Submissions for variant NM_004415.4(DSP):c.2468C>T (p.Ser823Leu)

gnomAD frequency: 0.00015  dbSNP: rs141834182

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181300	SCV000233591	uncertain significance	not provided	2014-11-10	criteria provided, single submitter	clinical testing	p.Ser823Leu (TCG>TTG): c.2468 C>T in exon 18 of the DSP gene (NM_004415.2). The Ser823Leu variant in the DSP gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Ser823Leu results in a non-conservative amino acid substitution of a neutral, polar Serine with a non-polar Leucine at a position that is class conserved in mammals. In silico algorithms are not consistent in their predictions but at least two concur that Ser823Leu is possibly damaging to the protein structure/function. The Ser823Leu variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. Nevertheless, no mutations in nearby residues have been reported in association with ARVC. With the clinical and molecular information available at this time, we cannot definitively determine if Ser823Leu is a disease-causing mutation or a rare benign variant. The variant is found in ARVC, ARRHYTHMIA panel(s).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001048380	SCV001212381	benign	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2024-12-18	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001179618	SCV001344326	likely benign	Cardiomyopathy	2022-11-16	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002444728	SCV002733895	likely benign	Cardiovascular phenotype	2022-01-03	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Fulgent Genetics, Fulgent Genetics	RCV002485189	SCV002792588	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	2021-09-03	criteria provided, single submitter	clinical testing
New York Genome Center	RCV003227697	SCV003925209	uncertain significance	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8; Cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis	2022-07-01	criteria provided, single submitter	clinical testing	The c.2468C>T p.(Ser823Leu) variant identified in the DSP gene substitutes a conserved Serine for Leucine at amino acid 823/2872(exon 18/24). This variant is found with low frequency in population databases gnomADv3.1.2, gnomADv2.1.1, TOPMed Freeze 8, All of Us (allele frequency: 2.08e-4) suggesting it is not a common benign variant in the populations represented in those databases. This variant is reported as a Variant of Uncertain Significance in ClinVar (VarID:199869), and has been reported in two individuals in the literature with either dilated or hypertrophic cardiomyopathy [Supp File 2; PMID:30847666], though with uncertain clinical significance. Given the lack of compelling evidence for its pathogenicity, the c.2468C>T p.(Ser823Leu) variant identified in the DSP gene is reported as a Variant of Uncertain Significance.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV002444728	SCV005882761	uncertain significance	Cardiovascular phenotype	2025-02-17	criteria provided, single submitter	clinical testing