ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.14695G>A (p.Asp4899Asn) (rs794728807)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182849 SCV000235237 likely pathogenic not provided 2014-01-16 criteria provided, single submitter clinical testing p.Asp4899Asn (GAC>AAC): c.14695 G>A in exon 103 of the RYR2 gene (NM_001035.2). The D4899N variant in the RYR2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. The D4899N variant is a semi-conservative amino acid substitution as these residues share similar properties, but differ in size, charge, or other properties which may impact secondary structure. The D4899 residue is conserved across species, and D4899N is located in the mutation hotspot channel region of the RYR2 gene (Medeiros-Domingo A et al., 2009). In silico analysis predicts D4899N is probably damaging to the protein structure/function. Mutations in nearby residues (N4895D, P4902L, P4902S, F4905L) have been reported in association with CPVT, further supporting the functional importance of this region of the protein. Furthermore, the D4899N 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 D4899N is a good candidate for a disease-causing mutation, we cannot unequivocally determine the clinical significance of this variant. The variant is found in ARRHYTHMIA panel(s).

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