Submissions for variant NM_001035.3(RYR2):c.3883A>G (p.Ser1295Gly)

gnomAD frequency: 0.00010  dbSNP: rs200574919

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002529892	SCV000760586	likely benign	Catecholaminergic polymorphic ventricular tachycardia 1	2024-11-17	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000773286	SCV000906978	uncertain significance	Cardiomyopathy	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces serine with glycine at codon 1295 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 cardiovascular disorders in the literature. This variant has been identified in 22/277116 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000773286	SCV002042909	uncertain significance	Cardiomyopathy	2020-07-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002358805	SCV002620569	uncertain significance	Cardiovascular phenotype	2023-08-29	criteria provided, single submitter	clinical testing	The p.S1295G variant (also known as c.3883A>G), located in coding exon 31 of the RYR2 gene, results from an A to G substitution at nucleotide position 3883. The serine at codon 1295 is replaced by glycine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002499074	SCV002776835	uncertain significance	Arrhythmogenic right ventricular dysplasia 2; Catecholaminergic polymorphic ventricular tachycardia 1; Ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome	2021-12-07	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004003860	SCV004819327	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia	2024-09-11	criteria provided, single submitter	clinical testing	This missense variant replaces serine with glycine at codon 1295 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 cardiovascular disorders in the literature. This variant has been identified in 22/277116 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.
GeneDx	RCV001090708	SCV005078001	uncertain significance	not provided	2024-06-12	criteria provided, single submitter	clinical testing	In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; 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)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004782484	SCV005394938	likely benign	not specified	2024-09-30	criteria provided, single submitter	clinical testing	Variant summary: RYR2 c.3883A>G (p.Ser1295Gly) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0036 in 245715 control chromosomes. The observed variant frequency is approximately 103.71 fold of the estimated maximal expected allele frequency for a pathogenic variant in RYR2 causing Catecholaminergic Polymorphic Ventricular Tachycardia phenotype (3.4e-05). To our knowledge, no occurrence of c.3883A>G in individuals affected with Catecholaminergic Polymorphic Ventricular Tachycardia and no experimental evidence demonstrating its impact on protein function have been reported. The following publication has been ascertained in the context of this evaluation (PMID: 35819174). ClinVar contains an entry for this variant (Variation ID: 532318). Based on the evidence outlined above, the variant was classified as likely benign.
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001090708	SCV001951673	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001090708	SCV001968839	uncertain significance	not provided		no assertion criteria provided	clinical testing