Submissions for variant NM_001035.3(RYR2):c.7175A>G (p.Tyr2392Cys)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002472263	SCV002769377	pathogenic	Catecholaminergic polymorphic ventricular tachycardia 1	2021-05-06	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative, loss of function and gain of function are known mechanisms of disease in this gene and are associated with disease. PMID: 12459180. PMID: 27646203. PMID: 29477366. (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from tyrosine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2.1.1) <0.001 for a dominant condition (1 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools, and very highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants. Central region, one of the variant cluster regions. (PMID: 19926015). (SP) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals: PMID 12106942: A family with two patients with polymorphic ventricular arrhythmia and two sudden deaths. PMID 21954897: Five patients with CPVT, although it is unclear if they are related. PMID 22677073: One patient who suffered a sudden death after exertion, with a family history of sudden death. PMID 27251404: One patient who had previously been given a clinical diagnosis of LQTS. PMID 29434162: One patient with CPVT and bradycardia. PMID 29453246: One patient with CPVT. At VCGS, previously reported twice in our CPVT patient cohort. (SP) 0903 - This variant has limited evidence for segregation with disease. PMID 12106942: A family with premature polymorphic ventricular complexes (two patients, and two sudden deaths (not tested), and two relatives with the variant who showed no arrhythmia on the bicycle stress test. (SP) 1010 - Functional evidence for this variant is conflicting. PMID 12459180: Functional studies in yeast constructs indicated that this variant decreased binding affinity to the gating protein FKBP12.6, leading to disrupted channel-gating and increased calcium release. However, other variants from this study have been tested in other studies with results showing a different effect or no effect on FKBP12.6 binding (PMID: 16239587). (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting Pathogenic, (I) – Information, (SB) – Supporting Benign
Labcorp Genetics (formerly Invitae), Labcorp	RCV002472263	SCV004292013	pathogenic	Catecholaminergic polymorphic ventricular tachycardia 1	2023-12-07	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 2392 of the RYR2 protein (p.Tyr2392Cys). This variant is present in population databases (rs772220753, gnomAD 0.0009%). This missense change has been observed in individuals with clinical features of autosomal dominant catecholaminergic polymorphic ventricular tachycardia (PMID: 12106942, 29434162, 29453246; Invitae). ClinVar contains an entry for this variant (Variation ID: 1805845). 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%. Experimental studies have shown that this missense change affects RYR2 function (PMID: 12459180). For these reasons, this variant has been classified as Pathogenic.