Submissions for variant NM_004415.4(DSP):c.4754C>T (p.Ser1585Leu)

gnomAD frequency: 0.00001  dbSNP: rs773622004

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	RCV000589614	SCV000698436	uncertain significance	not provided	2017-02-20	criteria provided, single submitter	clinical testing	Variant summary: The DSP c.4754C>T (p.Ser1585Leu) variant involves the alteration of a non-conserved nucleotide and is predicted to be benign by 4/5 in silico tools. This variant is located outside of some of known domains/repeats (InterPro, UniProt). This variant was found in 1/119252 control chromosomes from ExAC at a frequency of 0.0000084, which does not exceed the estimated maximal expected allele frequency of a pathogenic DSP variant (0.00001). The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories, nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000641775	SCV000763423	uncertain significance	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2024-07-31	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 1585 of the DSP protein (p.Ser1585Leu). This variant is present in population databases (rs773622004, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with DSP-related conditions. ClinVar contains an entry for this variant (Variation ID: 496244). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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.
Color Diagnostics, LLC DBA Color Health	RCV001189482	SCV001356788	uncertain significance	Cardiomyopathy	2023-03-31	criteria provided, single submitter	clinical testing	This missense variant replaces serine with leucine at codon 1585 of the DSP 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 DSP-related disorders in the literature. This variant has been identified in 1/250344 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	RCV002341501	SCV002640359	uncertain significance	Cardiovascular phenotype	2022-08-08	criteria provided, single submitter	clinical testing	The p.S1585L variant (also known as c.4754C>T), located in coding exon 23 of the DSP gene, results from a C to T substitution at nucleotide position 4754. The serine at codon 1585 is replaced by leucine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health	RCV004002434	SCV004833156	uncertain significance	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma	2024-05-17	criteria provided, single submitter	clinical testing	This missense variant replaces serine with leucine at codon 1585 of the DSP 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 DSP-related disorders in the literature. This variant has been identified in 1/250344 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.