ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.2360A>G (p.Asp787Gly) (rs369868954)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181251 SCV000233530 uncertain significance not provided 2018-11-12 criteria provided, single submitter clinical testing The D787G variant of uncertain significance in the DSG2 gene has not been published as pathogenic or been reported as benign to our knowledge. This variant is observed in 12/277032 (0.004%) alleles from individuals of multiple ethnic backgrounds in large population cohorts (Lek et al., 2016). However, the D787G variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000642314 SCV000763983 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 10 2020-10-25 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glycine at codon 787 of the DSG2 protein (p.Asp787Gly). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant is present in population databases (rs369868954, ExAC 0.04%). This variant has not been reported in the literature in individuals with DSG2-related disease. ClinVar contains an entry for this variant (Variation ID: 199832). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Possibly Damaging; Align-GVGD: Class C0). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Color Health, Inc RCV001184497 SCV001350476 likely benign Cardiomyopathy 2019-11-14 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001193616 SCV001362565 uncertain significance not specified 2019-11-18 criteria provided, single submitter clinical testing Variant summary: DSG2 c.2360A>G (p.Asp787Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 249394 control chromosomes, predominantly at a frequency of 0.00045 within the African or African-American subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2360A>G in individuals affected with Cardiomyopathy and no experimental evidence demonstrating an impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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