ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.1195G>A (p.Glu399Lys)

gnomAD frequency: 0.00002  dbSNP: rs774863785
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181216 SCV000233495 uncertain significance not provided 2020-11-12 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function
Labcorp Genetics (formerly Invitae), Labcorp RCV001341325 SCV001535193 uncertain significance Arrhythmogenic right ventricular dysplasia 10 2023-12-31 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 399 of the DSG2 protein (p.Glu399Lys). This variant is present in population databases (rs774863785, gnomAD 0.007%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 32826072). ClinVar contains an entry for this variant (Variation ID: 199807). 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.
Ambry Genetics RCV002336441 SCV002643193 uncertain significance Cardiovascular phenotype 2024-04-12 criteria provided, single submitter clinical testing The p.E399K variant (also known as c.1195G>A), located in coding exon 9 of the DSG2 gene, results from a G to A substitution at nucleotide position 1195. The glutamic acid at codon 399 is replaced by lysine, an amino acid with similar properties. This alteration has been reported in a dilated cardiomyopathy (DCM) cohort (Peña-Peña ML et al. Med Clin (Barc), 2021 May;156:485-495). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
Color Diagnostics, LLC DBA Color Health RCV003532016 SCV004363183 uncertain significance Cardiomyopathy 2023-02-08 criteria provided, single submitter clinical testing This missense variant replaces glutamic acid with lysine at codon 399 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 been reported in an individual affected with dilated cardiomyopathy and also in an unaffected relative in the family (PMID: 32826072). This variant has been identified in 6/249404 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.
All of Us Research Program, National Institutes of Health RCV003996615 SCV004819520 uncertain significance Arrhythmogenic right ventricular cardiomyopathy 2024-07-29 criteria provided, single submitter clinical testing This missense variant replaces glutamic acid with lysine at codon 399 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 been reported in an individual affected with dilated cardiomyopathy and also in an unaffected relative in the family (PMID: 32826072). This variant has been identified in 6/249404 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.
Breakthrough Genomics, Breakthrough Genomics RCV000181216 SCV005193294 uncertain significance not provided criteria provided, single submitter not provided

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