ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.12470G>A (p.Arg4157Gln) (rs794728786)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182819 SCV000235205 pathogenic not provided 2015-04-23 criteria provided, single submitter clinical testing p.Arg4157Gln (CGA>CAA): c.12470 G>A in exon 90 of the RYR2 gene (NM_001035.2). The Arg4157Gln mutation in the RYR2 gene has been reported previously in one individual with CPVT, and this mutation was absent from 400 control alleles (Medeiros-Domingo A et al., 2009). In addition, the NHLBI ESP Exome Variant Server reports Arg4157Gln 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. Located in the channel region mutation hot spot, other mutations in nearby codons (Ser4153Arg, Thr4158Pro, Gln4159Pro) have also been reported in association with CPVT, further supporting the functional importance of this region of the protein. In summary, Arg4157Gln in the RYR2 is interpreted as a disease-causing mutation. The variant is found in POSTMORTEM panel(s).
Invitae RCV000693231 SCV000821091 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2019-05-21 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 4157 of the RYR2 protein (p.Arg4157Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in individuals affected with catecholaminergic polymorphic ventricular tachycardia (CPVT; PMID: 28237968) and has been observed in individuals referred for CPVT testing (PMID: 29453246). ClinVar contains an entry for this variant (Variation ID: 201333). 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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