ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.6883G>A (p.Gly2295Arg) (rs794728745)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182747 SCV000235132 likely pathogenic not provided 2017-07-10 criteria provided, single submitter clinical testing p.Gly2295Arg (GGA>AGA): c.6883 G>A in exon 45 of the RYR2 gene (NM_001035.2). The G2295R variant in the RYR2 gene has not been published previously in association with CPVT, nor as a benign polymorphism to our knowledge. The G2295R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is well conserved across species throughout evolution. The G2295R variant is located in the central domain hot-spot" region of the RYR2 gene (Medeiros-Domingo A et al., 2009), and another missense mutation in a nearby residue (E2296Q) has been reported in association with CPVT, supporting the functional importance of this region of the protein. Furthermore, the G2295R 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. Therefore, this variant is a strong candidate for a pathogenic mutation, however the possibility that it is a benign variant cannot be excluded. CPVT is primarily caused by autosomal dominant mutations in the RYR2 and KCNJ2 genes. Less commonly, CPVT is caused by autosomal recessive mutations in the CASQ2 gene (Napolitano C et al., 2012). Approximately 50% of patients with autosomal dominant CPVT have been reported to have a mutation in the RYR2 gene, while mutations in the RYR2 gene associated with ARVC are rare (McNally E et al., 2009; Napolitano C et al., 2012). The variant is found in POSTMORTEM panel(s)."

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