ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.8205C>A (p.Asp2735Glu) (rs794728823)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182878 SCV000235266 uncertain significance not provided 2017-06-09 criteria provided, single submitter clinical testing p.Asp2735Glu (GAC>GAA): c.8205 C>A in exon 54 of the RYR2 gene (NM_001035.2). The D2735E variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The D2735E variant was not observed in approximately 5,800 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This substitution occurs at a position that is conserved in most mammals. However, the D2735E variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Additionally, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Furthermore, missense mutations in nearby residues have not been reported, indicating this region of the protein may be tolerant of change. 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 ARVC panel(s).
Invitae RCV001068756 SCV001233888 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2019-01-15 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glutamic acid at codon 2735 of the RYR2 protein (p.Asp2735Glu). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and glutamic acid. 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 conditions. ClinVar contains an entry for this variant (Variation ID: 201388). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamic acid amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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 RCV001175682 SCV001339373 uncertain significance Cardiomyopathy 2019-06-25 criteria provided, single submitter clinical testing

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