Submissions for variant NM_004415.4(DSP):c.2858T>C (p.Leu953Pro)

gnomAD frequency: 0.00001  dbSNP: rs745641212

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000418326	SCV000535275	uncertain significance	not provided	2021-10-29	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 392069; Landrum et al., 2016)
Color Diagnostics, LLC DBA Color Health	RCV001191136	SCV001358839	uncertain significance	Cardiomyopathy	2023-02-09	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with proline at codon 953 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 3/249016 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	RCV002436353	SCV002749922	uncertain significance	Cardiovascular phenotype	2021-09-21	criteria provided, single submitter	clinical testing	The p.L953P variant (also known as c.2858T>C), located in coding exon 20 of the DSP gene, results from a T to C substitution at nucleotide position 2858. The leucine at codon 953 is replaced by proline, an amino acid with similar 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.
Fulgent Genetics, Fulgent Genetics	RCV002488974	SCV002800143	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	2021-09-10	criteria provided, single submitter	clinical testing
Invitae	RCV002522666	SCV002984991	likely benign	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2024-01-29	criteria provided, single submitter	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV003483614	SCV004228824	not provided	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy; Cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 12-22-2020 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.