Submissions for variant NM_001035.3(RYR2):c.11140T>G (p.Phe3714Val)

dbSNP: rs794728771

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182792	SCV000235178	uncertain significance	not provided	2018-01-02	criteria provided, single submitter	clinical testing	p.Phe3714Val (TTT>GTT): c.11140 T>G in exon 80 of the RYR2 gene (NM_001035.2). The F3714V variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The F3714V variant was not observed in approximately 6,000 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 F3714V variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, no missense mutations in nearby residues have been reported in association with CPVT, indicating that this region of the protein may be tolerant of change. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in CPVT panel(s).
Invitae	RCV003525873	SCV004334917	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2023-10-13	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 3714 of the RYR2 protein (p.Phe3714Val). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RYR2-related conditions. ClinVar contains an entry for this variant (Variation ID: 201308). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RYR2 protein function. 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.