ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.11024C>G (p.Ala3675Gly) (rs794728770)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182791 SCV000235177 uncertain significance not provided 2014-06-02 criteria provided, single submitter clinical testing p.Ala3675Gly (GCT>GGT): c.11024 C>G in exon 78 of the RYR2 gene (NM_001035.2). The A3675G variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The A3675G 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 A3675G variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. 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. However, in silico analysis predicts this variant is probably damaging to the protein structure/function. 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 RCV000696846 SCV000825426 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2018-02-14 criteria provided, single submitter clinical testing This sequence change replaces alanine with glycine at codon 3675 of the RYR2 protein (p.Ala3675Gly). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and glycine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with RYR2-related disease. ClinVar contains an entry for this variant (Variation ID: 201307). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.

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