ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.1880-2A>G (rs397514038)

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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 RCV000211716 SCV000060933 likely pathogenic Arrhythmogenic right ventricular cardiomyopathy 2010-12-17 criteria provided, single submitter clinical testing The 1880-2A>G variant has been reported in two siblings with ARVC and was absent from 560 matched control chromosomes, supporting a pathogenic role. However, b oth siblings also carried a second, possibly disease causing variant on the othe r copy of the DSG2 gene (Pilichou, 2006). RNA studies demonstrated that the 1880 -2A>G abolishes the splice site, leading to the use of a cryptic splice site 38 bp downstream. The aberrantly spliced mRNA was shown to lack the first 38 bp of exon 13, which is predicted to cause a frameshift starting at position 627 and p remature termination 19 amino acids later, leading to a truncated or absent prot ein (Pilichou, 2006). In summary, the severity of the change as well as absence from controls suggest that this variant is likely pathogenic.
GeneDx RCV000181225 SCV000233504 pathogenic not provided 2020-03-17 criteria provided, single submitter clinical testing Identified in association with ARVC (Pilichou et al., 2006; Walsh et al., 2017); variant reported as c.1881-2 A>G (due to alternate nomenclature) in an affected patient and her sister who both also harbored a missense variant in the DSG2 gene (Pilichou et al 2006); Published functional studies demonstrate that this variant leads to the inactivation of the natural intron 12 splice acceptor site and the activation of a cryptic splice acceptor site in exon 13, resulting in abnormal gene splicing (Pilichou et al., 2006); Not observed in large population cohorts (Lek et al., 2016); Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Reported in ClinVar as either pathogenic or likely pathogenic (ClinVar Variant ID# 16817; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 16505173, 23381804, 25525159, 27532257, 31402444, 32686758)
Invitae RCV000018310 SCV000814564 pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 10 2018-06-12 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 12 of the DSG2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in heterozygosis in an individual affected with right ventricular cardiomyopathy and in compound heterozygosis (in trans) with rare missense varaint in two siblings affected with ARVC (PMID: 16505173, 27532257). This variant is also known as c.1881-2A>G in the literature. ClinVar contains an entry for this variant (Variation ID: 16817). Experimental studies have shown that this intronic change leads to the inactivation of the natural intron 12 donor splice site and to the activation of a cryptic splice site in exon 13 that results in a transcript susceptible to NMD (PMID: 16505173). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in DSG2 are known to be pathogenic (PMID: 23381804, 23911551). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000018310 SCV000038589 pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 10 2006-03-07 no assertion criteria provided literature only

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