ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.991G>A (p.Glu331Lys) (rs121913012)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Advanced Laboratory Medicine, UC San Diego Health,University of California San Diego RCV000852473 SCV000995167 uncertain significance Cardiomyopathy 2017-09-08 criteria provided, single submitter clinical testing
Color Health, Inc RCV000852473 SCV001342495 uncertain significance Cardiomyopathy 2020-02-25 criteria provided, single submitter clinical testing
Invitae RCV000018309 SCV001404871 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 10 2020-06-07 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 331 of the DSG2 protein (p.Glu331Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs121913012, ExAC 0.01%). This variant has been observed in individuals with clinical features of arrhythmogenic right ventricular cardiomyopathy (PMID: 16505173, 28471438, 24070718). ClinVar contains an entry for this variant (Variation ID: 16816). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Tolerated; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). 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.
OMIM RCV000018309 SCV000038588 pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 10 2006-03-07 no assertion criteria provided literature only
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000029673 SCV000052325 uncertain significance Arrhythmogenic right ventricular cardiomyopathy 2015-10-02 no assertion criteria provided clinical testing The c.991G>A (p.Glu331Lys) missense variant changes evolutionary conserved Glu to Lys, which changes the charge from negative to positive. 3/4 in silico tools predict this variant to be damaging. This variant lies in cadherin 3 domain (source ARVC db) and other missense changes have also been detected in and around this codon such as p.D326V, p.N330D, p.I333T and p.T335A (source: HGMD) in ARVC patients. This suggests that this variant may alter protein functionality. The variant is found in only 3 alleles across 120630 chromosomes in ExAC. Although the allele frequency in general population is lower than the maximal expected allele frequency based on the disease prevalence of ARVC, the possibility of this variant being a rare polymorphism cannot be ruled out. Two studies reported this variant in two ARVD families; however, segregation analysis in one family does not prove the variant as a high penetrance disease-causing variant.

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