ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.430G>A (p.Glu144Lys) (rs199842209)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000171897 SCV000050910 uncertain significance not provided 2013-06-24 criteria provided, single submitter research
GeneDx RCV000171897 SCV000233482 uncertain significance not provided 2016-06-01 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the DSG2 gene. While the E144K variant has not been published as a pathogenic or benign variant, it has been reported in one patient in the ClinSeq study and classified as a variant of uncertain significance (Ng et al., 2013). The E144K variant was not observed with any significant frequency in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The E144K 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. However, this substitution occurs at a position where amino acids with similar properties to Glutamic acid are tolerated across species. Finally, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Ambry Genetics RCV000620333 SCV000736921 uncertain significance Cardiovascular phenotype 2019-09-26 criteria provided, single submitter clinical testing The p.E144K variant (also known as c.430G>A), located in coding exon 5 of the DSG2 gene, results from a G to A substitution at nucleotide position 430. The glutamic acid at codon 144 is replaced by lysine, an amino acid with some similar properties. This alteration has been reported as a secondary cardiac variant in an exome cohort (Ng D et al. Circ Cardiovasc Genet. 2013;6(4):337-46). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Health, Inc RCV000778025 SCV000914136 uncertain significance Cardiomyopathy 2020-10-20 criteria provided, single submitter clinical testing This missense variant replaces glutamic acid with lysine at codon 144 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 exome sequencing participant not selected for arrhythmia, cardiomyopathy, or a family history of sudden death (PMID: 23861362). This variant has been identified in 26/280688 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.
Invitae RCV000810288 SCV000950481 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 10 2018-09-17 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 144 of the DSG2 protein (p.Glu144Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs199842209, ExAC 0.01%). This variant has not been reported in the literature in individuals with DSG2-related disease. ClinVar contains an entry for this variant (Variation ID: 191626). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.

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