Submissions for variant NM_001035.3(RYR2):c.2251A>G (p.Thr751Ala)

gnomAD frequency: 0.00002  dbSNP: rs878854154

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV002518313	SCV000285711	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2023-01-31	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 not expected to disrupt RYR2 protein function. ClinVar contains an entry for this variant (Variation ID: 238227). This variant has not been reported in the literature in individuals affected with RYR2-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.01%). This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 751 of the RYR2 protein (p.Thr751Ala).
GeneDx	RCV000429451	SCV000536009	uncertain significance	not provided	2017-01-16	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the RYR2 gene. The T751A variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This 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. The T751A variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals. However, Alanine is the wild-type amino acid at this position in at least three species. In addition, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Furthermore, the T751A variant is not 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).
Color Diagnostics, LLC DBA Color Health	RCV001188443	SCV001355502	uncertain significance	Cardiomyopathy	2023-04-20	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with alanine at codon 751 of the RYR2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with RYR2-related disorders in the literature. This variant has been identified in 1/31398 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The 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.