ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.160G>A (p.Ala54Thr)

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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 RCV001195230 SCV001365537 uncertain significance not specified 2019-03-15 criteria provided, single submitter clinical testing The p.Ala54Thr variant in DSG2 has not been previously reported in individuals with ARVC but has been identified in 0.003% (1/30602) of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Ala54Thr variant is uncertain. ACMG/AMP Criteria applied: PM2, BP4.
Invitae RCV001215860 SCV001387627 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 10 2019-10-30 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 54 of the DSG2 protein (p.Ala54Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs549421694, ExAC 0.006%). This variant has not been reported in the literature in individuals with DSG2-related conditions. 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: Possibly 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.
Color Health, Inc RCV001525624 SCV001735795 uncertain significance Cardiomyopathy 2021-01-05 criteria provided, single submitter clinical testing This missense variant replaces alanine with threonine at codon 54 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 cardiovascular disorder, who also carried a pathogenic variant in the KCNQ1 gene that could explain the observed phenotype (Brockman et al. 2020, DOI: 10.1101/2020.09.03.20181073). This variant has been identified in 1/249490 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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