Submissions for variant NM_001035.3(RYR2):c.12980T>C (p.Val4327Ala)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV003350804	SCV004054095	uncertain significance	Cardiovascular phenotype	2023-08-16	criteria provided, single submitter	clinical testing	The p.V4327A variant (also known as c.12980T>C), located in coding exon 90 of the RYR2 gene, results from a T to C substitution at nucleotide position 12980. The valine at codon 4327 is replaced by alanine, an amino acid with 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003638941	SCV004536303	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2024-01-04	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 4327 of the RYR2 protein (p.Val4327Ala). 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: 2587830). 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) performed at Invitae 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.
All of Us Research Program, National Institutes of Health	RCV004011279	SCV004820461	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia	2024-06-11	criteria provided, single submitter	clinical testing	This missense variant replaces valine with alanine at codon 4327 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 RYR2-related disorders in the literature. This variant has not been identified 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.