rs397514040

Positions:

• chr6-7583351-CTT-C

Variant summary

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

The ENST00000379802.8(DSP):​c.6091_6092del​(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 (★★). Synonymous variant affecting the same amino acid position (i.e. S2030S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: DSP ENST00000379802.8 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 18 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 74 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/exons	MANE	Protein	UniProt
DSP	NM_004415.4	c.6091_6092del	p.Leu2031GlyfsTer29	frameshift_variant	24/24	ENST00000379802.8	NP_004406.2
DSP	NM_001008844.3	c.4294_4295del	p.Leu1432GlyfsTer29	frameshift_variant	24/24		NP_001008844.1
DSP	NM_001319034.2	c.4762_4763del	p.Leu1588GlyfsTer29	frameshift_variant	24/24		NP_001305963.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.6091_6092del	p.Leu2031GlyfsTer29	frameshift_variant	24/24	1	NM_004415.4	ENSP00000369129	P2
DSP	ENST00000418664.2	c.4294_4295del	p.Leu1432GlyfsTer29	frameshift_variant	24/24	1		ENSP00000396591	A2
DSP	ENST00000710359.1	c.4762_4763del	p.Leu1588GlyfsTer29	frameshift_variant	24/24			ENSP00000518230	A2

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

Pathogenic, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Feb 08, 2024

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 21, 2023

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 individual(s) with autosomal recessive Carvajal syndrome (PMID: 31073624). This variant has been reported in individual(s) with autosomal recessive lethal acantholytic epidermolysis bullosa (PMID: 16175511); however, the role of the variant in this condition is currently unclear. 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

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 2005

- -

Arrhythmogenic right ventricular dysplasia 8 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Nov 14, 2023

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

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 22, 2023

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

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 09, 2024

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 16, 2021

- -

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;