ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.848+1G>A (rs772984053)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766706 SCV000235248 uncertain significance not provided 2017-09-08 criteria provided, single submitter clinical testing The c.848+1 G>A variant in the RYR2 gene has not been reported as a disease-causing mutation, nor as a benign polymorphism, to our knowledge. The c.848+1 G>A variant destroys the canonical splice donor site in intron 11 and is expected to cause abnormal gene splicing. This may lead to loss of protein function due to protein truncation or absence of protein from this allele due to mRNA decay. However, the majority of disease-causing mutations in the RYR2 gene are missense changes, and there are no reported frameshift mutations associated with the RYR2 gene, to our knowledge. In summary, with the clinical and molecular information available at this time, we cannot definitively determine whether the c.848+1 G>A variant in the RYR2 gene is a disease-causing mutation or rare benign variant. The variant is found in POSTMORTEM panel(s).
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000182860 SCV000540258 uncertain significance not specified 2016-08-12 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: LOF not a known disease mechanism for this gene.
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000999616 SCV001156320 pathogenic Catecholaminergic polymorphic ventricular tachycardia 2018-03-08 criteria provided, single submitter research RYR2 c.848+1G>A has been described previously in at least 1 CPVT and 1 sudden death case (Genedx, Pers. Comm.) The variant in our family was identified in a branch of the family in the Netherlands, where the young proband had an out of hospital cardiac arrest and subsequent clinical diagnosis of CPVT (Pers. Comm.). Our patient, a fifth-degree relative of the proband, also has a clinical diagnosis of CPVT and harbours the variant. Co-segregation of this variant with disease has been reportedly demonstrated in the Netherlands in 9 additional family members. This variant is present in the Genome Aggregation Database (http://gnomad.broadinstitute.org/) at an allele frequency (AF) of 0.000016. Splice prediction tools MaxEntScan and AdaBoost both predict that this variant results in aberrant splicing. Loss of function is not an established mechanism of disease, however in-house RNA studies have shown that this variant causes skipping of exon 11, resulting in an in-frame deletion. In summary, this variant has found to segregate strongly in one family (PP1_strong), is rare in the general population (PM2), results in a shortened protein (PM4) and has been seen in at least 2 probands diagnosed with CPVT (PS4_supporting), therefore we classify RYR2 c.848+1G>A as 'pathogenic'.
Invitae RCV000999616 SCV001388660 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2019-05-16 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 11 of the RYR2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs772984053, ExAC 0.003%). This variant has not been reported in the literature in individuals with RYR2-related conditions. ClinVar contains an entry for this variant (Variation ID: 201371). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. The current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in RYR2 cause disease. 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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