ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.495dup (p.Gly166fs) (rs781532110)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000290082 SCV000330130 pathogenic not provided 2018-06-26 criteria provided, single submitter clinical testing The c.495dupT pathogenic variant in the DSG2 gene has been reported in one individual with ARVC (Walsh et al., 2017). This variant causes a shift in reading frame starting at codon glycine 166, changing it to a tryptophan, and creating a premature stop codon at position 4 of the new reading frame, denoted p.Gly166TrpfsX4. This variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Multiple other downstream frameshift variants in the DSG2 gene have been reported in HGMD in association with ARVC (Stenson et al., 2014). Furthermore, the c.495dupT variant is not observed at any significant frequency in large population cohorts (Lek et al., 2016).
Invitae RCV000813935 SCV000954319 pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 10 2019-11-19 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gly166Trpfs*4) in the DSG2 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs781532110, ExAC 0.01%). This variant has been observed in an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 280230). Loss-of-function variants in DSG2 are known to be pathogenic (PMID: 23381804, 23911551). For these reasons, this variant has been classified as Pathogenic.

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