ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.2681T>G (p.Leu894Trp)

gnomAD frequency: 0.00001  dbSNP: rs759746836
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Diagnostics, LLC DBA Color Health RCV001177201 SCV001341375 uncertain significance Cardiomyopathy 2023-02-21 criteria provided, single submitter clinical testing This missense variant replaces leucine with tryptophan at codon 894 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 individual(s) with arrhythmogenic right ventricular cardiomyopathy (PMID: 29178656, 32877757, doi:10.24509/jpccs.20-004). This variant has been identified in 3/248914 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV002558844 SCV003516620 uncertain significance Arrhythmogenic right ventricular dysplasia 10 2022-03-05 criteria provided, single submitter clinical testing This missense change has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (PMID: 29178656). 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. 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: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 919189). This variant is present in population databases (rs759746836, gnomAD 0.02%). This sequence change replaces leucine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 894 of the DSG2 protein (p.Leu894Trp).
Ambry Genetics RCV003293927 SCV003997607 uncertain significance Cardiovascular phenotype 2023-03-18 criteria provided, single submitter clinical testing The p.L894W variant (also known as c.2681T>G), located in coding exon 15 of the DSG2 gene, results from a T to G substitution at nucleotide position 2681. The leucine at codon 894 is replaced by tryptophan, an amino acid with similar properties. This alteration has been reported in an arrhythmogenic right ventricular cardiomyopathy (ARVC) cohort; however, clinical details were limited (Wada Y et al. Mol Genet Genomic Med, 2017 Nov;5:639-651). This alteration was observed in a Japanese population cohort of 2049 individuals who underwent whole-genome sequencing (Yamaguchi-Kabata Y et al. J Hum Genet, 2018 Feb;63:213-230). 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.

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