rs397516955

Positions:

• chr6-7562753-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_004415.4(DSP):​c.699G>A​(p.Trp233Ter) variant causes a stop gained change. 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 (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DSP NM_004415.4 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 4.83

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-7562753-G-A is Pathogenic according to our data. Variant chr6-7562753-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 44946.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-7562753-G-A is described in Lovd as [Pathogenic]. Variant chr6-7562753-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSP	NM_004415.4	c.699G>A	p.Trp233Ter	stop_gained	5/24	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.699G>A	p.Trp233Ter	stop_gained	5/24		NP_001305963.1
DSP	NM_001008844.3	c.699G>A	p.Trp233Ter	stop_gained	5/24		NP_001008844.1
DSP	NM_001406591.1	c.699G>A	p.Trp233Ter	stop_gained	5/11		NP_001393520.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.699G>A	p.Trp233Ter	stop_gained	5/24	1	NM_004415.4	ENSP00000369129	P2
DSP	ENST00000418664.2	c.699G>A	p.Trp233Ter	stop_gained	5/24	1		ENSP00000396591	A2
DSP	ENST00000710359.1	c.699G>A	p.Trp233Ter	stop_gained	5/24			ENSP00000518230	A2
DSP	ENST00000506617.1	n.217G>A		non_coding_transcript_exon_variant	2/4	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 09, 2024

This sequence change creates a premature translational stop signal (p.Trp233*) in the DSP gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DSP are known to be pathogenic (PMID: 20716751, 24503780, 25227139). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with autosomal dominant arrhythmogenic right ventricular cardiomyopathy (PMID: 16917092, 24503780; Invitae). ClinVar contains an entry for this variant (Variation ID: 44946). For these reasons, this variant has been classified as Pathogenic. -

Arrhythmogenic right ventricular cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 15, 2019

proposed classification - variant undergoing re-assessment, contact laboratory -

Cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Nov 28, 2017

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 16, 2022

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published functional studies indicate this variant results in nonsense-mediated decay (Yang et al., 2006); Not observed in large population cohorts (gnomAD); Reported in ClinVar as pathogenic or likely pathogenic (ClinVar Variant ID# 44946; ClinVar); This variant is associated with the following publications: (PMID: 16917092, 27532257, 17363426, 20738328, 31402444, Atak2021[Computational], 34076677, 32372669, 34352074, 33684294, 28471438, 35325485, 36142674, 24503780) -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 13, 2022

The p.W233* pathogenic mutation (also known as c.699G>A), located in coding exon 5 of the DSP gene, results from a G to A substitution at nucleotide position 699. This changes the amino acid from a tryptophan to a stop codon within coding exon 5. This alteration has been reported in dilated cardiomyopathy (DCM) and arrhythmogenic right ventricular cardiomyopathy (ARVC) cohorts (Yang Z et al. Circ Res, 2006 Sep;99:646-55; Haggerty CM et al. Genet Med, 2017 11;19:1245-1252; Walsh R et al. Genet Med, 2017 02;19:192-203). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Alterations in DSP that result in haploinsufficiency or protein truncation have been reported in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) and dilated cardiomyopathy (DCM) (Fressart V et al. Europace. 2010;12(6):861-8; Elliott P et al. Circ Cardiovasc Genet. 2010;3(4):314-22; Quarta G et al. Circulation. 2011;123(23):2701-9; Garcia-Pavia P et al. Heart. 2011;97(21):1744-52; Rasmussen TB et al. Clin Genet. 2013;84(1):20-30; Pugh TJ et al. Genet Med. 2014;16(8):601-8). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Cardiac arrhythmia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Feb 21, 2020

Variant summary: DSP c.699G>A (p.Trp233X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. In addition, in vitro studies of the affected patients blood cells support that this nonsense substitution results in haploinsufficiency, probably due to increased decay of nonsense mRNA (Yang_2006). Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251830 control chromosomes (gnomAD). c.699G>A has been reported in individuals affected with arrhythmogenic right ventricular cardiomyopathy (Yang_2006, ClinVar submitter) as well as one individual affected with dilated cardiomyopathy who was Caucasian adult and segregated with disease in at least on relative (Pugh_2014, ClinVar database SCV000061748.4). At least one in vitro study showed that this mutant results in DSP protein formed perinuclear aggregates and was neither localized at the cell membrane nor seen diffusively in the cytoplasm (Yang_2006). Five ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (3x) and likely pathogenic (2x). Based on the evidence outlined above, the variant was classified as pathogenic. -

Woolly hair-skin fragility syndrome;C1843896:Arrhythmogenic right ventricular dysplasia 8;C1852127:Keratosis palmoplantaris striata 2;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma;C1864826:Lethal acantholytic epidermolysis bullosa;C4014393:Cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.97	D
MutationTaster	Benign	1.0	A;A
Vest4		0.93
GERP RS		5.8

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: rs397516955; hg19: chr6-7562986;