ClinVar Miner

Submissions for variant NM_024422.6(DSC2):c.631-2A>G (rs397514042)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000211713 SCV000063121 uncertain significance not specified 2018-08-28 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The c.631-2A>G variant in DSC2 has been reported in 2 individuals with ARVC and 1 individual wi th LVNC (Heuser 2006, LMM data). It was also reported in a 110-year-old individu al (Gierman 2014) and in ClinVar (Variation ID: 16850). This variant has been id entified in 4/111556 European chromosomes by the Genome Aggregation Database (gn omAD, http://gnomad.broadinstitute.org). This variant occurs in the invariant re gion (+/- 1,2) of the splice consensus sequence, and in vitro studies confirmed that it leads to aberrant splicing and reduced DSC2 protein levels (Heuser 2006) . Splice and other loss-of-function variants in DSC2 have been reported in indiv iduals with ARVC; however, the clinical significance of these variants is not ye t fully understood. Although ARVC has primarily been described as a dominant dis order, in several reports of loss-of function variants, only those individuals w ith a variant on the second allele were affected, suggesting that LOF variants m ay either act in a recessive manner or have a much milder effect than missense v ariants. In summary, while there is some suspicion for a pathogenic role in the heterozygous state, the clinical significance of the c.631-2A>G variant, with re gard to dominant ARVC is uncertain. ACMG/AMP Criteria applied: PS4_Supporting, PM2, PP3, PS3_Supporting.
GeneDx RCV000181140 SCV000233417 pathogenic not provided 2018-09-19 criteria provided, single submitter clinical testing The c.631-2A>G variant in the DSC2 gene has been reported previously in a patient with ARVC (Heuser et al., 2006). The c.631-2A>G was also identified in an asymptomatic individual from a cohort of supercentenarians undergoing whole genome sequencing (Gierman et al., 2014). This splice site variant destroys the canonical splice acceptor site in intron 5 and is predicted to cause abnormal gene splicing (Heuser et al., 2006). This variant is predicted to lead to either an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. The c.631-2A>G variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret c.631-2A>G as a pathogenic variant.
Invitae RCV000018344 SCV000950273 pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 11 2018-09-06 criteria provided, single submitter clinical testing This sequence change affects acceptor splice site in intron 5 of the DSC2 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 (rs397514042, ExAC 0.002%). This variant has been observed in individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 17186466, 23812740). ClinVar contains an entry for this variant (Variation ID: 16850). Experimental studies have shown that this change results in aberrant splicing, decreased mRNA expression, and zebrafish morpholinos containing this variant show significant cardiac defects (PMID: 17186466). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in DSC2 are known to be pathogenic (PMID: 18957847, 23863954, 23911551). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000018344 SCV000038623 pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 11 2006-12-01 no assertion criteria provided literature only

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