NM_004415.4:c.6091_6092delTT

Variant names:

• chr6-7583351-CTT-C
• rs397514040
• NM_004415.4:c.6091_6092delTT

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.6091_6092delTT​(p.Leu2031GlyfsTer29) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: DSP NM_004415.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: -0.0890

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 16 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-7583351-CTT-C is Pathogenic according to our data. Variant chr6-7583351-CTT-C is described in ClinVar as [Pathogenic]. Clinvar id is 16844.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSP	NM_004415.4	c.6091_6092delTT	p.Leu2031GlyfsTer29	frameshift_variant	Exon 24 of 24	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.4762_4763delTT	p.Leu1588GlyfsTer29	frameshift_variant	Exon 24 of 24		NP_001305963.1
DSP	NM_001008844.3	c.4294_4295delTT	p.Leu1432GlyfsTer29	frameshift_variant	Exon 24 of 24		NP_001008844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.6091_6092delTT	p.Leu2031GlyfsTer29	frameshift_variant	Exon 24 of 24	1	NM_004415.4	ENSP00000369129.3
DSP	ENST00000418664.2	c.4294_4295delTT	p.Leu1432GlyfsTer29	frameshift_variant	Exon 24 of 24	1		ENSP00000396591.2
DSP	ENST00000710359.1	c.4762_4763delTT	p.Leu1588GlyfsTer29	frameshift_variant	Exon 24 of 24			ENSP00000518230.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461878 Hom.: 0 AF XY: 0.00000275 AC XY: 2 AN XY: 727240

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Pathogenic:1

Feb 08, 2024

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.6091_6092del (p.Leu2031Glyfs*29) variant of DSP is in the last exon (exon 24) of the gene and is predicted to alter the protein amino acid sequence beginning at position 2031, leading to a premature termination codon 29 amino acids downstream. This termination codon occurs within the last exon and is likely to escape nonsense mediated decay (NMD) and result in a truncated protein that misses >10% of the coding region. This variant has been observed in trans with another disease-causing variant in an individual diagnosed with Carvajal syndrome based on phenotypes including woolly hair, striate PPK, and left-dominant arrhythmogenic cardiomyopathy (PMID: 31073624). Also, this variant was found in combination with another truncating mutation in an individual with severe fragility of skin and mucous membranes (PMID: 16175511). In addition, multiple other C-terminal truncating variants downstream of the amino acid 2031 in the DSP gene, p.Arg2284*, p.Gln2667*, p.Gln2730Serfs*16, have been reported in individuals with ARVC/D or DCM (PMID: 20400443, 27194543, 27532257). This variant is absent in the general population (gnomAD). Therefore, the c.6091_6092del (p.Leu2031Glyfs*29) variant of DSP is classified as pathogenic. -

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

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Leu2031Glyfs*29) in the DSP gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 841 amino acid(s) of the DSP protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with autosomal recessive Carvajal syndrome or lethal acantholytic epidermolysis bullosa (PMID: 16175511, 31073624). ClinVar contains an entry for this variant (Variation ID: 16844). This variant disrupts a region of the DSP protein in which other variant(s) (p.Gln2667*) have been determined to be pathogenic (PMID: 20400443, 27194543). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Lethal acantholytic epidermolysis bullosa Pathogenic:1

Oct 01, 2005

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Arrhythmogenic right ventricular dysplasia 8 Pathogenic:1

Nov 14, 2023

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.6091_6092del (p.Leu2031Glyfs*29) variant of DSP is in the last exon (exon 24) of the gene and is predicted to alter the protein amino acid sequence beginning at position 2031, leading to a premature termination codon 29 amino acids downstream. This termination codon occurs within the last exon and is likely to escape nonsense mediated decay (NMD) and result in a truncated protein that misses >10% of the coding region. This variant has been observed in trans with another disease-causing variant in an individual diagnosed with Carvajal syndrome based on phenotypes including woolly hair, striate PPK, and left-dominant arrhythmogenic cardiomyopathy (PMID: 31073624). Also, this variant was found in combination with another truncating mutation in an individual with severe fragility of skin and mucous membranes (PMID: 16175511). In addition, multiple other C-terminal truncating variants downstream of the amino acid 2031 in the DSP gene, p.Arg2284*, p.Gln2667*, p.Gln2730Serfs*16, have been reported in individuals with ARVC/D or DCM (PMID: 20400443, 27194543, 27532257). This variant is absent in the general population (gnomAD). Therefore, the c.6091_6092del (p.Leu2031Glyfs*29) variant of DSP is classified as pathogenic. -

not provided Pathogenic:1

Sep 22, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); Frameshift variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31073624, 34998950, 16175511) -

Cardiovascular phenotype Pathogenic:1

Feb 09, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.6091_6092delTT pathogenic mutation, located in coding exon 24 of the DSP gene, results from a deletion of two nucleotides at nucleotide positions 6091 to 6092, causing a translational frameshift with a predicted alternate stop codon (p.L2031Gfs*29). This alteration occurs at the 3' terminus of theDSP gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 29% 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). Furthermore, this alteration has been reported in the compound heterozygous state in a neonate with lethal acantholytic epidermolysis bullosa (Jonkman MF et al. Am. J. Hum. Genet. 2005;77:653-60). 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. -

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

Oct 16, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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: rs397514040; hg19: chr6-7583584;