ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.3230T>C (p.Val1077Ala) (rs202176504)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000036726 SCV000060381 uncertain significance not specified 2016-06-10 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Val1077Ala va riant in RYR2 has been identified in 0.2% (23/9702) of African chromosomes by th e Exome Aggregation Consortium (ExAC,; dbSNP rs20 2176504). Computational prediction tools and conservation analysis suggest that the p.Val1077Ala variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of the p.Val1077Ala variant is uncertain, these data suggest that i t is more likely to be benign.
Invitae RCV000230919 SCV000285718 likely benign Catecholaminergic polymorphic ventricular tachycardia 2019-12-31 criteria provided, single submitter clinical testing
GeneDx RCV000036726 SCV000514439 likely benign not specified 2018-03-06 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Color RCV001191833 SCV001359746 likely benign Cardiomyopathy 2018-11-26 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000036726 SCV001360980 likely benign not specified 2019-01-21 criteria provided, single submitter clinical testing Variant summary: RYR2 c.3230T>C (p.Val1077Ala) results in a non-conservative amino acid change located in the Ryanodine receptor, SPRY domain 2 of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00024 in 276622 control chromosomes. The observed variant frequency is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in RYR2 causing Arrhythmia phenotype (6e-05), strongly suggesting that the variant is benign. c.3230T>C has been reported in the literature in one individual in a cohort of clinical whole exome genetic test referrals. This report does not provide unequivocal conclusions about association of the variant with Arrhythmia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (2 likely benign, 1 VUS). Based on the evidence outlined above, the variant was classified as likely benign.

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