ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.1274A>C (p.His425Pro)

dbSNP: rs746180213
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001754273 SCV001987318 uncertain significance not provided 2019-04-25 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function
Labcorp Genetics (formerly Invitae), Labcorp RCV002543930 SCV002992401 uncertain significance Arrhythmogenic right ventricular dysplasia 10 2022-02-06 criteria provided, single submitter clinical testing ClinVar contains an entry for this variant (Variation ID: 1302384). 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with DSG2-related conditions. This variant is present in population databases (rs746180213, gnomAD 0.0009%). This sequence change replaces histidine, which is basic and polar, with proline, which is neutral and non-polar, at codon 425 of the DSG2 protein (p.His425Pro).
All of Us Research Program, National Institutes of Health RCV004008979 SCV004840690 uncertain significance Arrhythmogenic right ventricular cardiomyopathy 2023-12-18 criteria provided, single submitter clinical testing This missense variant replaces histidine with proline at codon 425 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 DSG2-related disorders in the literature. This variant has been identified in 1/249154 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.
Ambry Genetics RCV004995982 SCV005575798 uncertain significance Cardiovascular phenotype 2024-07-05 criteria provided, single submitter clinical testing The c.1274A>C (p.H425P) alteration is located in exon 9 (coding exon 9) of the DSG2 gene. This alteration results from a A to C substitution at nucleotide position 1274, causing the histidine (H) at amino acid position 425 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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