ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.13735C>T (p.His4579Tyr) (rs794728830)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182893 SCV000235282 uncertain significance not provided 2017-07-10 criteria provided, single submitter clinical testing The H4579Y variant of uncertain significance in the RYR2 gene has been previously reported in association with CPVT (Larsen et al., 2013; Broendberg et al., 2017). Larsen et al. (2013) originally reported this variant in a 34 year-old woman who died suddenly during physical activity. Cascade genetic testing revealed that the patient's mother, maternal aunt, and maternal uncle each harbored H4579Y, yet after Cardiology evaluation of all three relatives, only the maternal aunt met clinical criteria for CPVT (Larsen et al., 2013). More recently, Broendberg et al. (2017) identified H4579Y in a proband presenting with sudden cardiac death; familial testing confirmed the variant was present in seven symptomatic relatives and three asymptomatic relatives, although specific clinical information and relatives' relationship to the proband were not provided. H4579Y is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The H4579Y 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. Moreover, 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. Furthermore, the H4579Y variant is 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). Nevertheless, this variant lacks observation in a significant number of affected individuals, informative segregation data, and functional evidence, which would further clarify its pathogenicity.

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