Submissions for variant NM_001035.3(RYR2):c.9412T>C (p.Tyr3138His)

dbSNP: rs794728765

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182777	SCV000235163	uncertain significance	not provided	2013-01-11	criteria provided, single submitter	clinical testing	p.Tyr3138His (TAT>CAT): c.9412 T>C in exon 66 of the RYR2 gene (NM_001035.2). The Tyr3138His variant in the RYR2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Tyr3138His results in a non-conservative amino acid substitution of a neutral polar Tyrosine with a positively charged Histidine at a position that is conserved across species. In silico analysis predicts Tyr3138His is probably damaging to the protein structure/function. The NHLBI ESP Exome Variant Server reports Tyr3138His was not observed in approximately 6,000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. Nevertheless, Tyr3138His does not occur in one of the mutation hot spot regions of the RYR2 gene (Medeiros-Domingo A et al., 2009), and no mutations in nearby codons have been reported in association with arrhythmia. We cannot definitively determine if Tyr3138His is a disease-causing mutation or a rare benign variant. The variant is found in ARVC panel(s).
Invitae	RCV002516889	SCV003502088	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2022-10-17	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 3138 of the RYR2 protein (p.Tyr3138His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 201294). 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. 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.
Color Diagnostics, LLC DBA Color Health	RCV003532032	SCV004360734	uncertain significance	Cardiomyopathy	2022-05-10	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with histidine at codon 3138 of the RYR2 protein. Computational prediction 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). To our knowledge, functional studies have not been reported for this variant. This variant has not 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). 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.