Submissions for variant NM_004415.4(DSP):c.7583A>G (p.Tyr2528Cys)

gnomAD frequency: 0.00001  dbSNP: rs746932951

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780212	SCV000917295	uncertain significance	not specified	2018-10-01	criteria provided, single submitter	clinical testing	Variant summary: DSP c.7583A>G (p.Tyr2528Cys) results in a non-conservative amino acid change located in the Plectin repeat of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 246270 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.7583A>G in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170146	SCV001332693	uncertain significance	Cardiomyopathy	2018-03-22	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002535669	SCV003523857	likely benign	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2024-11-21	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004001513	SCV004837743	uncertain significance	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma	2023-11-02	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with cysteine at codon 2528 of the DSP protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with DSP-related disorders in the literature. This variant has been identified in 3/251494 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	RCV004027315	SCV005022499	uncertain significance	Cardiovascular phenotype	2024-02-04	criteria provided, single submitter	clinical testing	The p.Y2528C variant (also known as c.7583A>G), located in coding exon 24 of the DSP gene, results from an A to G substitution at nucleotide position 7583. The tyrosine at codon 2528 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear.