Submissions for variant NM_004415.4(DSP):c.6610C>T (p.Gln2204Ter)

dbSNP: rs876657798

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000214350	SCV000271741	uncertain significance	not specified	2015-07-02	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The p.Gln2204X variant in DSP has not been previously reported in individuals with cardiomyopat hy and was absent from large population studies. This nonsense variant leads to a premature termination codon within the last exon. Nonsense variants are well r eported patients with ARVC (http://arvcdatabase.info/) and this type of variant is generally expected to lead to nonsense medicated mRNA decay (NMD), resulting in loss of function. However, this is less likely in the last exon and therefore the effect of this variant on the protein is not clear. Some evidence for a rol e in ARVC comes from reports of homozygous truncating variants in the last exon in individuals with Carvajal syndrome and/or acantholytic epidermolysis bullosa (Cheong 2005, Jonkman 2005, Rasmussen 2013), though it is less clear if heterozy gous carriers exhibit any features. In summary, while there is some suspicion f or a pathogenic role, the clinical significance of the p.Gln2204X variant is unc ertain.
PreventionGenetics, part of Exact Sciences	RCV004751379	SCV005342975	pathogenic	DSP-related disorder	2024-03-25	no assertion criteria provided	clinical testing	The DSP c.6610C>T variant is predicted to result in premature protein termination (p.Gln2204*). This variant was reported in the compound heterozygous state in a pair of monozygotic twins with lethal acantholytic epidermolysis bullosa, while the heterozygous carriers in this family were reported asymptomatic (Kim et al. 2017. PubMed ID: 28442525). This variant has not been reported in a large population database, indicating this variant is rare. This variant is located in the large terminal exon and multiple downstream loss-of-function variants have been documented in individuals with autosomal dominant DSP-associated cardiomyopathy or arrhythmogenic right ventricular dysplasia (Fressart et al. 2010. PubMed ID: 20400443; Tables S1 and S2, Smith et al. 2020. PubMed ID: 32372669; Table S1, Wang et al. 2022. PubMed ID: 34352074). In summary, this variant is interpreted as pathogenic for autosomal dominant and recessive DSP-associated disorders.