ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.2305G>A (p.Glu769Lys)

gnomAD frequency: 0.00015  dbSNP: rs371146201
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000150543 SCV000197766 uncertain significance not specified 2013-09-13 criteria provided, single submitter clinical testing The Glu769Lys variant in DSG2 has not been reported in individuals with cardiomy opathy but has been identified in 3/3994 African American chromosomes by the NHL BI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs37114620 1). Computational analyses (biochemical amino acid properties, conservation, Ali gnGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an imp act to the protein. Additional information is needed to fully assess the clinica l significance of the Glu769Lys variant.
Department Of Translational Genomics (developmental Genetics Section), King Faisal Specialist Hospital & Research Centre RCV000171269 SCV000221466 likely pathogenic not provided criteria provided, single submitter research
Invitae RCV000705050 SCV000834030 uncertain significance Arrhythmogenic right ventricular dysplasia 10 2023-12-19 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 769 of the DSG2 protein (p.Glu769Lys). This variant is present in population databases (rs371146201, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with DSG2-related conditions. ClinVar contains an entry for this variant (Variation ID: 163217). 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) performed at Invitae indicates that this missense variant is not expected to disrupt DSG2 protein function with a negative predictive value of 95%. 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 Diagnostics, LLC DBA Color Health RCV001181125 SCV001346211 uncertain significance Cardiomyopathy 2023-01-27 criteria provided, single submitter clinical testing This missense variant replaces glutamic acid with lysine at codon 769 of the DSG2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with DSG2-related disorders in the literature. This variant has been identified in 13/245478 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.
Ambry Genetics RCV002444613 SCV002735544 likely benign Cardiovascular phenotype 2022-12-09 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Fulgent Genetics, Fulgent Genetics RCV002478422 SCV002791990 uncertain significance Arrhythmogenic right ventricular dysplasia 10; Dilated cardiomyopathy 1BB 2021-10-19 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV000171269 SCV003829131 uncertain significance not provided 2022-06-29 criteria provided, single submitter clinical testing
GeneDx RCV000171269 SCV004021606 uncertain significance not provided 2023-07-12 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge

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