Submissions for variant NM_001035.3(RYR2):c.6523A>G (p.Met2175Val)

dbSNP: rs794728820

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182873	SCV000235261	uncertain significance	not provided	2018-02-07	criteria provided, single submitter	clinical testing	This variant is denoted c.6523 A>G at the cDNA level or p.Met2175Val (M2175V) at the protein level. The Met2175Val variant in the RYR2 gene has not been reported previously as a disease-causing mutation or as a benign polymorphism, to our knowledge. Met2175Val results in a conservative amino acid substitution of one non-polar amino acid for another. Although the Met2175 residue is conserved across species, it is not located in a mutation hot spot region of the RYR2 gene. In silico analysis predicts Met2175Val to be possibly damaging to protein structure or function (Adzhubei et al. 2010; Kumar et al. 2009; Schwarz et al. 2011). The NHLBI ESP Exome Variant Server reports Met2175Val was not observed in approximately 5,000 samples from individual of European and African American backgrounds, indicating it is not a common benign variant in these populations. In summary, with the clinical and molecular information available at this time, we cannot determine if the Met2175Val variant is a disease-causing mutation or a benign variant. The variant is found in CPVT panel(s).
Labcorp Genetics (formerly Invitae), Labcorp	RCV005089918	SCV005731340	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2025-01-15	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 2175 of the RYR2 protein (p.Met2175Val). This variant is not present in population databases (gnomAD no frequency). 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: 201384). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt RYR2 protein function with a positive predictive value of 95%. 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.