rs727505271

chr6-7579713-AG-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.3526del(p.Val1176PhefsTer20) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. 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 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 5.33

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 6-7579713-AG-A is Pathogenic according to our data. Variant chr6-7579713-AG-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 179994.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.3526del	p.Val1176PhefsTer20	frameshift_variant	23/24	ENST00000379802.8
DSP	NM_001319034.2	c.3526del	p.Val1176PhefsTer20	frameshift_variant	23/24
DSP	NM_001008844.3	c.3526del	p.Val1176PhefsTer43	frameshift_variant	23/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSP	ENST00000379802.8	c.3526del	p.Val1176PhefsTer20	frameshift_variant	23/24	1	NM_004415.4	P2
DSP	ENST00000418664.2	c.3526del	p.Val1176PhefsTer43	frameshift_variant	23/24	1		A2
DSP	ENST00000710359.1	c.3526del	p.Val1176PhefsTer20	frameshift_variant	23/24			A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

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

Invitae

Apr 06, 2020

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in DSP are known to be pathogenic (PMID: 20716751, 24503780, 25227139). This variant has not been reported in the literature in individuals with DSP-related conditions. ClinVar contains an entry for this variant (Variation ID: 179994). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Val1176Phefs*20) in the DSP gene. It is expected to result in an absent or disrupted protein product. -

Arrhythmogenic right ventricular cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 15, 2017

The p.Val1176fs variant in DSP has been identified by our laboratory in 1 Caucas ian individual with ARVC and recurrent myocarditis and 1 individual with a compl ex presentation (biventricular cardiomyopathy, VT, Brugada/ARVC pattern EKG) who carried a second variant (of uncertain significance) in the SCN5A gene. Both va riants were present in a sib with reduced ejection fraction but also in the unaf fected mother. The p.Val1176fs variant was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein?s ami no acid sequence beginning at position 1176 and leads to a premature termination codon 20 amino acids downstream. This alteration is predicted to lead to a trun cated or absent protein. Heterozygous loss of function of the DSP gene is an est ablished disease mechanism in individuals with ARVC and/or DCM. In summary, alth ough additional studies are required to fully establish its clinical significanc e, the p.Val1176fs variant is likely pathogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 05, 2018

The c.3526delG pathogenic mutation, located in coding exon 23 of the DSP gene, results from a deletion of one nucleotide at nucleotide position 3526, causing a translational frameshift with a predicted alternate stop codon (p.V1176Ffs*20). 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. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

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: rs727505271; hg19: chr6-7579946;