chr6-7582719-C-CA

Position:

• chr6-7582719-C-CA

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_004415.4(DSP):​c.5460dupA​(p.Val1821fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,280 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. V1821V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DSP NM_004415.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.32

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 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 18 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-7582719-C-CA is Pathogenic according to our data. Variant chr6-7582719-C-CA is described in ClinVar as [Pathogenic]. Clinvar id is 464966.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.5460dupA	p.Val1821fs	frameshift_variant	24/24	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.4131dupA	p.Val1378fs	frameshift_variant	24/24		NP_001305963.1
DSP	NM_001008844.3	c.3663dupA	p.Val1222fs	frameshift_variant	24/24		NP_001008844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.5460dupA	p.Val1821fs	frameshift_variant	24/24	1	NM_004415.4	ENSP00000369129.3
DSP	ENST00000418664.2	c.3663dupA	p.Val1222fs	frameshift_variant	24/24	1		ENSP00000396591.2
DSP	ENST00000710359.1	c.4131dupA	p.Val1378fs	frameshift_variant	24/24			ENSP00000518230.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461280 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726932

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: 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

Labcorp Genetics (formerly Invitae), Labcorp

May 17, 2018

This sequence change results in a premature translational stop signal in the DSP gene (p.Val1821Serfs*15). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1051 amino acids of the DSP protein. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with DSP-related disease. A different truncation (p.Ser2168Argfs*18) that lies downstream of this variant has been determined to be pathogenic (Invitae). This suggests that deletion of this region of the DSP protein is causative of disease. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Likely pathogenic, no assertion criteria provided

provider interpretation

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Jun 21, 2017

This variant was identified in a patient with DCM and cardiac arrest. Given the variant type and absence in control populations, we consider this variant likely disease causing and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). This is a novel variant and does not have an entry in ClinVar. However, the majority of the mutations in the DSP gene associated with ARVC in HGMD are nonsense or frameshifts mutations (Stenson P et al., 2009). Of the reported nonsense and frameshift variants, several have been reported downstream of this variant, suggesting that this is a critical region of the protein. Furthermore, in the ExAC constraint analyses indicates DSP is intolerant to loss of function/truncating variation (pLI - 1.000) and cardiodb.org lists truncating variants in DSP enriched both cases of ARVC and DCM vs. controls. Walsh et al (2016) found that truncating DSP variants were enriched in cases of DCM over ExAC controls with odds ration of 41.0. The c-terminal end of the protein, which is altered by this frameshift, is important for protein interactions with IFs to anchor them to the desmosome (Kouklis et al. 1994; Bornslaeger et al. 1996). Groeneweg et al. (2016) reports on 1001 ARVC index patients from the Hopkins cohort. Nine of eleven index patients have either nonsense or frameshift variants in the DSP gene. This variant is absent in both ExAC and gnomAD. This site is well covered in both databases (>70X). Together, these databases includes variant calls on >140,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 21, 2022

The c.5460dupA pathogenic mutation, located in coding exon 24 of the DSP gene, results from a duplication of A at nucleotide position 5460, causing a translational frameshift with a predicted alternate stop codon (p.V1821Sfs*15). This alteration occurs at the 3' terminus of the DSP gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 36% of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). 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 variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, 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: rs1554108609; hg19: chr6-7582952;