ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.12526G>A (p.Val4176Met) (rs794728828)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182891 SCV000235280 likely pathogenic not provided 2012-01-12 criteria provided, single submitter clinical testing This mutation is denoted Val4176Met (aka V4176M) at the protein level and c.12526 G>A at the cDNA level. The Val4176Met variant in the RYR2 gene has not been reported previously as a disease-causing mutation or as a benign polymorphism to our knowledge. Although Val4176Met results in a conservative amino acid substitution of one non-polar residue for another, the Val4176 residue is highly conserved throughout evolution. In addition, Val4176Met is located in a mutation hot spot within the channel region of the RYR2 gene, supporting the functional significance of this region (Medeiros-Domingo A et al., 2009). In silico analysis predicts this change to be damaging to the structure/function of the protein and disease-causing (Adzhubei IA et al., 2010; Kumar P et al., 2009; Schwarz JM et al., 2011). Furthermore, Val4176Met was not observed in up to 600 control alleles from individuals of African American and Caucasian ancestry tested at GeneDx, and the NHLBI ESP Exome Variant Server reports Val4176Met was not observed in approximately 5,000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. In summary, while the Val4176Met is a good candidate for a disease-causing mutation, we cannot unequivocally determine the clinical significance of this variant. The variant is found in ARVC panel(s).

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