ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.14251A>C (p.Lys4751Gln) (rs794728802)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000621431 SCV000737686 likely pathogenic Cardiovascular phenotype 2017-12-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Rarity in general population databases (dbsnp, esp, 1000 genomes)
GeneDx RCV000182843 SCV000235231 pathogenic not provided 2014-05-05 criteria provided, single submitter clinical testing p.Lys4751Gln (AAG>CAG): c.14251 A>C in exon 99 of the RYR2 gene (NM_001035.2). The K4751Q mutation in the RYR2 gene has been reported in one Japanese individual diagnosed with CPVT and atrial flutter (Kawamura M et al., 2013). K4751Q is a semi-conservative amino acid substitution as these residues share similar properties, but differs in size, charge, or other properties which may impact secondary structure. K4751Q occurs at a position that is conserved across species and is located in the channel region, which is a known hotspot for mutations (Medeiros-Domingo A et al, 2009). Mutations in nearby residues (H4742Y, H4762P) have been reported in association with sudden cardiac death and CPVT, respectively, further supporting the functional importance of this region of the protein. In silico analysis predicts that K4751Q is probably damaging to protein structure/function. Additionally, the K4751Q mutation was not observed inapproximately 6000 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, K4751Q in the RYR2 gene is interpreted as a disease-causing mutation. The variant is found in CPVT panel(s).

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