Submissions for variant NM_001035.3(RYR2):c.14311G>A (p.Val4771Ile)

dbSNP: rs794728804

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182845	SCV000235233	pathogenic	not provided	2023-01-26	criteria provided, single submitter	clinical testing	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); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 12093772, 21292648, 21616285, 19398665, 24136861, 29434162, 22383456, 24025405, 15913575, 23022705, 16272262, 25554238, 25651173, 19926015, 26114861, 23595086, 30170228, 28202948, 28237968, 31231889, 31112425)
Labcorp Genetics (formerly Invitae), Labcorp	RCV002517805	SCV000541672	pathogenic	Catecholaminergic polymorphic ventricular tachycardia 1	2023-11-20	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 4771 of the RYR2 protein (p.Val4771Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant catecholaminergic polymorphic ventricular tachycardia (PMID: 12093772, 19926015, 21292648, 23595086, 26114861). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 201357). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002390463	SCV002701051	pathogenic	Cardiovascular phenotype	2021-11-09	criteria provided, single submitter	clinical testing	The p.V4771I pathogenic mutation (also known as c.14311G>A), located in coding exon 100 of the RYR2 gene, results from a G to A substitution at nucleotide position 14311. The valine at codon 4771 is replaced by isoleucine, an amino acid with highly similar properties. This variant has been detected in individuals with known or suspected catecholaminergic polymorphic ventricular tachycardia, and has been reported as occurring de novo in two cases (Priori SG et al. Circulation. 2002;106(1):69-74; Hayashi M et al. Circulation. 2009;119(18):2426-34; Pott C et al. Europace. 2011;13(6):897-901; Van der Werf C et al. J Am Coll Cardiol. 2011;57(22):2244-54; Jabbari J et al. Circ Cardiovasc Genet. 2013;6(5):481-9; Illikova V et al. J Electrocardiol. 2015;48:150-6; Ohno S et al. PLoS ONE. 2015;10(6):e0131517; McLeod KA et al. Cardiol Young. 2017;27(7):1271-1279; Kapplinger JD et al. Circ Genom Precis Med. 2018;11(2):e001424). The variant was reported to co-segregate with disease features in at least two families (Postma AV et al. J Med Genet. 2005; 42(11):863-70; Kawamura M et al. Circ J. 2013; 77(7):1705-13). Additionally, this variant has been reported as occurring in the channel region, considered to be a mutation "hot spot" (Medeiros-Domingo A et al. J Am Coll Cardiol. 2009;54(22):2065-74). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by BayesDel in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002517805	SCV003921908	pathogenic	Catecholaminergic polymorphic ventricular tachycardia 1	2023-07-17	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and gain of function are known mechanisms of disease in this gene and are associated with catecholaminergic polymorphic ventricular tachycardia 1 (MIM#604772) and left ventricular non-compaction (PMIDs: 12459180, 27646203, 29477366, 31875585, 33500567). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. Penetrance for CPVT is estimated to be 60-70% (PMID: 23549275). (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to isoleucine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (v3: 1 heterozygote, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and high conservation. (I) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (PMID: 19926015). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in at least ten individuals with CPVT and consistently classified as pathogenic by diagnostic laboratories in ClinVar (PMID: 16272262, 19926015, 21292648, 29453246, 26114861, 33606749). (SP) 1204 - This variant has been shown to be de novo in the proband (parental status not tested but assumed) (by segregation analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign