Submissions for variant NM_001035.3(RYR2):c.9392A>G (p.Tyr3131Cys)

dbSNP: rs1342384519

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001177234	SCV001341409	uncertain significance	Cardiomyopathy	2019-09-12	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with cysteine at codon 3131 of the RYR2 protein. Computational prediction tool is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 1/248428 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.
Invitae	RCV002559720	SCV002593471	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2022-10-10	criteria provided, single submitter	clinical testing	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. ClinVar contains an entry for this variant (Variation ID: 919217). 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 0.004%). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 3131 of the RYR2 protein (p.Tyr3131Cys).
Ambry Genetics	RCV002375065	SCV002686398	uncertain significance	Cardiovascular phenotype	2020-11-30	criteria provided, single submitter	clinical testing	The p.Y3131C variant (also known as c.9392A>G), located in coding exon 66 of the RYR2 gene, results from an A to G substitution at nucleotide position 9392. The tyrosine at codon 3131 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Dept of Medical Biology, Uskudar University	RCV003318392	SCV004022000	uncertain significance	Long QT syndrome	2024-01-08	criteria provided, single submitter	research	Criteria: PM2, PP2, PP3