Submissions for variant NM_001035.3(RYR2):c.11914A>G (p.Met3972Val)

dbSNP: rs1085307997

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000490203	SCV000577799	likely pathogenic	not provided	2015-05-08	criteria provided, single submitter	clinical testing	The M3972V variant has not been published to our knowledge, a variant at this same residue (M3972I) has been reported in an individual with CPVT; however, no additional clinical information or segregation studies were provided (Medeiros-Domingo et al., 2009; Jabbari et al., 2013). The M3972V variant is located in one of the three hot-spot regions of the RYR2 gene, and numerous missense variants in nearby residues (D3973H, L3974Q, D3977Y, M3978I) have been reported in association with CPVT according to the Human Gene Mutation Database (Medeiros-Domingo et al., 2009; Stenson et al., 2014), supporting the functional importance of this region of the protein. The M3972V variant was not observed in approximately 6,100 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This substitution occurs at a position that is conserved by class across species. However, the M3972V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Additionally, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.Therefore, this variant is a strong candidate for a pathogenic variant, however the possibility that it is a benign variant cannot be excluded.
Invitae	RCV002523420	SCV002252701	likely pathogenic	Catecholaminergic polymorphic ventricular tachycardia 1	2022-09-12	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Met3972 amino acid residue in RYR2. Other variant(s) that disrupt this residue have been observed in individuals with RYR2-related conditions (Invitae), which suggests that this may be a clinically significant amino acid residue. 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 not expected to disrupt RYR2 protein function. ClinVar contains an entry for this variant (Variation ID: 427164). This missense change has been observed in individual(s) with catecholaminergic polymorphic ventricular tachycardia (CPVT) and/or clinical features of RYR2-related conditions (Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 3972 of the RYR2 protein (p.Met3972Val).