ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.10913A>C (p.Asp3638Ala) (rs1064793255)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000483438 SCV000565511 uncertain significance not provided 2017-12-01 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the RYR2 gene. The D3638A variant has been previously reported in a two-year-old Japanese male without typical arrhythmias, but whose symptomatic father died suddenly in his 30's and was reportedly genetically diagnosed with CPVT (Kawamura et al., 2013); however, confirmation that this variant was identified in the affected father was not reported and no further segregation studies were described. Nevertheless, the D3638A variant was not observed in approximately 5,900 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, and was not observed in the Exome Aggregation Consortium (ExAC), indicating it is not a common benign variant in these populations. The D3638A 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. Furthermore, this substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, the D3638A variant is not located in one of the three hot-spot regions of the RYR2 gene, where the majority of pathogenic missense variants occur (Medeiros-Domingo et al., 2009). Additionally, this variant has not been identified in a significant number of affected individuals, and there are no functional studies or segregation data available to clarify the role of this variant in disease. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.

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