex, and hippocampal regions",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1717e62b-6b1e-47fd-a335-de3fd597f7a4-2025-03-13T160000.000Z,3036,PubMed:22461884
+Reduced cytokine production in non-patient cells,Functional Alteration Non-patient cells,"Wu B, et al., 2021, PMID: 34908525","Similar to patient T cells, CRACR2A CRISPR/Cas9 KO Jurkat T cells showed reduced IL-2 production. Stable expression of WT CRACR2A in these cells substantially rescued the IL-2 production defect, validating that the decrease was caused due to loss of CRACR2A. However, expression of E278D or R144G/E300* mutants showed very marginal rescue of IL-2 expression in CRACR2A KO Jurkat T cells under the same condition.
+Accordingly, CRACR2A KO Jurkat T cells showed reduced Ca2+ entry triggered by TCR stimulation. Expression of WT CRACR2A fully rescued the decreased level of Ca2+ entry in KO cells while that of R144G/E300* and E278D mutants did not.",Score,1 (0.5),"The authors also validated these results with primary human CD4+ cells. They found that transduction with lentiviral vectors encoding sgRNA to delete CRACR2A resulted in reduced IFN-γ production in primary cells, which was completely rescued by expression of WT CRACR2A (Figure 5B). However, both E278D and R144G/E300* mutants did not rescue cytokine production in the KO primary T cells, similar to our observations with Jurkat T cells.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_404d2603-e070-4798-81b0-ebf683a76efe-2024-09-19T160000.000Z,524,PubMed:34908525
+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
+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
+Vesicle Fusion Rate Rescue in Patient Cells,Rescue Patient cells,"Van Bergen NJ, et al., 2020, PMID: 32639540","Patient derived fibroblasts with homozygous loss-of-function variants were transduced with EXOC2 wild-type lentiviral particles. Protein expression was restored to control level, and subsequently, global vesicle fusion rates restored to control levels.",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_8813a496-aad3-4854-83de-8c935d07ad44-2024-08-01T170000.000Z,2756,PubMed:32639540
+Tani et al. SHMT2 Knock Out Mice,Model Systems Non-human model organism,"Tani H, et al., 2018, PMID: 29323231","Model system provides evidence that SHMT2 deficiency causes deficiencies in mitochondrial respiration which the authors posit is due to deficiencies in production of N-formylmethionine-tRNA and mitochondrial translation. However, there is limited phenotype overlap between SHMT2 knock out mice and probands with SHMT2 variants, as knock out mice were embryonic lethal while probands survive at least through childhood with cardiomyopathy, spasticity,
+and brain abnormalities.",Score,1 (2),"Downscored to 1 due to a recapitulation of the disease at the molecular level, but a lack of recapitulation of the disease phenotype at the organ/organism level. Follow up paper on same knock out embryos at 13.5 post coitum by same authors (PMID: 31690790) demonstrated that the livers but not the brains presented mitochondrial respiration defects and growth retardation. Additionally, the authors found that Shmt2 deficiency induced foetal liver-specific downregulation of 1C-metabolic pathways that create taurine and nucleotides required for mitochondrial respiratory function and cell division, respectively, resulting in the manifestation of mitochondrial respiration defects and growth retardation. Fiddler et al. also demonstrated that homozygous KO mice are embryonic lethal  (PMID:34383924).",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_cf0af939-9015-47dd-bbcd-192114220334-2024-07-12T160000.000Z,2884,PubMed:29323231
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+"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
+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
+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
+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
+Le Coz_Rescue,Rescue Human,"Le Coz C, et al., 2021, PMID: 33951726",The authors showed that PU.1 expression normalised and B cell & cDC deficiencies resolved in the proband following adoptive transfer of hematopoietic stem and progenitor cells (HSPCs) from the proband's unaffected sibling.,Score,0 (2),The evidence is not scored because the rescue was an adoptive transfer of HSPCs and therefore not specifically targeted to the gene (SPI1) or protein product (PU.1).,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_76a93861-b7d3-4d08-8882-6a7a1456b51a-2024-12-12T170000.000Z,2966,PubMed:33951726
+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
+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
+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
+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
+Liberfarb similar to atypical class of mitochondrial disease,Biochemical Function A,", , PMID: 30858161","LONP1 encodes an enzyme of that participates in protein turnover within the mitochondrial matrix (Dikoglu et al., PMID 25808063). HSPA9 codes for mHSP70/mortalin, a mitochondrial chaperone protein essential in mitochondrial protein import, folding, and degradation (Royer-Bertrand et al., PMID 26598328). AIFM1 encodes mitochondria associated apoptosis-inducing factor (Mierzewska et al, PMID 27102849).",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c79d65c7-3c7b-42fa-a84b-894bc865316d-2024-10-02T160000.000Z,2844,PubMed:30858161
+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
+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
+transcription and protein expression in patine PBMC,Expression B,"Stremenova Spegarova J, et al., 2024, PMID: 38753439","TLR7 protein expression was increased, especially in B cells, monocytes, and dendritic cells. transcription was also increased",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6ad2864d-9d38-46ad-9bb0-5020b87cbe55-2024-10-11T190000.000Z,3041,PubMed:38753439
+Co-IP DNAH9-CCDC114,Protein Interaction,"Loges NT, et al., 2018, PMID: 30471718",DNAH9 is essential for ODA type 2 assembly. The docking of ODAs type 2 occurs via direct interaction of DNAH9 with the docking complex protein CCDC114.,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7d4c2324-1f4e-48d6-b7e9-cc66f7a9dda3-2024-09-19T160000.000Z,627,PubMed:30471718
+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
+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
+physical interaction between G4C2 RNA and MATR3,Protein Interaction,"Ramesh N, et al., 2020, PMID: 33129345","Using fluorescent in situ hybridization (FISH) coupled with immunocytochemistry, the authors analyzed the nuclei of these cells and observed colocalization between G4C2 RNA foci and MATR3 in two independent C9-ALS patient-derived iPSC-MNs. There was apparent colocalization between G4C2 foci with both punctate and diffuse forms of MATR3 within the nuclei of C9 iPSC-MNs.",Score,0.5 (0.5),"Here it was shown that the ALS-associated RNA-binding protein, Matrin-3 (MATR3), colocalizes with G4C2 RNA foci in patient tissues as well as iPSC-derived motor neurons harboring the C9orf72 mutation. Hyperexpansion of C9 repeats perturbed subcellular distribution and levels of endogenous MATR3 in C9-ALS patient-derived motor neurons.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_97ed1e35-c1b2-40c7-a60e-54b3c24004c4-2024-10-08T160000.000Z,2811,PubMed:33129345
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+Blackburn 2016_COG7 protein interaction,Protein Interaction,"Bailey Blackburn J, et al., 2016, PMID: 27066481",Encoding subunits of a complex protein,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_398c1212-8417-499e-8427-79a752745aec-2024-10-19T170000.000Z,453,PubMed:27066481
+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
+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
+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
+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
+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
+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
+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
+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
+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
+CYB5A Function - Methemoglobin Reduction,Biochemical Function B,"Hall R, et al., 2022, PMID: 36441026","Cytochrome b5 is a known cofactor for cytochrome b5 reductase 3. In erythrocytes, this enzyme acts to reduce methemoglobin (Fe3+) to hemoglobin (Fe2+), and b5 is an essential cofactor in this process. Therefore, loss of b5 function inhibits methemoglobin reduction, leading to elevated serum methemoglobin and a state of hypoxia.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_895f7f88-9dcc-42fd-8773-e20dadb6756c-2024-12-13T190000.000Z,2388,PubMed:36441026
+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
+Stimulation studies in Patient derived DIAPH1 deficient cell,Functional Alteration Patient cells,"Azizoglu ZB, et al., 2024, PMID: 39120629","Cytoskeleton regulation defects observed in individuals cells with DIAPH1 defects by exhibiting lower T cell migration across the transwell chamber. This was further supported by evidence of significantly elevated percentage of FOXP3+ Treg cells in the peripheral blood of DIAPH1- deficient patients compared with healthy controls (Fig. 3d) suggesting that the expansion of Treg cells is negatively affected by DIAPH1 deficiency, and is consistent with cytoskeletonopathies.",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1a6bb748-bda5-4d57-ab9c-00882cbefdf6-2024-11-21T170000.000Z,2744,PubMed:39120629
+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
+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
+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
+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
+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
+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
+Fly mutant,Model Systems Non-human model organism,"Santiago-Martínez E, et al., 2008, PMID: 18663139",abnormal heart lumen formation,Score,0.5 (2),Fly heart only partially replicates human cardiac development,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a0d0c93c-abf7-4bf2-8b0f-e47cfce87656-2024-09-03T160000.000Z,1876,PubMed:18663139
+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
+STAT5 phosphorylation assay in DIAPH1 knockdown Jurkat Cells,Functional Alteration Non-patient cells,"Azizoglu ZB, et al., 2024, PMID: 39120629","Findings confirmed a decrease in STAT5 phosphorylation when DIAPH1-silenced Jurkat cells with shRNA were activated with IL-2 (Fig. 4c). STAT5 phosphorylation was also reduced in the DIAPH-silenced Jurkat cells compared with scrambled shRNA, suggesting DIAPH1- mediated regulation of the IL-2/STAT5 axis (Fig. 4d). CD25 surface expression was significantly lower on the cell surface of Jurkat cells after DIAPH1 knockdown, which may partly explain reduced STAT5 phosphorylation in response to IL-2 (Fig. 4e). There was no observe a significant difference in IL-2-mediated STAT5 phosphorylation in primary T cells which may be due to lower knockdown efficiency or compensatory mechanisms (Fig. S3d). Collectively these results support a role for DIAPH1 in IL-2, IL-7 and IL-15-mediated STAT5 phosphorylation. The deficiency of these three signaling pathways may thus partly explain not only the Treg cell expansion, but also the non-Treg T cell activation and proliferation defects.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1a6bb748-bda5-4d57-ab9c-00882cbefdf6-2024-11-21T170000.000Z,2744,PubMed:39120629
+Rescue Experiment,Rescue Patient cells,"Erger F, et al., 2023, PMID: 37216524",resulted in a partial rescue,Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5a5ca158-bc76-49f8-84a0-fc60e6b13fdb-2025-01-28T170000.000Z,2998,PubMed:37216524
+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
+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
+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
+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
+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
+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
+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
+TMEM16K knockout mice,Model Systems Non-human model organism,"Petkovic M, et al., 2020, PMID: 32620747","In humans, variants in ANO10 have been linked to ataxia. TMEM16K KO mice display a reduction in the size of neuromuscular junctions, increased hindlimb clasping, and impaired ability to complete a ledge-walking test which indicate impaired neuromuscular function, a symptom of ataxia.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5ae3de38-041c-4440-8302-7a33de494755-2024-12-11T170000.000Z,126,PubMed:32620747
+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
+Zheng_Dnah9_KD_mice,Model Systems Non-human model organism,"Zheng R, et al., 2022, PMID: 35729109","Partial absence of outer dynein arms and a reduced distal ciliary bending in patients and in model.
+Low sperm motility in some patients.",Score,1 (2),"Although the model demonstrates a ciliary defect, it does not account for the observed clinical signs in patients.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7d4c2324-1f4e-48d6-b7e9-cc66f7a9dda3-2024-09-19T160000.000Z,627,PubMed:35729109
+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
+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
+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
+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
+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
+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
+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
+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
+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
+Gable HCT116 Cell Model,Model Systems Cell culture model,", , PMID: 31488579",Human proband and cell model both show decreased fraction of mature telomerase RNA present.,Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c0a97a49-6f40-4009-9215-2c61901d8087-2024-10-17T190000.000Z,2367,PubMed:31488579
+CH70 Expression detected with anti-CD70 AB (pt versus HC),Biochemical Function B,"Caorsi R, et al., 2018, PMID: 29434583",CD27–CD70 binding provides a costimulatory signal for CD4 and CD8 activation and studies in mice have provided evidences for its role in memory expansion and protection upon reinfection,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_69aa819c-1f25-42fe-8469-4641fc088a57-2025-02-05T170000.000Z,2989,PubMed:29434583
+Ungar 2002_Protein Interactions,Protein Interaction,"Ungar D, et al., 2002, PMID: 11980916","The Conserved Oligomeric Golgi (COG) complex, a multi-subunit vesicle tethering complex of the CATCHR (Complexes Associated with Tethering Containing Helical Rods) family, controls several aspects of cellular homeostasis by orchestrating retrograde vesicle traffic within the Golgi.
+The COG complex has eight subunits, encoded by eight different genes, and exists as a hetero-octameric complex or as lobe A (COG1, COG2, COG3, COG4) and lobe B subcomplexes (COG5, COG6, COG7, COG8)",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_398c1212-8417-499e-8427-79a752745aec-2024-10-19T170000.000Z,453,PubMed:11980916
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+The variant fails to rescue Prph4 knockdown zebrafish.,Rescue Non-human model organism,"Linder B, et al., 2014, PMID: 25383878","The wild-type Prph4 mRNA partially rescues the phenotype (Figures 2E, 2I), while the variant mRNA does not rescue (Figures 2F, 2J).",Score,0 (2),"Scoring has not been recommended as this evidence is non-ocular and therefore primarily supports the effect of the variant on overall Prpf4 function, not the connection between Prpf4 and retinal disease.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_8db34ddb-4693-4efe-b62a-a2238f5696c8-2024-08-01T160000.000Z,1766,PubMed:25383878
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+Wilken et al. 2024,Biochemical Function A,"Wilken A, et al., 2024, PMID: 39056782","DNAH1 was classified as having a ""limited"" relationship with PCD 37 and a “definitive” relationship with spermatogenic failure 18 by the Motile Ciliopathy GCEP. Refer to the curation for further details.",Score,0 (0.5),The relationship between DNAH1 and PCD is limited.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0e919f48-1c90-45d9-b909-9a619e4e71d0-2025-01-09T170000.000Z,3071,PubMed:39056782
+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
+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
+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
+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
+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
+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
+Protein interactions of COG5 with 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.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0104222e-f6a3-445c-becb-b45fa0f7f108-2024-12-15T170000.000Z,2486,PubMed:11980916
+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
+FKRP and α-DG Glycosylation,Biochemical Function B,"Kanagawa M, et al., 2017, PMID: 29081423","Proper function of dystroglycan, the central component of the dystrophin-glycoprotein complex (DGC), is essential for the DGC's function of connecting the basement membrane to dystrophin-actin cytoskeleton across the plasma membrane. α-DG must be glycosylated in order to properly function via ligand binding activities. Any interruption in the glycosylation, including defective tandem RboP biosynthesis, can cause significantly lowered or absent levels of functional α-DG and cause moderate to severe phenotypes in the muscle, brain, and eyes during development or later in life. These shared phenotypes are observed resulting from variants in many genes relating to the glycosylation pathway.",Score,1 (0.5),"FKRP's biochemical function is both very well-known and shared with a group of many other genes that share similar phenotypes due to identical molecular mechanisms. Therefore, this evidence is upgraded to 1 point.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6cb46400-ca4b-48cd-aaf7-dd493f0d2971-2024-08-13T190000.000Z,2759,PubMed:29081423
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+activation by cellular compression,Biochemical Function B,"Nordgaard C, et al., 2022, PMID: 35899396","Here, the authors show that the ubiquitously expressed MAP3K20 splice form ZAKβ is activated by osmotic shock and mechanical compression of cells. This process is mediated through a C‐terminal domain that responds to the mechanical perturbation of cytoskeletal stress fibers. In skeletal muscle, Z‐disc localized ZAKβ responds to muscle fiber contraction to mediate MAP kinase activation and is required to prevent muscle pathology.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_03628749-51d6-437e-9816-1e32852645cf-2024-10-28T160000.000Z,2809,PubMed:35899396
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+interacting partners ORAI1 and STIM1,Protein Interaction,"Wu B, et al., 2021, PMID: 34908525",Coimmunoprecipitation of CRACR2A with ORAI1 and with STIM1,Score,0.5 (0.5),ORAI1 and with STIM1 have assertions for a gene-disease relationship with immunodeficiency but have not yet been evaluated by the CID-SCID GCEP.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_404d2603-e070-4798-81b0-ebf683a76efe-2024-09-19T160000.000Z,524,PubMed:34908525
+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
+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
+CYB5R3 Biochemical Function,Biochemical Function B,"Hall R, et al., 2022, PMID: 36441026","Cytochrome b5 reductase is the primary enzyme responsible for the reduction of methemoglobin in erythrocytes. Loss of enzyme function leads to elevated serum methemoglobin. Further, this enzyme acts as a major regulator of redox homeostasis in numerous tissues and cell types, which may contribute to the neurological defects observed in severely affected individuals. Of note, these neurological defects are not secondary to elevated serum methemoglobin, as this symptom can be treated by ascorbic acid or methylene blue, but neurological issues continue to progress.",Score,1 (0.5),Score upgraded due to the thoroughness of the review,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_aa135949-7d13-41e7-bbee-5cefb3b77774-2024-12-13T190000.000Z,2389,PubMed:36441026
+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
+"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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+Tandem Ubiquitin-Binding Entity based mass spectrometry,Protein Interaction,"Beck DB, et al., 2021, PMID: 33523931","The interacting genes ARID1A, ARID1B, HDAC2 and UBR5 are involved in diseases with similar phenotypes.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1a19f1fb-a027-4580-92e5-936b8ca10692-2024-07-19T160000.000Z,1604,PubMed:33523931
+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
+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
+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
+BAAV mediated GJB2 gene transfer,Rescue Non-human model organism,"Crispino G, et al., 2011, PMID: 21876744","Gap junction coupling is restored. These results suggest that restoration of normal connexin levels by gene delivery via recombinant AAV could be a way to rescue hearing function in DFNB1 mouse models and might, in future, lead to the development of therapeutic interventions in humans, particularly in children.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9af2d792-a1fc-4b96-ae23-ee7a31dd2f99-2024-09-24T160000.000Z,894,PubMed:21876744
+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
+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
+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
+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
+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
+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
+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
+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
+CRISPR/Cas9 LGMD Insertion in Mice,Model Systems Non-human model organism,"Demonbreun AR, et al., 2019, PMID: 31582396","This model has many positive aspects compared to the default mouse model, although it also has some challenges to overcome. In terms of the generation, CRISPR-Cas9 gene editing via HDR is a relatively simple way to modify the genome as needed and create only the variant of interest while leaving the rest untouched. This results in a knock-in with a reasonable assurance that whatever phenotypes are displayed stem solely from the change in the SGCG gene. Specifically the muscle atrophy, elevated serum creatine kinase, progressive weakness (half the strength of controls at 4 months), and signifiacntly increased muscle fibrosis/necrosis are all hallmarks of the human LGMD presentation and are recapitulated here. However, the presence of a known muscular dystrophy-modifying background raises the question of whether some of these phenotypes would not be seen in a mouse with the C57BL/6J background. Unfortunately this is not answered in the paper, so it introduces some doubt as to the total validity of the results.",Score,3 (2),"Because the model knocks-in a well characterized variant and recapitulates most of the hallmark phenotypes of human LGMD in the mice, this model warrants an increaed score. However, there is the complicating factor of the differing background being used to increase the dystrophic phenotype to consider. Therefore, this model earns 3.0 points.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_dc0d70af-ecb5-4755-a840-9e8bb6f4e0a7-2024-11-14T170000.000Z,2883,PubMed:31582396
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+Kim Functional Alteration (Sedimentation Analysis),Functional Alteration Non-patient cells,"Kim HJ, et al., 2013, PMID: 23455423","Wild-type hnRNPA2 was intrinsically aggregation prone with a lag phase of ~4h (Fig. 4e, g). EM revealed that wild-type hnRNPA2 spontaneously formed self-seeding fibrils (Fig. 4f, h; supplementary figure 7), like due to containing steric-zipper motifs that give rise to the spine of an amyloid fibril. Authors deleted the steric zipper residues 287–292 from hnRNPA2 and assessed fibrillization in vitro. Importantly, hnRNPA2Δ287–292 did NOT form fibrils (Fig. 4e, g). Moreover, hnRNPA2Δ287–292 did not fibrillize when seeded by fibrils of wild-type or mutant hnRNPA2 (Supplementary Fig. 7c). Thus, residues 287–292 of hnRNPA2 are critical for spontaneous and seeded fibrillization of the full-length protein. Collectively, these findings indicate that steric zipper motifs centered in the PrLD of wild-type hnRNPA2 are critical to its intrinsic tendency to fibrillize and that disease mutations introduce more potent steric zippers, which accelerate nucleation and polymerization (Supplementary Fig. 6). Importantly, the disease mutation greatly accelerated hnRNPA2 fibrillization (Fig. 4e–h). In all cases, the lag phase was curtailed and fibrillization was well advanced while the wild-type protein remained in lag phase. Thus, the disease mutations directly promote nucleation of hnRNPA2 into fibrils. Moreover, fibrils formed by hnRNPA2-D290V not only seeded their own assembly (Supplementary Fig. 7b, f, g), but also promoted fibrillization of their respective wild-type counterparts (Supplementary Fig. 7d, i).",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1ffe711b-1ff6-4b11-b329-c0f820904764-2024-10-24T190000.000Z,2785,PubMed:23455423
+expression of ARPP21 in HeLa and cultured mouse neurons,Biochemical Function A,"Rehfeld F, et al., 2018, PMID: 29581509",co-localization within stress granules,Score,0.25 (0.5),"Localization within stress granules upon expression in HeLa cells could be a non-specific phenotype; however, endogenous ARPP21 in mouse neurons also shows localization to stress granules under stress conditions. The default score was reduced because the cultured neurons were not specifically motor cortex cells.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_02d4089a-94dd-42b6-ab09-dc258db00ae9-2025-01-14T200000.000Z,3024,PubMed:29581509
+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
+COQ5 Mitochondrial Expression,Expression A,"Nguyen TP, et al., 2014, PMID: 25152161","Northern blot analysis detected a single human COQ5 transcript of about 1.5 kb expressed in all tissues tested including brain, placenta, skeletal muscle, heart, kidney, pancreas, liver, lung, spleen, and colon (Fig. 2A). Further, GFP-tagged COQ5 was expressed in HeLa cells stably expressing mitochondrial-targeted RFP, and the two were found to overlap (Fig. 3A), indicating a mitochondrial localization of hCOQ5. Finally, the results of a proteinase K protection assay in HEK293 cells transfected with pCOQ5-myc were consistent with COQ5 being peripherally associated with the mitochondrial inner membrane on the matrix side (Fig. 3C). These experiments demonstrate the mitochondrial localization of this protein.",Score,0 (0.5),"Since expression is ubiquitous in all tissues and it is known to be mitochondrial, the experts feel that no points should be awarded.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9b9c2846-d034-46f4-87ba-525bed7efe9c-2024-07-10T160000.000Z,500,PubMed:25152161
+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
+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
+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
+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
+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
+DCM vs. Control CTF1 Expression,Expression B,"Rubiś P, et al., 2021, PMID: 34071085","In a cohort of 102 DCM patients and 27 controls, CTF-1 expression was higher in the DCM group then the control group. There was no correlation between CTF-1 expression and myocardial fibrosis on MRI in the DCM group.",Score,0 (0.5),"Did not score; maximum number of points for function experimental evidence was previously reached from other papers (PMIDs: 21771897, 24366078, 12234945, 8833032).",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ef19cc13-543b-451e-b278-ec1fc04f694c-2024-08-07T160000.000Z,2738,PubMed:34071085
+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
+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
+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
+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
+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
+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
+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
+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
+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
+Mini-nebulin in skeletal myocytes,Functional Alteration Non-patient cells,"Pappas CT, et al., 2010, PMID: 20498015","Immunofluorescence microscopy and Western blot analysis showed the full-length mini-nebulin is successfully transcribed and translated and uniformly assembles in the same orientation and manner as endogenous nebulin but extends a shorter distance from the Z-disc. The full-length mini-nebulin protein whose expression is not affected by chicken-specific nebulin siRNA, unlike that of endogenous nebulin. Mini-nebulin was introduced into chick skeletal myocytes depleted of endogenous nebulin via nebulin-specific siRNA. In these myocytes, mini-nebulin staining flanked the Z-disc but not near the center of the sarcomere. No Tmod1 staining was detected in the vicinity of the N terminus of mini-nebulin, suggesting no colocalization of Tmod1 and N terminus of mini-nebulin.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_8c47ca02-4d1a-492a-9836-d7db52a8af3d-2025-03-11T160000.000Z,3032,PubMed:20498015
+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
+Over expression of human AGPAT2 in Agpat2 null mice,Rescue Non-human model organism,"Agarwal AK, et al., 2023, PMID: 37752957","In both sexes of Agpat2-/- null mice, adipose-tissue-specific re-expression of hAGPAT2 resulted in partial regeneration of white and brown adipose tissue (but only 30%–50% compared with wild-type mice, which had molecular signatures of adipocytes, including leptin secretion. This suggests an important role of Agpat2 in adipocyte differentiation. Knockdown of hAGPAT2 expression in vivo resulted in total loss of regenerated adipose tissue, clear evidence that Agpat2 is essential for adipocyte differentiation in vivo.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_dfa30e7e-e750-4b65-bcd5-9421cc34fc43-2024-11-13T170000.000Z,73,PubMed:37752957
+Knockdown of TRAPPC11 with siRNA in HeLa cells,Functional Alteration Non-patient cells,"DeRossi C, et al., 2016, PMID: 26912795","48 h after TRAPPC11 siRNA transfection, TRAPα displayed two additional moieties with increased electrophoretic mobility compared with cells transfected with a nontargeting control siRNA. This finding suggested that knockdown of TRAPPC11, but not other TRAPP subunits, resulted in accumulation of nonglycosylated TRAP-alpha in HeLa cells. In addition, authors found evidence for Golgi complex fragmentation, which was also previously observed by Scrivens et al., 2011.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_8b835ba1-afbd-48ac-afec-b9396acc5521-2024-08-14T190000.000Z,2915,PubMed:26912795
+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
+Kim Functional Alteration (HeLa Cells),Functional Alteration Non-patient cells,"Kim HJ, et al., 2013, PMID: 23455423","Disease mutations may promote excess incorporation of hnRNPA2 into stress granules and drive the formation of cytoplasmic inclusions. To examine the impact of disease mutations, authors expressed Flag-tagged versions of wild- type and mutant hnRNPA2 in HeLa cells and found that there was significantly greater incorporation of mutant hnRNPA2 into constitutive SGs than wild-type hnRNPA2 (Fig. 5). Authors also showed that following arsenite treatment, hnRNPA2B1 relocalized from nuclei to cytoplastmic puncta, showing the recruitment of endogenous hnRNPA2B1 to SGs (supp figure 10) and more rapid accumulation/incorporation compared to WT (Figure 5). HnRNPA2 aggregate in yeast and are toxic (supp figure 9). Yeast cells expressing YFP alone or YFP-tagged WT and mutant human RBPs HNRNPA2B1 and HNRNPA1. Disease-associated variant caused toxic cytoplasmic protein aggregates compared to WT (supp fig 9).",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1ffe711b-1ff6-4b11-b329-c0f820904764-2024-10-24T190000.000Z,2785,PubMed:23455423
+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
+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
+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
+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
+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
+"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
+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
+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
+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
+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
+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
+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
+"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
+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
+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
+"Leishmania Mexicana, McCoy et al., 2023",Model Systems Non-human model organism,"McCoy CJ, et al., 2023, PMID: 36989043","Defective motile cilia are present in both Leishmania KO models and human PCD, with abnormal movement due to structural defects, and most cells lack functional flagella. Leishmania KO mutants display microtubule arrangement abnormalities, similar to human PCD, leading to impaired ciliary movement and a key structural defect in the 9+2 microtubule structure which is commonly the absence of the central pair or misalignment.",Score,0.5 (2),The animal model do not seem to exhibit some of the complex and systemic phenotypes seen in human PCD.,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7881f30d-7281-42d0-9352-0e7fff26f14f-2024-12-05T050000.000Z,2895,PubMed:36989043
+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
+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
+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
+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
+Munis Cell Culture Model,Model Systems Cell culture model,"Munis AM, et al., 2021, PMID: 33426150",Both the model and patient cells show absence or lack of SP-B mature protein.,Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_4bfa265f-3b7a-4091-8e97-b13a7f4f2de7-2024-10-17T190000.000Z,1966,PubMed:33426150
+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
+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
+"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
+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
+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
+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
+"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
+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
+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
+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
+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
+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
+Reh Functional Alteration,Functional Alteration Non-patient cells,"Reh WA, et al., 2017, PMID: 27924006","We found that RAD51D-deficient cells had a significantly higher frequency of spontaneous and ISceI DSB-induced selectable marker loss. These cells also had a severely reduced capacity for HR-mediated gene conversion events. Further, higher marker loss and inefficiency to complete HR manifested as detrimental loss of large segments of the reporter locus via large deletions and SSA
+events.
+RAD51D is implicated in genome stability and HR
+RAD51D-deficient CHO cells exhibit a significant increase in I-Scel induced marker loss compared to wt cells.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_2d2e5a83-03cb-4483-915d-6ac32a84dc0a-2024-08-29T170000.000Z,1816,PubMed:27924006
+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
+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
+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
+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
+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
+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
+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
+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
+"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
+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
+DIAPH1 Deficiency in Patient cells,Functional Alteration Patient cells,"Azizoglu ZB, et al., 2024, PMID: 39120629","Activation of T cells with various mitogens such as CD3/28 and PHA for 4 days, the proliferation
+of T cells was severely impaired in DIAPH1-deficient T cells (Fig. 2a, b), early activation markers CD25 and CD69 surface expressions were significantly reduced by DIAPH1-deficient T cells (Fig. 2c-h). The same impairments in proliferation and activation were observed when sorted CD4+ T cells were used (Fig. S1b), suggesting a T-cell intrinsic defect. Cytokine production of T cells upon
+anti-CD3/CD28 or PMA/Ionomycin activation was examined in patient derived DIAPH1-deficient T cells. They produced significantly lower levels of TNFα and IL-22 (but not IL-17 A, IL-2 and IFN-γ, although a trend was observed) (Fig. 3a) consistent with a defect in the TCR signaling pathway. Serum levels of TNF-α, IL-17 A, and IL-4 were significantly reduced in the patients compared with those of healthy age and sex-matched controls (Fig. 3b).",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1a6bb748-bda5-4d57-ab9c-00882cbefdf6-2024-11-21T170000.000Z,2744,PubMed:39120629
+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
+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
+Transcriptional assay,Biochemical Function B,"Francis GA, et al., 2006, PMID: 16412238",The mechanism underlying the disease association in affected heterozygotes is haploinsufficiency rather than dominant negative interference of the function of the normal allele product,Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b4c76c1c-7e8a-418f-ba62-b7eeb3c3d472-2024-08-14T160000.000Z,1739,PubMed:16412238
+H295R knockdown by shRNA,Functional Alteration Non-patient cells,"Meimaridou E, et al., 2018, PMID: 29046340","H295R Cells (human adrenocortical)
+NNT knockdown by shRNA compared to scrambled knockdown
+Significantly higher NADP/NADPH ratio than scramble
+OCR shows significant reductions in basal, oligomycin, FCCP, and Antimycin / Rotenone measures",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b4e0dd90-67d0-496d-9252-5a374c53ddb9-2024-07-15T040000.000Z,3035,PubMed:29046340
+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
+AGPAT2 Knockout mice using an antisense oligonucleotide,Model Systems Non-human model organism,"Sakuma I, et al., 2023, PMID: 38127985","Turning off the expression of human AGPAT2 in vivo resulted in total loss of adipose tissue in the mice. Conversely, re-expressing human AGPAT2 in both sexes of Agpat2-null mice resulted in partial regeneration of both white and brown adipose tissue.",Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_dfa30e7e-e750-4b65-bcd5-9421cc34fc43-2024-11-13T170000.000Z,73,PubMed:38127985
+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
+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
+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
+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
+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
+Rupp et al. 2003,Biochemical Function B,"Rupp G, et al., 2003, PMID: 12847082","As seen in Figures 5B and 5D), the absence of the GAS8 equivalent (""PF2"") causes ciliary beating defects.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d34bf201-5f6d-41c0-842d-5c029823ef60-2024-11-08T170000.000Z,3006,PubMed:12847082
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+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
+SOCS1 haploinsufficiency impacts on intracellular JAK/STAT,Functional Alteration Patient cells,"Körholz J, et al., 2021, PMID: 34421895","SOCS1 haploinsufficiency impacts on intracellular JAK/STAT signaling of patient immune cells. Figure 3 shows quantifications of immunoblots of IFN-γ stimulation in PBMCs for SOCS1, FAK and pAKT in P1 and P2 compared to two matched healthy controls. The results show that SOCS1 had reduced protein expression, predicting organ damage through chronic infections and/or autoimmunity. While FAK and pAKT show increaded expression, and the increased activity in the FAK – AKT – RS6K pathway may explain the accumulation of autoimmunity.",Score,1 (1),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_68f51e4f-ce10-493b-949a-29eda10e4ccb-2025-02-18T170000.000Z,3009,PubMed:34421895
+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
+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
+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
+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
+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
+Phosphoroteomic profile of WT & ALPK3mut CMs,Biochemical Function A,"McNamara JW, et al., 2023, PMID: 39196058","ALPK3 is critical for the phosphorylation of sarcomeric & protein quality control proteins
+i.e critical for the 9 definitive sarcomereic HCM genes",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ace85164-0b70-46a2-ac6b-253088f4514d-2025-01-16T010000.000Z,2956,PubMed:39196058
+CD4-specific IL10-/- results in intestinal inflammation,Model Systems Non-human model organism,"Roers A, et al., 2004, PMID: 15534372",Deletion of IL-10 from CD4 expressing cells (T cells) resuted in spontaneous IBD,Score,2 (2),CD4-specific deletion of IL10 resulted in phenotype recapitulating human disease. Supporting the importance of IL10 derived from CD4 T cells in preventing intestinal inflammation,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_4b07cbe7-442e-421f-8fc9-7344027dd7dc-2025-02-18T170000.000Z,3028,PubMed:15534372
+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
+Chan_Interaction with SGCD,Protein Interaction,"Chan YM, et al., 1998, PMID: 9864373","Cell lysates from mouse myotubes were subjected to coimmunoprecipitation experiments. All four sarcoglycans were co-immunoprecipitated when an antibody against β-sarcoglycan was used, indicating that β-sarcoglycan was part of the sarcoglycan complex. The association between β- and δ-Sarcoglycan was the strongest, with the complex not dissociating even with washes with higher concentrations of SDS.",Score,0.5 (0.5),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c90753f2-8252-400f-b7b3-9d0b04e1e12c-2024-11-14T170000.000Z,2881,PubMed:9864373
+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
+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
+DNAJB6_sarparnta,Model Systems Non-human model organism,"Sarparanta J, et al., 2012, PMID: 22366786",Muscle fiber detachment is similar to fiber splitting or abnormal fibre pathology,Score,2 (2),,https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_97c1cb24-7c3b-4cd2-90f4-2b56fb539539-2024-08-13T190000.000Z,2747,PubMed:22366786
+Chlamydomonas rescue experiment,Rescue Non-human model organism,"Desai PB, et al., 2015, PMID: 25558044","Phage clones carrying ODA8 rescue the slow swimming phenotype of an oda8 mutant (This experiment was part of the molecular identification of the oda8 locus). HA-tagged ODA8 expressed from an integrated transgene rescues the beat frequency of oda8 cells to wild type levels (60 Hz).  Expression of the HA-tagged transgene (WT*) rescues the assembly of flagellar ODA subunit IC2 to wild type levels, suggesting the restoration of axonemal ODAs that are reduced in oda8 flagella..",Score,1 (2),"Down-scored to 1 because this model can only address axonemal defects and cannot fully recapitulate the ciliary dysfunction seen in humans with PCD that have laterality, heart, fertility, and respiratory symptoms. In addition, while the Chlamydomonas model for ODA8 knockout results in the absence of ODAs, the human LRRC56 cases show no ODA defect. There appears to be a difference in the mechanism of LRRC56/ ODA8 function between species.",https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ceef14a8-34d2-41ac-8c03-47c5eaff8986-2024-11-19T200000.000Z,1227,PubMed:25558044