rs1554106742

Positions:

• chr6-7567801-TA-T

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.1162del​(p.Thr388LeufsTer5) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DSP NM_004415.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 5.25

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 6-7567801-TA-T is Pathogenic according to our data. Variant chr6-7567801-TA-T is described in ClinVar as [Pathogenic]. Clinvar id is 464957.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSP	NM_004415.4	c.1162del	p.Thr388LeufsTer5	frameshift_variant	10/24	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.1162del	p.Thr388LeufsTer5	frameshift_variant	10/24		NP_001305963.1
DSP	NM_001008844.3	c.1162del	p.Thr388LeufsTer5	frameshift_variant	10/24		NP_001008844.1
DSP	NM_001406591.1	c.1162del	p.Thr388LeufsTer5	frameshift_variant	10/11		NP_001393520.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.1162del	p.Thr388LeufsTer5	frameshift_variant	10/24	1	NM_004415.4	ENSP00000369129	P2
DSP	ENST00000418664.2	c.1162del	p.Thr388LeufsTer5	frameshift_variant	10/24	1		ENSP00000396591	A2
DSP	ENST00000710359.1	c.1162del	p.Thr388LeufsTer5	frameshift_variant	10/24			ENSP00000518230	A2
DSP	ENST00000682228.1	n.817del		non_coding_transcript_exon_variant	3/3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

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

Oct 09, 2018

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in DSP are known to be pathogenic. This particular variant has been reported in the literature in an individual with cardiomyopathy  (PMID: 26735901). This sequence change deletes 1 nucleotide from exon 10 of the DSP mRNA (c.1162delA), causing a frameshift at codon 388. This creates a premature translational stop signal (p.Thr388Leufs*5) and is expected to result in an absent or disrupted protein product. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 28, 2020

The c.1162delA variant, located in coding exon 10 of the DSP gene, results from a deletion of one nucleotide at nucleotide position 1162, causing a translational frameshift with a predicted alternate stop codon (p.T388Lfs*5). This variant (referred to as chr6:7568034TA>T) has been detected in a peripartum cardiomyopathy cohort (Ware JS et al. N Engl J Med, 2016 Jan;374:233-41). In addition to the clinical data presented in the literature, 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: rs1554106742; hg19: chr6-7568034;