ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.1790C>T (p.Ser597Leu) (rs606231294)

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Total submissions: 3
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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.
OMIM RCV000144960 SCV000191987 pathogenic Cardiomyopathy, dilated, with woolly 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.

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