ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.2328C>A (p.Phe776Leu) (rs771104668)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000460621 SCV000551022 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 10 2016-07-02 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with leucine at codon 776 of the DSG2 protein (p.Phe776Leu). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and leucine. This variant is present in population databases (rs771104668, ExAC <0.01%) but has not been reported in the literature in individuals with a DSG2-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). The leucine amino acid residue is also found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Center for Advanced Laboratory Medicine, UC San Diego Health,University of California San Diego RCV000852475 SCV000995169 uncertain significance Primary dilated cardiomyopathy 2018-04-06 criteria provided, single submitter clinical testing
Color Health, Inc RCV001180045 SCV001344894 uncertain significance Cardiomyopathy 2021-02-19 criteria provided, single submitter clinical testing This missense variant replaces phenylalanine with leucine at codon 776 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 12/224368 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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