Submissions for variant NM_001035.3(RYR2):c.4130C>T (p.Ala1377Val)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002651431	SCV003524186	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2024-06-11	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 1377 of the RYR2 protein (p.Ala1377Val). This variant is present in population databases (no rsID available, gnomAD 0.004%). This missense change has been observed in individual(s) with sudden arrhythmic death syndrome (PMID: 28449774). ClinVar contains an entry for this variant (Variation ID: 2203007). 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	RCV003533366	SCV004360587	uncertain significance	Cardiomyopathy	2022-07-07	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 1377 of the RYR2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with sudden arrhythmic death syndrome (PMID: 28449774). This variant has been identified in 2/246680 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.
Ambry Genetics	RCV004072128	SCV005037037	uncertain significance	Cardiovascular phenotype	2024-02-22	criteria provided, single submitter	clinical testing	The p.A1377V variant (also known as c.4130C>T), located in coding exon 31 of the RYR2 gene, results from a C to T substitution at nucleotide position 4130. The alanine at codon 1377 is replaced by valine, an amino acid with similar properties. This variant has been detected in an individual with sudden arrhythmic death during exercise at 15 years of age who also had a reported history of seizures (Lahrouchi N et al. J Am Coll Cardiol, 2017 May;69:2134-2145). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear.