Submissions for variant NM_001035.3(RYR2):c.12608C>T (p.Ala4203Val)

dbSNP: rs794728792

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182826	SCV000235212	uncertain significance	not specified	2017-02-07	criteria provided, single submitter	clinical testing	Although the A4203V variant has not been published as a pathogenic variant or as a benign variant to our knowledge. This variant was not observed in approximately 6,200 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The A4203V variant is located in the channel region of the RYR gene, one of the three hot-spot regions where the majority of pathogenic missense variants occur (Medeiros-Domingo et al., 2009). In addition, 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. However, the A4203V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Furthermore, only one missense variant in a nearby residue (Q4201R) has been reported in the Human Gene Mutation Database in association with ventricular tachycardia (Stenson et al., 2014). Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae	RCV002470800	SCV000760635	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2023-05-31	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: 201339). This missense change has been observed in individual(s) with clinical features of RYR2-related conditions (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 4203 of the RYR2 protein (p.Ala4203Val).
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002470800	SCV002767431	likely pathogenic	Catecholaminergic polymorphic ventricular tachycardia 1	2021-05-06	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely 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 (CPVT) (MIM#604772). Functional studies have shown that pathogenic variants can have dominant negative (reduced calcium ion release) or gain of function (increased calcium ion release) effects on the RYR2 pore (PMID: 27646203, 29477366). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. Average penetrance for CPVT is estimated at 70% to 80% (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to valine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0804 - This variant has previously been described as a variant of uncertain significance in multiple independent cases with consistent phenotype despite being absent in the general population. This variant has been reported twice as a VUS in the ClinVar database by diagnostic laboratories. These laboratories have observed the variant in three unrelated individuals with history of sudden cardiac arrest (personal correspondence). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Revvity Omics, Revvity	RCV003137706	SCV003820581	uncertain significance	not provided	2019-09-18	criteria provided, single submitter	clinical testing