Submissions for variant NM_004415.4(DSP):c.3550C>T (p.Arg1184Trp)

gnomAD frequency: 0.00001  dbSNP: rs761331634

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769228	SCV000900604	uncertain significance	Cardiomyopathy	2017-08-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000769228	SCV002052644	uncertain significance	Cardiomyopathy	2023-05-31	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 1184 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 been reported in two related individuals affected with palmoplantar keratoderma and in an individual affected with atrial fibrillation (PMID: 30276209). This variant has also been identified in 5/250030 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.
Invitae	RCV001869065	SCV002187886	likely benign	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2023-11-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002271582	SCV002556110	uncertain significance	not specified	2022-06-23	criteria provided, single submitter	clinical testing	Variant summary: DSP c.3550C>T (p.Arg1184Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 250030 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3550C>T has been reported in the literature in individuals affected with palmoplantar keratoderma and Paroxysmal (Atrial fibrillation) (examples: Xue_2018 and Donate Puertas_2018). Xue_2018 demonstrated that the individuals carrying this variant have reduced mRNA for DSP. These reports do not provide unequivocal conclusions about association of the variant with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics	RCV002493401	SCV002783016	uncertain significance	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8; Lethal acantholytic epidermolysis bullosa; Woolly hair-skin fragility syndrome; Keratosis palmoplantaris striata 2; Cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis	2021-11-16	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003279049	SCV004007835	uncertain significance	Cardiovascular phenotype	2023-05-22	criteria provided, single submitter	clinical testing	The p.R1184W variant (also known as c.3550C>T), located in coding exon 23 of the DSP gene, results from a C to T substitution at nucleotide position 3550. The arginine at codon 1184 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported in two siblings with palmoplantar keratoderma (Xue K et al. J Cosmet Dermatol, 2019 Feb;18:371-376). This alteration was also noted in an atrial fibrillation cohort (Do&ntilde;ate Puertas R et al. Biomed Res Int, 2018 Sep;2018:4862480). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.