The relationship between DSC2 and arrhythmogenic right ventricular dysplasia (autosomal dominant) and arrhythmogenic right ventricular dysplasia with mild palmoplantar keratoderma with or without woolly hair (autosomal recessive) was evaluated using the ClinGen Clinical Validity Framework as of July, 2018. Variants in DSC2 were first reported in humans with this disease as early as 2006 (Syrris et al., PMID: 17033975). At least 13 variants (e.g. missense, nonsense, frameshift) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Summary of Case Level Data: 8.5 points. Variants in this gene have been reported in at least 13 probands in 6 publications (PMIDs: 17963498, 21062920, 23863954, 17186466, 18957847, 17033975). This gene-disease relationship is supported by animal models, expression studies, and protein interactions. In summary, DSC2 is definitively associated with ARVD (AD) and ARVD with mild palmoplantar keratoderma with or without woolly hair (AR). This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Arrythmogenic Right Ventricular Cardiomyopathy Gene Curation Expert Panel on September 14, 2018 (SOP Version 6).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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