Submissions for variant NM_001035.3(RYR2):c.13984G>A (p.Gly4662Ser)

gnomAD frequency: 0.00001  dbSNP: rs886039213

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000244610	SCV000320684	uncertain significance	Cardiovascular phenotype	2023-01-25	criteria provided, single submitter	clinical testing	The p.G4662S variant (also known as c.13984G>A), located in coding exon 97 of the RYR2 gene, results from a G to A substitution at nucleotide position 13984. The glycine at codon 4662 is replaced by serine, an amino acid with similar properties. This variant was detected in trans with another alteration in RYR2 (p.H4762P, c.14285A>C) in a proband with catecholaminergic polymorphic ventricular tachycardia. The p.G4662S variant was inherited from the reportedly unaffected father, only the proband was known to have both variants, and no other carriers of either variant were reported to be affected at the time of study (Postma AV et al. J Med Genet. 2005;42(11):863-70). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
GeneDx	RCV000481567	SCV000568210	uncertain significance	not provided	2017-03-17	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the RYR2 gene. The G4662S variant has been previously reported in at least one individual with CPVT (Postma et al., 2005; Hayashi et al., 2009). Postma et al. (2005) reported this variant in a French female with CPVT, who also harbored the H4762P variant in the RYR2 gene, and had a brother with sudden death at 20 years of age. Although familial testing was not completed in the deceased brother, the G4662S variant was paternally inherited, and the H4762P variant was maternally inherited and present in her two children, and these relatives were all clinically unaffected (Postma et al., 2005). Nevertheless, the G4662S variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The G4662S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Moreover, this substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, G4662S 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). However, this variant has not been observed in a significant number of affected individuals and it lacks large segregation studies and functional evidence, which would further clarify its role in disease. Finally, this variant is also classified in ClinVar as a variant of uncertain significance by a different clinical laboratory (ClinVar SCV000320684.1; Landrum et al., 2016).
Illumina Laboratory Services, Illumina	RCV001096505	SCV001252723	uncertain significance	Arrhythmogenic right ventricular dysplasia 2	2017-04-27	criteria provided, single submitter	clinical testing	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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001096506	SCV001252724	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2017-04-27	criteria provided, single submitter	clinical testing	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001269221	SCV001448530	uncertain significance	not specified	2020-11-16	criteria provided, single submitter	clinical testing	Variant summary: RYR2 c.13984G>A (p.Gly4662Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 243586 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.13984G>A has been reported in the literature in at least one individual affected with Catecholaminergic Polymorphic Ventricular Tachycardia. This report does not provide unequivocal conclusions about association of the variant with Catecholaminergic Polymorphic Ventricular Tachycardia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae	RCV001096506	SCV003443785	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2022-09-10	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 264631). This missense change has been observed in individual(s) with catecholaminergic polymorphic ventricular tachycardia (PMID: 16272262). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 4662 of the RYR2 protein (p.Gly4662Ser).