ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.470C>T (p.Pro157Leu) (rs587782938)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000480826 SCV000568158 uncertain significance not provided 2017-12-28 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the DSG2 gene. While the P157L variant has not been published as a pathogenic variant or as a benign variant, it has been reported as likely to have pathogenic effects" in a review paper of desmosomal proteins which did not provide additional information (Al-Jassar et al., 2013). Additionally, the P157L variant has been classified as a variant of uncertain significance by another clinical laboratory in ClinVar (SCV000188750.1; Landrum et al., 2016). The P157L variant was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The P157L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, additional evidence is needed to determine whether this is a pathogenic or rare benign variant."
Invitae RCV000702467 SCV000831323 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 10 2020-10-27 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 157 of the DSG2 protein (p.Pro157Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs587782938, ExAC 0.006%) but has not been reported in the literature in individuals with a DSG2-related disease. ClinVar contains an entry for this variant (Variation ID: 155784). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Health, Inc RCV001190411 SCV001357891 uncertain significance Cardiomyopathy 2018-11-13 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000143881 SCV000188750 uncertain significance Arrhythmogenic right ventricular cardiomyopathy 2014-01-29 no assertion criteria provided clinical testing

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