Submissions for variant NM_004415.4(DSP):c.1790C>T (p.Ser597Leu)

dbSNP: rs606231294

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181378	SCV000233679	likely pathogenic	not provided	2017-04-11	criteria provided, single submitter	clinical testing	The Ser597Leu substitution in the DSP gene has been reported in one family with autosomal dominant arrhythmogenic cardiomyopathy, palmoplantar keratoderma, woolly hair and oligodontia (Chalabreysse L et al., 2011). In this family, the heterozygous Ser597Leu variant co-segregated with this set of features in the proband, his affected sibling and affected father, and this variant was absent from 100 control alleles as well as the unaffected relatives tested in the reported family (Chalabreysse L et al., 2011). The Ser597Leu substitution was determined to be de novo in the proband's affected father (Chalabreysse L et al., 2011). Ser597Leu results in a non-conservative amino acid substitution of a neutral, polar Serine with a non-polar Leucine at a residue that is conserved across species. Therefore, we interpret p.S597L in DSP as a likely pathogenic variant.
Invitae	RCV001378477	SCV001576049	likely pathogenic	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2021-02-13	criteria provided, single submitter	clinical testing	Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant has been observed in individual(s) with clinical features of dilated cardiomyopathy, woolly hair, palmoplantar hyperkeratosis with, or without, oligodontia (PMID: 20940358, Invitae, external communication). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 157672). This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with leucine at codon 597 of the DSP protein (p.Ser597Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine.
OMIM	RCV000144960	SCV000191987	pathogenic	Cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis	2011-01-01	no assertion criteria provided	literature only
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000181378	SCV000280086	likely pathogenic	not provided	2011-12-02	no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. We classify this variant as likely disease-causing. This variant has been reported in one family with cardiomyopathy, palmoplantar keratoderma, woolly hair and oligodontia (Chalabreysse L et al 2011). This phenotype fits into the Carvajal/Naxos spectrum. The variant was present in the proband and his affected father (an affected brother declined genotyping). It was absent in two unaffected siblings and also in the paternal grandparents, indicating it was de novo in the father. While most previous reports of Carvajal have been due to biallelic variants in DSP, at least one other autosomal dominant case has been reported. In that family a father and daughter were affected and the daughter was found to have a 30 base pair insertion in DSP. (Norgett et al 2006). This is a non-conservative amino acid change with a polar Serine replaced with a non polar Leucine. Serine is conserved at this position across species. This variant is not listed in dbSNP (http://www.ncbi.nlm.nih.gov/projects/SNP/), 1000 Genomes (http://browser.1000genomes.org/index.html) or the NHLBI Exome Variant Server (http://evs.gs.washington.edu/EVS/), as of October 2011. Chalabreysse et al (2011) did not identify p.Ser597Leu in 100 presumably healthy control samples of unspecified ancestry. It was also not observed by Kapplinger et al (2011) in 427 presumably healthy individuals.