ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.11919T>G (p.Asp3973Glu) (rs370103782)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182801 SCV000235187 uncertain significance not specified 2016-04-14 criteria provided, single submitter clinical testing p.Asp3973Glu (GAT>GAG): c.11919 T>G in exon 89 of the RYR2 gene (NM_001035.2). The D3973E variant in the RYR2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. The D3973E variant is a conservative amino acid substitution as these residues share similar properties, and are least likely to impact secondary structure. In silico analysis was inconsistent with regard to the effect this variant may have on the protein structure/function. A variant affecting the same residue (D3973H), and variants affecting neighboring residues (M3972I, L3974Q) have been reported in association with CPVT (Medeiros- Domingo A et al., 2009), supporting the functional importance of this region of the protein. D3973E is located in the channel region, a mutation hotspot region of the RYR2 gene (Medeiros- Domingo A et al., 2009). The D3973E variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. We cannot definitively determine if D3973E is a disease-causing mutation or a rare benign variant. The variant is found in CPVT panel(s).
Invitae RCV000699516 SCV000828231 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2018-11-30 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glutamic acid at codon 3973 of the RYR2 protein (p.Asp3973Glu). 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 disease. ClinVar contains an entry for this variant (Variation ID: 201316). 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. 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.
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000656164 SCV000678358 uncertain significance Wolff-Parkinson-White pattern 2017-07-14 no assertion criteria provided research This variant was identified in an individual with Wolff-Parkinson-White syndrome

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