entry_index,variant,hgnc_gene,disease,mondo_id,assertion,mode_inheritance,expert_panel,pub_date,evidence_code,met_status,pmid,comments,summary,summary_comments,path
688,NM_000277.2(PAH):c.504C>A (p.Tyr168Ter),PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-05-26,PP4,met,PubMed:26666653,,The c.504C>A (p.Tyr168Ter) variant in PAH has been previously reported in one proband with mild hyperphenylalanemia (defined by the authors as plasma phenylalanine levels >180 umol/L and <600umol/L) (PMID: 26666653) (PP4).,The c.504C>A (p.Tyr168Ter) variant in PAH has been previously reported in one proband with mild hyperphenylalanemia (defined by the authors as plasma phenylalanine levels >180 umol/L and <600umol/L) (PMID: 26666653) (PP4). ,ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
715,NM_000277.2(PAH):c.887A>G (p.Asp296Gly),PAH,phenylketonuria,MONDO:0009861,Uncertain Significance,Autosomal recessive inheritance,Phenylketonuria,2019-07-14,PP4,met,PubMed:26666653,reported in a proband with classic PKU (plasma phenylalanine 1326 umol/L); BH4 deficiency does not appear to have been formally excluded,reported in a proband with classic PKU (plasma phenylalanine 1326 umol/L); BH4 deficiency does not appear to have been formally excluded (PP4).,reported in a proband with classic PKU (plasma phenylalanine 1326 umol/L); BH4 deficiency does not appear to have been formally excluded (PP4). reported in a proband with classic PKU (plasma phenylalanine 1326 umol/L); BH4 deficiency does not appear to have been formally excluded,ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
843,NM_000277.2(PAH):c.547_548delGAinsTT (p.Glu183Leu),PAH,phenylketonuria,MONDO:0009861,Likely Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-08-11,PP4,met,PubMed:26666653,A compound heterozygous proband with this variant was described with the classic PKU phenotype and PHE >1200umol/L. Defects in BH4 cofactor metabolism were not excluded.,A compound heterozygous proband with this variant was described with the classic PKU phenotype and PHE >1200umol/L. Defects in BH4 cofactor metabolism were not excluded.,A compound heterozygous proband with this variant was described with the classic PKU phenotype and PHE >1200umol/L. Defects in BH4 cofactor metabolism were not excluded. A compound heterozygous proband with this variant was described with the classic PKU phenotype and PHE >1200umol/L. Defects in BH4 cofactor metabolism were not excluded.,ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
954,NM_000277.2(PAH):c.169G>T (p.Glu57Ter),PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-10-02,PP4,met,PubMed:26666653,"The c.169G>T (p.Glu57Ter) variant in PAH has been previously reported Likely Pathogenic by one clinical laboratory in ClinVar (see variant ID 120268); the collection method is stated as “literature only” and no further information is provided. With respect to the published literature, it has been previously reported in one proband with classic PKU (defined by the authors as plasma phenylalanine levels > 1200umol/L) (PMID: 26666653) (PP4). The proband was said to be heterozygous for the variant and also harbor the known pathogenic allele (per ClinGen PAH working group classification, see ClinVar ID 636) c.194T>C (p.Ile65Thr); however, the manuscript did not specify whether the phase of the variants was confirmed via parental testing. Thus, at this point, PM3 cannot be applied with full confidence.","The c.169G>T (p.Glu57Ter) variant in PAH has been previously reported Likely Pathogenic by one clinical laboratory in ClinVar (see variant ID 120268); the collection method is stated as “literature only” and no further information is provided. With respect to the published literature, it has been previously reported in one proband with classic PKU (defined by the authors as plasma phenylalanine levels > 1200umol/L) (PMID: 26666653) (PP4). The proband was said to be heterozygous for the variant and also harbor the known pathogenic allele (per ClinGen PAH working group classification, see ClinVar ID 636) c.194T>C (p.Ile65Thr); however, the manuscript did not specify whether the phase of the variants was confirmed via parental testing. Thus, at this point, PM3 cannot be applied with full confidence.","The c.169G>T (p.Glu57Ter) variant in PAH has been previously reported Likely Pathogenic by one clinical laboratory in ClinVar (see variant ID 120268); the collection method is stated as “literature only” and no further information is provided. With respect to the published literature, it has been previously reported in one proband with classic PKU (defined by the authors as plasma phenylalanine levels > 1200umol/L) (PMID: 26666653) (PP4). The proband was said to be heterozygous for the variant and also harbor the known pathogenic allele (per ClinGen PAH working group classification, see ClinVar ID 636) c.194T>C (p.Ile65Thr); however, the manuscript did not specify whether the phase of the variants was confirmed via parental testing. Thus, at this point, PM3 cannot be applied with full confidence. The c.169G>T (p.Glu57Ter) variant in PAH has been previously reported Likely Pathogenic by one clinical laboratory in ClinVar (see variant ID 120268); the collection method is stated as “literature only” and no further information is provided. With respect to the published literature, it has been previously reported in one proband with classic PKU (defined by the authors as plasma phenylalanine levels > 1200umol/L) (PMID: 26666653) (PP4). The proband was said to be heterozygous for the variant and also harbor the known pathogenic allele (per ClinGen PAH working group classification, see ClinVar ID 636) c.194T>C (p.Ile65Thr); however, the manuscript did not specify whether the phase of the variants was confirmed via parental testing. Thus, at this point, PM3 cannot be applied with full confidence.",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
2641,NM_000277.1:c.1123C>G,PAH,phenylketonuria,MONDO:0009861,Likely Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2021-09-19,PP4-Moderate,not_met,PubMed:26503515,"Seen in 2 individuals with Classic PKU.  Biochemical testing data, including plasma phenylalanine (Phe) levels, dihydropteridine reductase activity, urinary biopterin and neopterin ratio, and tetrahydrobiopterin loading, were collected.","Seen in 2 individuals with Classic PKU. Biochemical testing data, including plasma phenylalanine (Phe) levels, dihydropteridine reductase activity, urinary biopterin and neopterin ratio, and tetrahydrobiopterin loading, were collected.  PMID: 26503515","Seen in 2 individuals with Classic PKU. Biochemical testing data, including plasma phenylalanine (Phe) levels, dihydropteridine reductase activity, urinary biopterin and neopterin ratio, and tetrahydrobiopterin loading, were collected.  PMID: 26503515 Seen in 2 individuals with Classic PKU.  Biochemical testing data, including plasma phenylalanine (Phe) levels, dihydropteridine reductase activity, urinary biopterin and neopterin ratio, and tetrahydrobiopterin loading, were collected.",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
3647,NM_001354304.2:c.920G>A,PAH,phenylketonuria,MONDO:0009861,Likely Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2022-06-12,PP4-Moderate,not_met,PubMed:26322415,BH4 defects excluded in all patients.  Single patient in this paper c.920G>A/C.331C>T (pathogenic) with mild PKU,BH4 defects excluded in all patients.  Single patient in this paper c.920G>A/C.331C>T (pathogenic) with mild PKU,BH4 defects excluded in all patients.  Single patient in this paper c.920G>A/C.331C>T (pathogenic) with mild PKU BH4 defects excluded in all patients.  Single patient in this paper c.920G>A/C.331C>T (pathogenic) with mild PKU,ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
76,NM_000277.1(PAH):c.926C>T (p.Ala309Val),PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-04-05,PM3,met,PubMed:26666653,"Genotype-phenotype association in French patients with PKU.  364 patients, 24hr BH4 loading test.","Single patient with classic PKU, c.842C>T (pathogenic in ClinVar) / c.926C>T","Single patient with classic PKU, c.842C>T (pathogenic in ClinVar) / c.926C>T Genotype-phenotype association in French patients with PKU.  364 patients, 24hr BH4 loading test.",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
1010,NM_000277.2(PAH):c.913-8A>G,PAH,phenylketonuria,MONDO:0009861,Uncertain Significance,Autosomal recessive inheritance,Phenylketonuria,2019-11-08,PM3,met,PubMed:26666653,"The c.913-8A>G intronic variant has been observed in trans with the previously assessed pathogenic variant c.1315+1G>A (ClinVar 576, Pathogenic).","The c.913-8A>G intronic variant has been observed in trans with the previously assessed pathogenic variant c.1315+1G>A (ClinVar 576, Pathogenic).","The c.913-8A>G intronic variant has been observed in trans with the previously assessed pathogenic variant c.1315+1G>A (ClinVar 576, Pathogenic). The c.913-8A>G intronic variant has been observed in trans with the previously assessed pathogenic variant c.1315+1G>A (ClinVar 576, Pathogenic).",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
688,NM_000277.2(PAH):c.504C>A (p.Tyr168Ter),PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-05-26,PM3-Supporting,not_met,PubMed:26666653,"The proband was said to be heterozygous for the variant and also harbor the known pathogenic allele (per ClinGen PAH working group classification, see ClinVar ID 92751) c. 898G > T (p.Ala300Ser) variant; however, the manuscript did not specify whether the phase of the variants was confirmed via parental testing.","Detected with c.898G>T (p.Ala300Ser), however, the manuscript did not specify whether the phase of the variants was confirmed via parental testing.","Detected with c.898G>T (p.Ala300Ser), however, the manuscript did not specify whether the phase of the variants was confirmed via parental testing. The proband was said to be heterozygous for the variant and also harbor the known pathogenic allele (per ClinGen PAH working group classification, see ClinVar ID 92751) c. 898G > T (p.Ala300Ser) variant; however, the manuscript did not specify whether the phase of the variants was confirmed via parental testing.",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
143,NM_206933.2(USH2A):c.12295-?_14133+?del,USH2A,Usher syndrome,MONDO:0019501,Likely Pathogenic,Autosomal recessive inheritance,Hearing Loss,2023-10-05,PM3,met,PubMed:26969326,"1 proband compound het with c.2276G>T, p.Cys759Phe. Unsure of phase.","3 LMM probands:
1 homozygote with Usher (0.5 points)
1 cmp het (VUS phase unknown) with hearing loss and light sensitivity (teens, 0.25 points)
1 cmp het (p.Tyr3747X, phase unknown) with hearing loss (<5 years old, 0.5 points)","3 LMM probands:
1 homozygote with Usher (0.5 points)
1 cmp het (VUS phase unknown) with hearing loss and light sensitivity (teens, 0.25 points)
1 cmp het (p.Tyr3747X, phase unknown) with hearing loss (<5 years old, 0.5 points) 1 proband compound het with c.2276G>T, p.Cys759Phe. Unsure of phase.","ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
745,NM_004004.5(GJB2):c.109G>A (p.Val37Ile),GJB2,nonsyndromic genetic deafness,MONDO:0019497,Pathogenic,Autosomal recessive inheritance,Hearing Loss,2019-07-17,PM3,met,PubMed:31160754,>120 compound hets with the p.V37I variant,"Shen et al 2019 demonstrated in the combined analysis of at least 10 clinical sites that there were >120 compound heterozygotes with the p.Val37Ile variant. However, because the variant is also very frequent in the general population, the HL group decided to only apply this criteria at the usual strength of Moderate.","Shen et al 2019 demonstrated in the combined analysis of at least 10 clinical sites that there were >120 compound heterozygotes with the p.Val37Ile variant. However, because the variant is also very frequent in the general population, the HL group decided to only apply this criteria at the usual strength of Moderate. >120 compound hets with the p.V37I variant","ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
968,NM_004004.5(GJB2):c.516G>C (p.Trp172Cys),GJB2,nonsyndromic genetic deafness,MONDO:0019497,Pathogenic,Autosomal recessive inheritance,Hearing Loss,2019-10-17,PS4,met,PubMed:31195736,"220 Tuvinians (Southern Siberia, Russia) with hearing loss were tested for variants in GJB2. The p.Trp172Cys accounted for 62.9% of all mutant GJB2 alleles. It was present in 25 homozygous individuals, 7 compound heterozygous individuals (with c.-23+1G>A, and in 9 heterozygotes. This variant was not found to be biallelic in any of the 157 ethnically-matched controls, but it was observed in 6 carriers.","A 2x2 conttingency analysis of total variant alleles in cases v controls was performed. The variant is present in 66/440 case alleles and 6/314 control alleles. With a fisher exact test, the p value is <0.0001. which is highly significant.","A 2x2 conttingency analysis of total variant alleles in cases v controls was performed. The variant is present in 66/440 case alleles and 6/314 control alleles. With a fisher exact test, the p value is <0.0001. which is highly significant. 220 Tuvinians (Southern Siberia, Russia) with hearing loss were tested for variants in GJB2. The p.Trp172Cys accounted for 62.9% of all mutant GJB2 alleles. It was present in 25 homozygous individuals, 7 compound heterozygous individuals (with c.-23+1G>A, and in 9 heterozygotes. This variant was not found to be biallelic in any of the 157 ethnically-matched controls, but it was observed in 6 carriers.","ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
649,NM_206933.2(USH2A):c.8559-2A>G,USH2A,Usher syndrome,MONDO:0019501,Pathogenic,Autosomal recessive inheritance,Hearing Loss,2019-07-17,PP1-Strong,not_met,PubMed:19023448,"2 Usher affected families:

F4:  2 individuals having a p.R34fs frameshift variant in trans with the splice variant. There were 4 unaffected sibs (2 het for p.R34fs, 2 WT/WT).

F3: Variant was inherited in trans with a p.T3936P variant in USH2A in other family. This individual has an unaffected sib with only the p.T3936P variant and experienced HL onset at age 10 while other individuals had congenital HL.","Dai et al. 2008 is the only paper with genotyping data for family members. They have a total of 6 unaffected sibs across 2 families and 3 affected individuals with the variant between the two families. (Figure 1) This would actually be 1 affected segregation and 5 unaffected segregations, LOD = 0.75

The variant has been reported in two probands with Usher syndrome. In one family, the variant was identified in trans with a frameshift variant in two affected siblings, and four unaffected siblings were either heterozygous for a single variant or wild-type for both variants. In the second family, an unaffected sibling was heterozygous for a single variant (PP1_Strong, PMID: 19023448).","Dai et al. 2008 is the only paper with genotyping data for family members. They have a total of 6 unaffected sibs across 2 families and 3 affected individuals with the variant between the two families. (Figure 1) This would actually be 1 affected segregation and 5 unaffected segregations, LOD = 0.75

The variant has been reported in two probands with Usher syndrome. In one family, the variant was identified in trans with a frameshift variant in two affected siblings, and four unaffected siblings were either heterozygous for a single variant or wild-type for both variants. In the second family, an unaffected sibling was heterozygous for a single variant (PP1_Strong, PMID: 19023448). 2 Usher affected families:

F4:  2 individuals having a p.R34fs frameshift variant in trans with the splice variant. There were 4 unaffected sibs (2 het for p.R34fs, 2 WT/WT).

F3: Variant was inherited in trans with a p.T3936P variant in USH2A in other family. This individual has an unaffected sib with only the p.T3936P variant and experienced HL onset at age 10 while other individuals had congenital HL.","ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
707,NM_004004.5(GJB2):c.101T>C (p.Met34Thr),GJB2,nonsyndromic genetic deafness,MONDO:0019497,Pathogenic,Autosomal recessive inheritance,Hearing Loss,2019-06-28,BS1,not_met,PubMed:31160754,Showed this variant is statistically enriched in affected populations therefore BA1 should not be applied,see BA1,see BA1 Showed this variant is statistically enriched in affected populations therefore BA1 should not be applied,"ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
985,NM_206933.3(USH2A):c.12295-3T>A,USH2A,Usher syndrome,MONDO:0019501,Pathogenic,Autosomal recessive inheritance,Hearing Loss,2023-02-06,PP4,met,PubMed:22135276,Patient diagnosed with Usher syndrome type 2 and found to have variants in only USH2A.,, Patient diagnosed with Usher syndrome type 2 and found to have variants in only USH2A.,"ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
2759,NM_006218.3(PIK3CA):c.2740G>A (p.Gly914Arg),PIK3CA,overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes,MONDO:0016054,Pathogenic,Autosomal dominant inheritance (mosaic),Brain Malformations,2022-02-12,PM6,not_met,PubMed:22729224,"102/811 reads in LCL and 56/313 in saliva in individual LR11-070, 112/818 in blood and 103/171 saliva in individual LR06-341",," 102/811 reads in LCL and 56/313 in saliva in individual LR11-070, 112/818 in blood and 103/171 saliva in individual LR06-341",ClinGenBrainMalformationsExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1.1.0_version=1.1.0.csv
2759,NM_006218.3(PIK3CA):c.2740G>A (p.Gly914Arg),PIK3CA,overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes,MONDO:0016054,Pathogenic,Autosomal dominant inheritance (mosaic),Brain Malformations,2022-02-12,PS2,met,PubMed:22729224,"102/811 reads in LCL and 56/313 in saliva in individual LR11-070, 112/818 in blood and 103/171 saliva in individual LR06-341",," 102/811 reads in LCL and 56/313 in saliva in individual LR11-070, 112/818 in blood and 103/171 saliva in individual LR06-341",ClinGenBrainMalformationsExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1.1.0_version=1.1.0.csv
183,NM_000257.3(MYH7):c.2717A>G (p.Asp906Gly),MYH7,hypertrophic cardiomyopathy,MONDO:0005045,Pathogenic,Autosomal dominant inheritance,Cardiomyopathy,2018-11-16,PM1,met,PubMed:27532257,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYH7Version2.0.0_version=2.0.0.csv
193,NM_000257.3(MYH7):c.2207T>C (p.Ile736Thr),MYH7,hypertrophic cardiomyopathy,MONDO:0005045,Pathogenic,Autosomal dominant inheritance,Cardiomyopathy,2018-11-16,PM1,met,PubMed:27532257,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYH7Version2.0.0_version=2.0.0.csv
249,NM_000257.3(MYH7):c.1750G>C (p.Gly584Arg),MYH7,hypertrophic cardiomyopathy,MONDO:0005045,Pathogenic,Autosomal dominant inheritance,Cardiomyopathy,2018-11-16,PM1,met,PubMed:27532257,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYH7Version2.0.0_version=2.0.0.csv
311,NM_002880.3(RAF1):c.775T>A (p.Ser259Thr),RAF1,RASopathy,MONDO:0021060,Pathogenic,Autosomal dominant inheritance,RASopathy,2020-04-13,PM1,met,PubMed:29493581,"Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of RAF1 (PM1; PMID 29493581).",The variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of RAF1 (PM1; PMID 29493581).,"The variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of RAF1 (PM1; PMID 29493581). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of RAF1 (PM1; PMID 29493581).",ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
381,NM_002880.3(RAF1):c.1472C>T (p.Thr491Ile),RAF1,RASopathy,MONDO:0021060,Pathogenic,Autosomal dominant inheritance,RASopathy,2018-12-10,PM1,met,PubMed:29493581,"Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of RAF1 (PM1; PMID 29493581).","Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of RAF1 (PM1; PMID 29493581).","Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of RAF1 (PM1; PMID 29493581). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of RAF1 (PM1; PMID 29493581).",ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
309,NM_007373.3(SHOC2):c.4A>G (p.Ser2Gly),SHOC2,Noonan syndrome-like disorder with loose anagen hair 1,MONDO:0054637,Pathogenic,Autosomal dominant inheritance,RASopathy,2018-12-10,PS3,met,PubMed:19684605,In vitro functional studies provide some evidence that the p.Ser2Gly variant may impact protein function (PS3; PMID: 19684605).,In vitro functional studies provide some evidence that the p.Ser2Gly variant may impact protein function (PS3; PMID: 19684605).,In vitro functional studies provide some evidence that the p.Ser2Gly variant may impact protein function (PS3; PMID: 19684605). In vitro functional studies provide some evidence that the p.Ser2Gly variant may impact protein function (PS3; PMID: 19684605).,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSHOC2Version2.3.0_version=2.3.0.csv
932,NM_004360.4(CDH1):c.2549_2550delCC (p.Ser850Phefs),CDH1,CDH1-related diffuse gastric and lobular breast cancer,MONDO:0007648,Uncertain Significance,Autosomal dominant inheritance,CDH1,2023-08-04,PS4,not_met,PubMed:29798843,"Family does not meet HDGC clinical criteria. Proband with bilateral/contralateral DCIS and IDC/ILC <50, and adenomatous polyps. Same case that has been submitted to ClinVar (SCV000185568.5).",No reported cases that meet HDGC clinical criteria.,"No reported cases that meet HDGC clinical criteria. Family does not meet HDGC clinical criteria. Proband with bilateral/contralateral DCIS and IDC/ILC <50, and adenomatous polyps. Same case that has been submitted to ClinVar (SCV000185568.5).",ClinGenCDH1ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion3.1_version=3.1.0.csv
523,NM_004360.4(CDH1):c.670C>T (p.Arg224Cys),CDH1,CDH1-related diffuse gastric and lobular breast cancer,MONDO:0007648,Likely Benign,Autosomal dominant inheritance,CDH1,2023-08-17,BS3,not_met,PubMed:27582386,Found variant weakly activates E-cadherin induced cell adhesion.,Two functional studies suggest little or no impact on cell adhesion.,Two functional studies suggest little or no impact on cell adhesion. Found variant weakly activates E-cadherin induced cell adhesion.,ClinGenCDH1ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion3.1_version=3.1.0.csv
523,NM_004360.4(CDH1):c.670C>T (p.Arg224Cys),CDH1,CDH1-related diffuse gastric and lobular breast cancer,MONDO:0007648,Likely Benign,Autosomal dominant inheritance,CDH1,2023-08-17,PS3,not_met,PubMed:27582386,Found variant weakly activates E-cadherin induced cell adhesion.,Two functional studies suggest little or no impact on cell adhesion.,Two functional studies suggest little or no impact on cell adhesion. Found variant weakly activates E-cadherin induced cell adhesion.,ClinGenCDH1ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion3.1_version=3.1.0.csv
898,NM_004360.4(CDH1):c.220C>T (p.Arg74Ter),CDH1,CDH1-related diffuse gastric and lobular breast cancer,MONDO:0007648,Pathogenic,Autosomal dominant inheritance,CDH1,2023-08-29,PS4-Supporting,not_met,PubMed:25123297,"Found in one individual (76 yo) with gastric adenocarcinoma with suspected family history of gastric cancer (mother, brother), but NOT germline.","Found in one individual (76 yo) with gastric adenocarcinoma with suspected family history of gastric cancer (mother, brother), but NOT germline.
SCV000288456.3 - one proband meet IGCLC HDGC criteria.
- one proband does not meet IGCLC HDGC criteria.
SCV000661607.2 - 3 cases do not meet HDGC criteria with unknown pathology.","Found in one individual (76 yo) with gastric adenocarcinoma with suspected family history of gastric cancer (mother, brother), but NOT germline.
SCV000288456.3 - one proband meet IGCLC HDGC criteria.
- one proband does not meet IGCLC HDGC criteria.
SCV000661607.2 - 3 cases do not meet HDGC criteria with unknown pathology. Found in one individual (76 yo) with gastric adenocarcinoma with suspected family history of gastric cancer (mother, brother), but NOT germline.",ClinGenCDH1ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion3.1_version=3.1.0.csv
1539,NM_001304717.5(PTEN):c.730-2_731del,PTEN,PTEN hamartoma tumor syndrome,MONDO:0017623,Pathogenic,Autosomal dominant inheritance,PTEN,2019-12-04,BS3,not_met,PubMed:28677221,Nomenclature c.210-4_c.210-1delTTAG: variant resulted in exon 4 skipping in pt cells.,, Nomenclature c.210-4_c.210-1delTTAG: variant resulted in exon 4 skipping in pt cells.,ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.1.0_version=3.1.0.csv
98,NM_000314.6(PTEN):c.50_51delAA (p.Gln17Argfs),PTEN,PTEN hamartoma tumor syndrome,MONDO:0017623,Pathogenic,Autosomal dominant inheritance,PTEN,2018-12-10,PS4-Supporting,not_met,PubMed:20223021,Proband(s) with phenotype specificity score of 1-1.5,, Proband(s) with phenotype specificity score of 1-1.5,ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.1.0_version=3.1.0.csv
4263,NC_012920.1:m.3291T>C,MT-TL1,mitochondrial disease,MONDO:0044970,Likely Pathogenic,Mitochondrial inheritance,Mitochondrial Diseases,2022-10-13,PS3-Supporting,not_met,PubMed:23273904,"Single fiber testing showed greater abundance of mutant genomes in COX-deficient (89.1± 9.9%, n=18), than in COX-positive fibers (51.1±27.1%, n=17; P < 0.001; PS3_supporting, PMID: 23273904).","Single fiber testing showed greater abundance of mutant genomes in COX-deficient (89.1± 9.9%, n=18), than in COX-positive fibers (51.1±27.1%, n=17; P < 0.001; PS3_supporting, PMID: 23273904).
","Single fiber testing showed greater abundance of mutant genomes in COX-deficient (89.1± 9.9%, n=18), than in COX-positive fibers (51.1±27.1%, n=17; P < 0.001; PS3_supporting, PMID: 23273904).
 Single fiber testing showed greater abundance of mutant genomes in COX-deficient (89.1± 9.9%, n=18), than in COX-positive fibers (51.1±27.1%, n=17; P < 0.001; PS3_supporting, PMID: 23273904).",ClinGenMitochondrialDiseaseNuclearandMitochondrialExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_mtDNA_version=1.0.0.csv
5109,m.7497G>A,MT-TS1,mitochondrial disease,MONDO:0044970,Likely Pathogenic,Mitochondrial inheritance,Mitochondrial Diseases,2023-05-19,PS3-Supporting,not_met,PubMed:16199753,"Cybrid studies showed a correlation between higher heteroplasmy level and lower complex I and IV activity (PS3_supporting, PMID: 16199753).  ","Cybrid studies showed a correlation between higher heteroplasmy level and lower complex I and IV activity (PS3_supporting, PMID: 16199753).  ","Cybrid studies showed a correlation between higher heteroplasmy level and lower complex I and IV activity (PS3_supporting, PMID: 16199753).   Cybrid studies showed a correlation between higher heteroplasmy level and lower complex I and IV activity (PS3_supporting, PMID: 16199753).  ",ClinGenMitochondrialDiseaseNuclearandMitochondrialExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_mtDNA_version=1.0.0.csv
7655,NC_012920.1:m.14597A>G,,mitochondrial disease,MONDO:0044970,Likely Pathogenic,Mitochondrial inheritance,Mitochondrial Diseases,2024-08-12,PS3-Supporting,not_met,PubMed:34045482,"Analysis of three cybrid fibroblast cell lines demonstrated significantly reduced complex I activity, respiration rate, & ATP content.
","Cybrid studies support the functional impact of this variant (PS3_supporting; PMIDs: 34045482) as significantly reduced complex I activity, respiration rate, and ATP content in three cybrid fibroblast cell lines were demonstrated.","Cybrid studies support the functional impact of this variant (PS3_supporting; PMIDs: 34045482) as significantly reduced complex I activity, respiration rate, and ATP content in three cybrid fibroblast cell lines were demonstrated. Analysis of three cybrid fibroblast cell lines demonstrated significantly reduced complex I activity, respiration rate, & ATP content.
",ClinGenMitochondrialDiseaseNuclearandMitochondrialExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_mtDNA_version=1.0.0.csv
1323,NM_000152.4(GAA):c.2662G>T (p.Glu888Ter),GAA,glycogen storage disease II,MONDO:0009290,Pathogenic,Autosomal recessive inheritance,Lysosomal Diseases,2020-05-27,PP4,met,PubMed:25526786,,"At least 6 patients have been reported with have been reported with this variant and GAA activity <10% normal in lymphocytes, leukocytes, or muscle samples, or <30% normal activity in cultured fibroblasts, or in the affected range in a GAA activity assay (PMIDs 16531044, 17723315, 18458862, 21232767, 25526786). This meets the specifications for PP4.","At least 6 patients have been reported with have been reported with this variant and GAA activity <10% normal in lymphocytes, leukocytes, or muscle samples, or <30% normal activity in cultured fibroblasts, or in the affected range in a GAA activity assay (PMIDs 16531044, 17723315, 18458862, 21232767, 25526786). This meets the specifications for PP4. ",ClinGenLysosomalStorageDisordersVariantCurationExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
1347,NM_000152.5(GAA):c.1352C>G (p.Pro451Arg),GAA,glycogen storage disease II,MONDO:0009290,Likely Benign,Autosomal recessive inheritance,Lysosomal Diseases,2023-05-26,PM3,not_met,PubMed:29149851,"Patient 21, with limb girdle muscular dystrophy, is compound heterozygous for c.1352C>G (p.Pro451Arg) and an intronic variant, c.1438-7_1438-5delTGT. The phase of the variants is unknown. No GAA activity is provided for the patient. The authors stated that this combination of variants was not thought to be causative of the patient’s phenotype.","A patient with limb-girdle muscle weakness has been reported to be compound heterozygous for  c.1352C>G (p.Pro451Arg) and an intronic variant, c.1438-7_1438-5delTGT (PMID 29149851). The phase of the variants is unknown and no GAA activity was provided for the patient. The authors stated that this combination of variants was not thought to be causative of the patient’s phenotype. Therefore, this criterion is not met.","A patient with limb-girdle muscle weakness has been reported to be compound heterozygous for  c.1352C>G (p.Pro451Arg) and an intronic variant, c.1438-7_1438-5delTGT (PMID 29149851). The phase of the variants is unknown and no GAA activity was provided for the patient. The authors stated that this combination of variants was not thought to be causative of the patient’s phenotype. Therefore, this criterion is not met. Patient 21, with limb girdle muscular dystrophy, is compound heterozygous for c.1352C>G (p.Pro451Arg) and an intronic variant, c.1438-7_1438-5delTGT. The phase of the variants is unknown. No GAA activity is provided for the patient. The authors stated that this combination of variants was not thought to be causative of the patient’s phenotype.",ClinGenLysosomalStorageDisordersVariantCurationExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
3162,NM_000261.2:c.731G>T,MYOC,primary open angle glaucoma,MONDO:0007665,Uncertain Significance,Autosomal dominant inheritance,Glaucoma,2022-07-11,BS3,not_met,PubMed:27092720,"The G244V protein is secreted.
This study does not meet the OddsPath threshold for  BS3_Supporting (< 0.48).","The study reporting functional evidence (PMID: 27092720) demonstrated that the Gly244Val protein had similar secretion levels compared to wild type myocilin protein, but did not meet the OddsPath threshold (< 0.48) for BS3_Supporting to be applied.","The study reporting functional evidence (PMID: 27092720) demonstrated that the Gly244Val protein had similar secretion levels compared to wild type myocilin protein, but did not meet the OddsPath threshold (< 0.48) for BS3_Supporting to be applied. The G244V protein is secreted.
This study does not meet the OddsPath threshold for  BS3_Supporting (< 0.48).",ClinGenGlaucomaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYOCVersion2.0.0_version=2.0.0.csv
3162,NM_000261.2:c.731G>T,MYOC,primary open angle glaucoma,MONDO:0007665,Uncertain Significance,Autosomal dominant inheritance,Glaucoma,2022-07-11,PS3,not_met,PubMed:27092720,"The G244V protein is secreted.
This study does not meet the OddsPath threshold for  BS3_Supporting (< 0.48).","Although the OddsPath threshold for BS3_Supporting was not met, no functional evidence indicating that this variant impacts protein function has been found.
","Although the OddsPath threshold for BS3_Supporting was not met, no functional evidence indicating that this variant impacts protein function has been found.
 The G244V protein is secreted.
This study does not meet the OddsPath threshold for  BS3_Supporting (< 0.48).",ClinGenGlaucomaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYOCVersion2.0.0_version=2.0.0.csv
4479,NM_000261.2:c.1037G>C,MYOC,primary open angle glaucoma,MONDO:0007665,Uncertain Significance,Autosomal dominant inheritance,Glaucoma,2022-12-14,PS3,not_met,PubMed:17615537,"The study reporting functional evidence (PMID: 17615537) demonstrated that the Arg346Thr
protein had reduced solubility levels compared to wild type myocilin protein, but did not meet the OddsPath threshold (> 2.1) for PS3_Supporting to be applied.    ","The study reporting functional evidence (PMID: 17615537) demonstrated that the Arg346Thr
protein had reduced solubility levels compared to wild type myocilin protein, but did not meet the OddsPath threshold (> 2.1) for PS3_Supporting to be applied.    
","The study reporting functional evidence (PMID: 17615537) demonstrated that the Arg346Thr
protein had reduced solubility levels compared to wild type myocilin protein, but did not meet the OddsPath threshold (> 2.1) for PS3_Supporting to be applied.    
 The study reporting functional evidence (PMID: 17615537) demonstrated that the Arg346Thr
protein had reduced solubility levels compared to wild type myocilin protein, but did not meet the OddsPath threshold (> 2.1) for PS3_Supporting to be applied.    ",ClinGenGlaucomaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYOCVersion2.0.0_version=2.0.0.csv
3859,NM_001754.5(RUNX1):c.496C>T (p.Arg166Ter),RUNX1,hereditary thrombocytopenia and hematologic cancer predisposition syndrome,MONDO:0011071,Pathogenic,Autosomal dominant inheritance,Myeloid Malignancy,2022-07-05,BS3,not_met,PubMed:33692461,"R139* shows Transactivation assays demonstrating altered transactivation (<20% of wt, and/or reduced to levels similar to well-established pathogenic variants such as R201Q or R166Q) in luciferase assay",: Transactivation assays demonstrating enhanced transactivation (>115% of wt) (PS3_Supporting; PMID: 33692461) Cannot be applied because meets PVS1,": Transactivation assays demonstrating enhanced transactivation (>115% of wt) (PS3_Supporting; PMID: 33692461) Cannot be applied because meets PVS1 R139* shows Transactivation assays demonstrating altered transactivation (<20% of wt, and/or reduced to levels similar to well-established pathogenic variants such as R201Q or R166Q) in luciferase assay",ClinGenMyeloidMalignancyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
800,NM_001754.5(RUNX1):c.442_449del (p.Thr148fs),RUNX1,hereditary thrombocytopenia and hematologic cancer predisposition syndrome,MONDO:0011071,Pathogenic,Autosomal dominant inheritance,Myeloid Malignancy,2024-03-26,PS4-Supporting,not_met,PubMed:27112265,One family with FPD/AML.,One family with FPD/AML.,One family with FPD/AML. One family with FPD/AML.,ClinGenMyeloidMalignancyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
1587,NM_000546.6(TP53):c.329G>A (p.Arg110His),TP53,Li-Fraumeni syndrome,MONDO:0018875,Likely Benign,Autosomal dominant inheritance,TP53,2025-01-16,BS3-Supporting,not_met,PubMed:33051313,Report a deleterious effect of this variant using a functional assay from patient blood sample.,"In vitro assays performed in yeast and/or human cell lines showed partially functional transactivation, and retained growth suppression activity indicating that this variant does not impact protein function
(BS3_Supporting; PMIDs: 12826609, 29979965, 30224644).","In vitro assays performed in yeast and/or human cell lines showed partially functional transactivation, and retained growth suppression activity indicating that this variant does not impact protein function
(BS3_Supporting; PMIDs: 12826609, 29979965, 30224644). Report a deleterious effect of this variant using a functional assay from patient blood sample.",ClinGenTP53ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTP53Version2.3.0_version=2.3.0.csv
1844,NM_000212.2:c.774_775del,ITGB3,Glanzmann's thrombasthenia,MONDO:0010119,Pathogenic,Autosomal recessive inheritance,Platelet Disorders,2021-01-28,PP4-Moderate,not_met,PubMed:25539746,,"From PMID: 25539746 The patient had a history of bleeding, normal platelet number and size, impaired aggregation to ADP and arachidonic acid but normal or only mildly reduced agglutination with ristocetin, and αIIbβ3 expression between 5% and 20% (measured by flow cytometry).",,ClinGenPlateletDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2.1_version=2.1.0.csv