ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.1319_1320del (p.Val440fs) (rs775256998)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000825031 SCV000966228 uncertain significance not specified 2018-06-27 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Val440fs variant in DSG2 has not been previously reported in individuals with ARVC, but h as been identified in 2/30266 South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs775256998). This var iant is predicted to cause a frameshift, which alters the protein?s amino acid s equence beginning at position 440 and leads to a premature termination codon 6 a mino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. In summary, while there is some suspicion for a pathogenic ro le, the clinical significance of the p.Val440fs variant is uncertain. ACMG/AMP c riteria applied: PM2, PVS1_Moderate.
Color Health, Inc RCV001175770 SCV001339482 uncertain significance Cardiomyopathy 2019-07-13 criteria provided, single submitter clinical testing
Division of Medical Genetics, University of Washington RCV001257462 SCV001434262 likely pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 10 2019-11-22 criteria provided, single submitter clinical testing This variant leads to a translational frameshift and the introduction of a premature termination codon 6 residues downstream. The variant transcript is predicted to be unstable and degraded by nonsense-mediated decay. Loss of expression of one allele of DSG2 is a well-established mechanism of disease for ARVC (Rasmussen 2013, Al-Jassar 2013). To our knowledge, this sequence variant has not been previously reported in the literature. This variant has an allele frequency of 0.000017 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). Thus, this variant is interpreted as likely pathogenic. PVS1
Invitae RCV001257462 SCV001590867 pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 10 2020-08-14 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Val440Glyfs*6) in the DSG2 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs775256998, ExAC 0.01%). This variant has not been reported in the literature in individuals with DSG2-related conditions. ClinVar contains an entry for this variant (Variation ID: 666600). Loss-of-function variants in DSG2 are known to be pathogenic (PMID: 23381804, 23911551). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV001564709 SCV001787912 likely pathogenic not provided 2021-06-03 no assertion criteria provided clinical testing Not observed at significant frequency in large population cohorts (Lek et al., 2016); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 27535533, 31638835, 26582918)

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