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,; 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 ( 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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