ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.2033G>C (p.Gly678Ala) (rs372494397)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000154704 SCV000204383 uncertain significance not specified 2013-07-31 criteria provided, single submitter clinical testing The Gly678Ala variant in DSG2 has not been reported in individuals with cardiomy opathy but has been identified in 1/4012 African American chromosomes by the NHL BI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/). Computational a nalyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that the Gly678Ala variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. Additional information is needed to fully assess the clinical significance of the Gly678Ala variant.
Invitae RCV000701131 SCV000829915 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 10 2019-12-13 criteria provided, single submitter clinical testing This sequence change replaces glycine with alanine at codon 678 of the DSG2 protein (p.Gly678Ala). The glycine residue is weakly conserved and there is a small physicochemical difference between glycine and alanine. This variant is present in population databases (rs372494397, ExAC 0.006%). This variant has been reported in individuals affected with arrhythmogenic right ventricular cardiomyopathy (ARVC) and hypertrophic cardiomyopathy (HCM) (PMID: 24070718, 26656175). ClinVar contains an entry for this variant (Variation ID: 178021). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The alanine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769512 SCV000900907 uncertain significance Cardiomyopathy 2016-05-18 criteria provided, single submitter clinical testing
Color Health, Inc RCV000769512 SCV001342476 uncertain significance Cardiomyopathy 2020-01-09 criteria provided, single submitter clinical testing

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