ClinVar Genomic variation as it relates to human health

The p.Ser1765Cys variant (rs564806219) has been observed in an individual included in a cohort of hypertrophic cardiomyopathy patients (Lopes 2015), an individual with a suspected diagnosis of catecholaminergic polymorphic ventricular tachycardia who did not meet full diagnostic criteria (Jimenez-Jaimez 2015), and in a case of sudden unexplained death (Brion 2014). However, so co-segregation data is available for this variant, and it is listed in the Genome Aggregation Database (gnomAD) browser with an overall frequency of 0.017% (identified in 48 out of 276,878 chromosomes). This variant is also listed in the ClinVar database as a variant of uncertain significance (Variation ID: 404210). The serine at codon 1765 is highly conserved considering 10 species up to chicken (Alamut software v2.9), although computational analyses return mixed results regarding the effect of this variant on RYR2 protein structure/function (SIFT: damaging, PolyPhen2: benign, and Mutation Taster: disease causing). Therefore, based on the available information, the clinical significance of the p.Ser1765Cys variant cannot be determined with certainty.

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

The p.S1765C variant (also known as c.5294C>G), located in coding exon 37 of the RYR2 gene, results from a C to G substitution at nucleotide position 5294. The serine at codon 1765 is replaced by cysteine, an amino acid with dissimilar properties. This alteration was reported in a case of sudden cardiac death (Brion M et al. Electrophoresis, 2014 Nov;35:3111-6), and in an individual with unexplained cardiac arrest who did not meet the diagnostic criteria of catecholaminergic polymorphic ventricular tachycardia (Jiménez-Jáimez J et al. Am. J. Cardiol., 2015 Sep;116:894-9). In addition, this alteration has been reported in a hypertrophic cardiomyopathy cohort; however, clinical details were limited (Lopes LR et al. Heart, 2015 Feb;101:294-301). This amino acid position is well 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.

Reported in association with HCM, ARVC, and sudden unexplained cardiac arrest/death (PMID: 24981977, 25351510, 26189708, 35819174, 32152366, 28771489); at least one patient harbored an additional cardiogenetic variant; Not located in one of the three hot-spot regions of the RYR2 gene, where the majority of pathogenic missense variants occur (PMID: 19926015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26189708, 25351510, 26899768, 28404607, 37510372, 24981977, 19926015, 35819174, 32152366, 28771489)

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).