ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.14869T>A (p.Cys4957Ser) (rs758500988)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182853 SCV000235241 likely pathogenic not provided 2013-09-24 criteria provided, single submitter clinical testing p.Cys4957Ser (TGC>AGC): c.14869 T>A in exon 105 of the RYR2 gene (NM_001035.2). The Cys4957Ser variant in the RYR2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Although Cys4957Ser results in a conservative amino acid substitution of one polar residue for another, the Cys4957 residue is conserved across species. In silico analysis predicts Cys4957Ser is probably damaging to the protein structure/function. Mutations in nearby residues (Glu4950Lys, Arg4959Gln) have been reported in association with polymorphic ventricular tachycardia, further supporting the functional importance of this region of the protein. Furthermore, the Cys4957Ser 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. In summary, while Cys4957Ser is a good candidate for a disease-causing mutation, we cannot unequivocally determine the clinical significance of this variant. The variant is found in POSTMORTEM,ARVC panel(s).

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