Submissions for variant NM_001035.3(RYR2):c.4882A>G (p.Met1628Val)

gnomAD frequency: 0.00001  dbSNP: rs757286828

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182871	SCV000235259	uncertain significance	not provided	2014-10-23	criteria provided, single submitter	clinical testing	p.Met1628Val (ATG>GTG): c.4882 A>G in exon 36 of the RYR2 gene (NM_001035.2). The Met1628Val variant in the RYR2 gene has not been reported previously as a disease-causing mutation or as a benign polymorphism, to our knowledge. Although Met1628Val results in a conservative amino acid substitution of one non-polar amino acid with another, the Met1628 position is conserved in mammals and chicken. The NHLBI ESP Exome Variant Server reports Met1628Val was not observed in approximately 5,000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. Nevertheless, no mutations in surrounding codons have been reported in association with CPVT, indicating this region of the protein may be tolerant of change. In summary, with the clinical and molecular information available at this time, we cannot unequivocally determine if the Met1628Val variant in the RYR2 gene is a disease-causing mutation or a rare benign variant. The variant is found in CPVT, POSTMORTEM panel(s).
Color Diagnostics, LLC DBA Color Health	RCV001804916	SCV002052082	uncertain significance	Cardiomyopathy	2023-09-20	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with valine at codon 1628 of the RYR2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, 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 3/247578 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.
Invitae	RCV002516908	SCV002111772	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2024-01-05	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1628 of the RYR2 protein (p.Met1628Val). This variant is present in population databases (rs757286828, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with RYR2-related conditions. ClinVar contains an entry for this variant (Variation ID: 201382). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RYR2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
AiLife Diagnostics, AiLife Diagnostics	RCV000182871	SCV002501960	uncertain significance	not provided	2022-02-09	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002336459	SCV002635669	uncertain significance	Cardiovascular phenotype	2021-11-19	criteria provided, single submitter	clinical testing	The p.M1628V variant (also known as c.4882A>G), located in coding exon 36 of the RYR2 gene, results from an A to G substitution at nucleotide position 4882. The methionine at codon 1628 is replaced by valine, an amino acid with highly similar properties. This amino acid position is highly 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.