ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.2648C>T (p.Ser883Phe) (rs371498622)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000150544 SCV000197770 uncertain significance not specified 2013-09-19 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The Ser883Phe varia nt in DSG2 has not been reported in individuals with cardiomyopathy but has been identified in 1/8208 European American chromosomes by the NHLBI Exome Sequencin g Project (http://evs.gs.washington.edu/EVS/). Serine (Ser) at position 883 is n ot conserved and a change to phenylalanine is seen in at least two mammals (dog, tarsier), suggesting that a change at this position may be tolerated. Addition al, computational analyses (biochemical amino acid properties, AlignGVGD, PolyPh en2, and SIFT) suggest that the this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. Additional information is needed to fully assess the clinical significance of the Ser883Phe variant.
Invitae RCV000823465 SCV000964325 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 10 2019-07-10 criteria provided, single submitter clinical testing This sequence change replaces serine with phenylalanine at codon 883 of the DSG2 protein (p.Ser883Phe). The serine residue is moderately conserved and there is a large physicochemical difference between serine and phenylalanine. This variant is present in population databases (rs371498622, ExAC 0.003%). This variant has not been reported in the literature in individuals with DSG2-related disease. ClinVar contains an entry for this variant (Variation ID: 163220). 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 phenylalanine amino acid residue is 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 and their clinical significance is uncertain. 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 Health, Inc RCV001526077 SCV001736353 uncertain significance Cardiomyopathy 2020-05-12 criteria provided, single submitter clinical testing This missense variant replaces serine with phenylalanine at codon 883 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 in an individual affected with definite or probable arrhythmogenic right ventricular cardiomyopathy (PMID: 20857253). This variant has also been identified in 4/248746 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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