Submissions for variant NM_001035.3(RYR2):c.8018C>T (p.Ala2673Val)

gnomAD frequency: 0.00002  dbSNP: rs869025513

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Blueprint Genetics	RCV000208294	SCV000264187	uncertain significance	Primary familial hypertrophic cardiomyopathy	2015-06-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002517404	SCV003469440	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2024-11-19	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2673 of the RYR2 protein (p.Ala2673Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of RYR2-related conditions (PMID: 27756708). ClinVar contains an entry for this variant (Variation ID: 222791). 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%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on RYR2 function (PMID: 27756708). 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.
3billion	RCV002517404	SCV003841431	likely pathogenic	Catecholaminergic polymorphic ventricular tachycardia 1	2024-07-30	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v4.0.0 dataset (total allele frequency: 0.001%). Missense changes are a common disease-causing mechanism. Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 27756708, 27756708). In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.71 (>=0.6, sensitivity 0.68 and specificity 0.92)]. The same nucleotide change resulting in the same amino acid change has been previously reported to be associated with RYR2-related disorder (PMID: 27756708). The variant has been observed in at least two similarly affected unrelated individuals (PMID: 27756708 / 3billion dataset). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
All of Us Research Program, National Institutes of Health	RCV003997690	SCV004832031	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia	2023-11-02	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 2673 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). An experimental study has shown that this variant causes a slight change in calcium channel properties (PMID: 27756708), but clinical relevance of this observation is not known. This variant has been reported in an individual affected with short-coupled variant of torsade de pointes (PMID: 27756708). This variant has been identified in 1/240770 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.
CeGaT Center for Human Genetics Tuebingen	RCV005243159	SCV005893237	uncertain significance	not provided	2024-12-01	criteria provided, single submitter	clinical testing	RYR2: PM2, PP3, PS3:Supporting, PS4:Supporting