ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.445G>A (p.Val149Ile)

gnomAD frequency: 0.00001  dbSNP: rs372606274
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia RCV000202938 SCV000257910 uncertain significance Arrhythmogenic right ventricular cardiomyopathy 2015-05-14 criteria provided, single submitter clinical testing
Ambry Genetics RCV000250711 SCV000319981 uncertain significance Cardiovascular phenotype 2024-11-12 criteria provided, single submitter clinical testing The p.V149I variant (also known as c.445G>A), located in coding exon 5 of the DSG2 gene, results from a G to A substitution at nucleotide position 445. The valine at codon 149 is replaced by isoleucine, an amino acid with highly similar properties. This alteration was detected in a family (who also had variants in other cardiac-related genes) from a cohort with definite or possible arrhythmogenic right ventricular cardiomyopathy (ARVC), and also co-occurred with a variant in the DSC2 gene in an individual from a dilated cardiomyopathy cohort; however, clinical details were limited (Rasmussen TB et al. Circ Cardiovasc Genet, 2014 Jun;7:230-40; Verdonschot JAJ et al. Circ Genom Precis Med. 2020 10;13(5):476-487). This variant has also been detected in an individual reported to have ARVC, and was also present in two unaffected relatives (Huang R et al. Int Med Case Rep J. 2021 May;14:307-313). This amino acid position is highly 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV000460609 SCV000551005 uncertain significance Arrhythmogenic right ventricular dysplasia 10 2022-10-31 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 149 of the DSG2 protein (p.Val149Ile). This variant is present in population databases (rs372606274, gnomAD 0.03%). This missense change has been observed in individual(s) with clinical features of DSG2-related conditions (PMID: 24704780, 32880476, 34012299). ClinVar contains an entry for this variant (Variation ID: 218601). 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. 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 RCV000777789 SCV000913773 uncertain significance Cardiomyopathy 2022-03-01 criteria provided, single submitter clinical testing This missense variant replaces valine with isoleucine at codon 149 of the DSG2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 24704780). This variant has been identified in 8/280720 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 RCV000202938 SCV004819442 uncertain significance Arrhythmogenic right ventricular cardiomyopathy 2024-05-14 criteria provided, single submitter clinical testing This missense variant replaces valine with isoleucine at codon 149 of the DSG2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 24704780, 34012299) and in one individual affected with dilated cardiomyopathy (PMID: 32880476). This variant has been identified in 8/280720 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.
Clinical Genetics, Academic Medical Center RCV001699232 SCV001917308 uncertain significance not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV001699232 SCV001932012 uncertain significance not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV001699232 SCV001951989 uncertain significance not provided no assertion criteria provided clinical testing

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