ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.122A>T (p.His41Leu)

gnomAD frequency: 0.00003  dbSNP: rs777373864
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000816462 SCV000956972 uncertain significance Arrhythmogenic right ventricular dysplasia 10 2023-10-28 criteria provided, single submitter clinical testing This sequence change replaces histidine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 41 of the DSG2 protein (p.His41Leu). This variant is present in population databases (rs777373864, gnomAD 0.002%). This missense change has been observed in individual(s) with clinical features of arrhythmogenic cardiomyopathy (Invitae). ClinVar contains an entry for this variant (Variation ID: 659450). 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.
Illumina Laboratory Services, Illumina RCV000816462 SCV001284488 uncertain significance Arrhythmogenic right ventricular dysplasia 10 2018-01-15 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Color Diagnostics, LLC DBA Color Health RCV001182541 SCV001348014 uncertain significance Cardiomyopathy 2022-12-14 criteria provided, single submitter clinical testing This missense variant replaces histidine with leucine at codon 41 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 cardiovascular disorders in the literature. This variant has been identified in 3/280906 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 RCV002363134 SCV002665057 uncertain significance Cardiovascular phenotype 2022-10-17 criteria provided, single submitter clinical testing The p.H41L variant (also known as c.122A>T), located in coding exon 3 of the DSG2 gene, results from an A to T substitution at nucleotide position 122. The histidine at codon 41 is replaced by leucine, an amino acid with similar properties. Another alteration affecting the same amino acid, p.H41N (c.121C>A), has been reported in association with hypertrophic cardiomyopathy (HCM) (Lopes LR et al. Heart, 2015 Feb;101:294-301). 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.
Fulgent Genetics, Fulgent Genetics RCV002501123 SCV002783228 uncertain significance Arrhythmogenic right ventricular dysplasia 10; Dilated cardiomyopathy 1BB 2021-09-09 criteria provided, single submitter clinical testing

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