ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.527C>T (p.Thr176Ile)

gnomAD frequency: 0.00002  dbSNP: rs536617217
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Diagnostics, LLC DBA Color Health RCV001178811 SCV001343345 uncertain significance Cardiomyopathy 2021-10-29 criteria provided, single submitter clinical testing This missense variant replaces threonine with isoleucine at codon 176 of the DSG2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a family affected with arrhythmogenic cardiomyopathy and has been shown not to segregate with disease in this family (PMID: 31156706). This variant has been identified in 4/280698 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
GeneDx RCV002509399 SCV002818945 uncertain significance not provided 2023-01-03 criteria provided, single submitter clinical testing Reported in an individual with ACM who also harbored a pathogenic nonsense variant in the PKP2 gene; the PKP2 variant segregated with disease in this family (Campuzano et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32268277, 31156706)
Invitae RCV002526508 SCV003463210 uncertain significance Arrhythmogenic right ventricular dysplasia 10 2023-08-24 criteria provided, single submitter clinical testing In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on DSG2 protein function. ClinVar contains an entry for this variant (Variation ID: 417865). This variant has not been reported in the literature in individuals affected with DSG2-related conditions. This variant is present in population databases (rs536617217, gnomAD 0.003%). This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 176 of the DSG2 protein (p.Thr176Ile).
Division of Human Genetics, Children's Hospital of Philadelphia RCV000477874 SCV000536718 uncertain significance Arrhythmogenic right ventricular dysplasia 10; Dilated cardiomyopathy 1BB 2016-01-25 no assertion criteria provided research

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