ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.445G>A (p.Val149Ile) (rs372606274)

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Total submissions: 4
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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 2017-11-14 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 Danish cohort of patients with definite or possible arrhythmogenic right ventricular cardiomyopathy; however, clinical details were limited (Rasmussen TB et al. Circ Cardiovasc Genet, 2014 Jun;7:230-40). This amino acid position is highly conserved in available vertebrate species, however, isoleucine is the reference amino acid other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Another alteration affecting this amino acid (p.V149F) has also been reported in association with ARVC; however clinical details were limited and it co-occurred with another variant (Cox MG et al. Circulation. 2011 Jun;123(23):2690-700). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000460609 SCV000551005 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 10 2019-06-28 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 149 of the DSG2 protein (p.Val149Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs372606274, ExAC 0.03%). This variant has been reported in an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 24704780). ClinVar contains an entry for this variant (Variation ID: 218601). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. It has been reported in both the population and affected individuals, but the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Health, Inc RCV000777789 SCV000913773 uncertain significance Cardiomyopathy 2021-02-19 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.

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