ClinVar Genomic variation as it relates to human health

The patient was diagnosed with typical polymorphic ventricular tachycardia at the age of 12 followed by ICD implantation. No relatives are available for genetic testing.

The p.R4959Q variant (also known as c.14876G>A), located in coding exon 105 of the RYR2 gene, results from a G to A substitution at nucleotide position 14876. The arginine at codon 4959 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been detected in several individuals with catecholaminergic polymorphic ventricular tachycardia (CPVT), Long QT syndrome (LQTS), and developmental delay (Laitinen PJ et al. Eur. J. Hum. Genet., 2003 Nov;11:888-91; Jabbari J et al. Circ Cardiovasc Genet, 2013 Oct;6:481-9; Medeiros-Domingo A et al. J. Am. Coll. Cardiol., 2009 Nov;54:2065-74; Tester DJ et al. Heart Rhythm, 2005 Oct;2:1099-105; Nature, 2017 02;542:433-438; Kapplinger JD et al. Circ Genom Precis Med, 2018 02;11:e001424; Avari Silva JN et al. J Am Heart Assoc, 2016 05;5:). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

This variant is interpreted as a Likely Pathogenic, for Ventricular tachycardia, catecholaminergic polymorphic, 1, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate => PS4 downgraded in strength to Moderate (PMID:14571276,16188589,27231019,15721128). PP1-Moderate => PP1 upgraded in strength to Moderate (PMID:15721128).

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PP1-S,PM2,PP3.

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; 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); This variant is associated with the following publications: (PMID: 16188589, 29766881, 24025405, 19926015, 20354512, 15765137, 15721128, 25713214, 29453246, 25514987, 31112425, 28135719, 31785789, 31737537, 14571276, 27231019, 33825858, 35101670, 34725342, 35135837)

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 4959 of the RYR2 protein (p.Arg4959Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with catecholaminergic polymorphic ventricular tachycardia, and RYR2-related disease (PMID: 14571276, 15721128, 16188589, 29453246). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 201365). 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. For these reasons, this variant has been classified as Pathogenic.