Submissions for variant NM_001035.3(RYR2):c.8060G>A (p.Ser2687Asn)

gnomAD frequency: 0.00023  dbSNP: rs202020477

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000520895	SCV000620571	uncertain significance	not provided	2024-04-10	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function; Not located in one of the three hot-spot regions of the RYR2 gene, where the majority of pathogenic missense variants occur (PMID: 19926015); This variant is associated with the following publications: (PMID: 19926015)
Labcorp Genetics (formerly Invitae), Labcorp	RCV002527633	SCV000830182	likely benign	Catecholaminergic polymorphic ventricular tachycardia 1	2025-01-20	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001188646	SCV001355735	uncertain significance	Cardiomyopathy	2023-05-24	criteria provided, single submitter	clinical testing	This missense variant replaces serine with asparagine at codon 2687 of the RYR2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with RYR2-related disorders in the literature. This variant has been identified in 10/278538 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Mayo Clinic Laboratories, Mayo Clinic	RCV000520895	SCV001715667	uncertain significance	not provided	2020-08-05	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002413416	SCV002675689	likely benign	Cardiovascular phenotype	2023-04-11	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
All of Us Research Program, National Institutes of Health	RCV004003630	SCV004822807	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia	2024-09-23	criteria provided, single submitter	clinical testing	This missense variant replaces serine with asparagine at codon 2687 of the RYR2 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 10/278538 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004689776	SCV005185200	likely benign	not specified	2024-05-20	criteria provided, single submitter	clinical testing	Variant summary: RYR2 c.8060G>A (p.Ser2687Asn) results in a conservative amino acid change in 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 3.5e-05 in 1612824 control chromosomes (gnomAD database 4.0.0). The observed variant frequency is above the estimated maximal expected allele frequency for a pathogenic variant in RYR2 causing Catecholaminergic Polymorphic Ventricular Tachycardia phenotype (3.4e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.8060G>A in individuals affected with Catecholaminergic Polymorphic Ventricular Tachycardia and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 451818). Based on the evidence outlined above, the variant was classified as likely benign.