rs606231294

Positions:

• chr6-7571471-C-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2 PM5 PP3 PP5_Very_Strong

The NM_004415.4(DSP):​c.1790C>T​(p.Ser597Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S597P) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DSP NM_004415.4 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.57

Genes affected

DSP (HGNC:3052): (desmoplakin) This gene encodes a protein that anchors intermediate filaments to desmosomal plaques and forms an obligate component of functional desmosomes. Mutations in this gene are the cause of several cardiomyopathies and keratodermas, including skin fragility-woolly hair syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-7571470-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 2131612.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.825
• PP5: Variant 6-7571471-C-T is Pathogenic according to our data. Variant chr6-7571471-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 157672.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSP	NM_004415.4	c.1790C>T	p.Ser597Leu	missense_variant	14/24	ENST00000379802.8
DSP	NM_001319034.2	c.1790C>T	p.Ser597Leu	missense_variant	14/24
DSP	NM_001008844.3	c.1790C>T	p.Ser597Leu	missense_variant	14/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSP	ENST00000379802.8	c.1790C>T	p.Ser597Leu	missense_variant	14/24	1	NM_004415.4	P2
DSP	ENST00000418664.2	c.1790C>T	p.Ser597Leu	missense_variant	14/24	1		A2
DSP	ENST00000710359.1	c.1790C>T	p.Ser597Leu	missense_variant	14/24			A2
DSP	ENST00000684395.1	n.174C>T		non_coding_transcript_exon_variant	2/5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Dec 02, 2011	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 11, 2017	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. -

Cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2011

- -

Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 13, 2021

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.90	D;.
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.83	D;D
MetaSVM	Uncertain	0.50	D
MutationAssessor	Uncertain	2.6	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-4.5	D;D
REVEL	Uncertain	0.63
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0060	D;T
Polyphen		1.0	D;.
Vest4		0.83
MutPred		0.33		Loss of disorder (P = 0.0182);Loss of disorder (P = 0.0182);
MVP		0.96
MPC		0.77
ClinPred		0.99	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.57
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs606231294; hg19: chr6-7571704;