Submissions for variant NM_001035.3(RYR2):c.12893T>C (p.Val4298Ala)

dbSNP: rs984942880

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV002527792	SCV000637503	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2022-03-08	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 not expected to disrupt RYR2 protein function. ClinVar contains an entry for this variant (Variation ID: 463561). This variant has not been reported in the literature in individuals affected with RYR2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 4298 of the RYR2 protein (p.Val4298Ala).
Color Diagnostics, LLC DBA Color Health	RCV001176126	SCV001339993	uncertain significance	Cardiomyopathy	2023-12-05	criteria provided, single submitter	clinical testing	This missense variant replaces valine with alanine at codon 4298 of the RYR2 protein. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
GeneDx	RCV001561600	SCV001784228	uncertain significance	not provided	2021-08-09	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 463561 ; Landrum et al., 2016) Not observed in large population cohorts (Lek et al., 2016) In silico analysis supports that this missense variant does not alter protein structure/function 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)