ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.12301C>T (p.Leu4101Phe) (rs794728785)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182815 SCV000235201 likely pathogenic not provided 2013-10-09 criteria provided, single submitter clinical testing p.Leu4101Phe (CTT>TTT): c.12301 C>T in exon 90 of the RYR2 gene (NM_001035.2). The Leu4101Phe variant in the RYR2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Although Leu4101Phe results in a conservative amino acid substitution of one non-polar amino acid with another, it occurs at a residue that is conserved across species. In silico analysis predicts Leu4101Phe is damaging to the protein structure/function. Leu4101Phe is located in the channel domain, a mutation hotspot region of the RYR2 gene (Medeiros-Domingo A et al., 2009). Furthermore, the Leu4101Phe 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. In summary, while Leu4101Phe is a good candidate for a disease-causing mutation, we cannot unequivocally determine the clinical significance of this variant. The variant is found in CPVT panel(s).

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