Submissions for variant NM_001035.3(RYR2):c.1319C>T (p.Ala440Val)

gnomAD frequency: 0.00002  dbSNP: rs758904216

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182619	SCV000234984	uncertain significance	not provided	2015-11-16	criteria provided, single submitter	clinical testing	The A440V variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. However, it has been reported in one other individual who underwent DNA-based testing for arrhythmia at GeneDx. The A440V variant was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. However, the A440V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where Valine is tolerated in many species. Consequently, in silico analysis predicts this variant likely does not alter the protein structure/function. Furthermore, only one missense variant in a nearby residue (L433P) has been reported in the Human Gene Mutation Database in association with ARVC (Stenson et al., 2014). Nevertheless, the A440V variant is located in one of the three hot-spot regions of the RYR2 gene, where the majority of pathogenic missense variants occur (Medeiros-Domingo et al., 2009). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae	RCV000509223	SCV000949844	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2024-01-22	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 440 of the RYR2 protein (p.Ala440Val). This variant is present in population databases (rs758904216, gnomAD 0.004%). 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: 201160). 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 not expected to disrupt RYR2 protein function with a negative 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.
Color Diagnostics, LLC DBA Color Health	RCV001186512	SCV001352961	likely benign	Cardiomyopathy	2019-03-09	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002381594	SCV002689729	likely benign	Cardiovascular phenotype	2022-05-02	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Revvity Omics, Revvity	RCV000182619	SCV003820586	uncertain significance	not provided	2022-06-05	criteria provided, single submitter	clinical testing
GenomeConnect, ClinGen	RCV000509223	SCV000607037	not provided	Catecholaminergic polymorphic ventricular tachycardia 1		no assertion provided	phenotyping only	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.