ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.11814C>A (p.Ser3938Arg) (rs794728704)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182651 SCV000235029 pathogenic not provided 2012-12-14 criteria provided, single submitter clinical testing p.Ser3938Arg (AGC>AGA): c.11814 C>A in exon 88 of the RYR2 gene (NM_001035.2). The Ser3938Arg mutation in the RYR2 gene has been reported in two unrelated patients with CPVT and it was absent from more than 400 reference alleles (Tester D et al., 2006; Medeiros-Domingo A et al., 2009). Additionally, NHLBI ESP Exome Variant Server reports Ser3938Arg was not observed in approximately 6,000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. Ser3938Arg is located in the channel region, a mutation hot spot, in the RYR2 gene (Medeiros-Domingo A et al., 2009). In summary, Ser3938Arg in the RYR2 gene is interpreted as a disease-causing mutation. The variant is found in CPVT panel(s).
Invitae RCV000639125 SCV000760687 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2017-12-12 criteria provided, single submitter clinical testing This sequence change replaces serine with arginine at codon 3938 of the RYR2 protein (p.Ser3938Arg). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual  affected with catecholaminergic polymorphic ventricular tachycardia (CPVT) (PMID: 16188589). ClinVar contains an entry for this variant (Variation ID: 201188). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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