rs1554108929

Variant names:

• chr6-7584211-AAG-A
• rs1554108929
• NM_004415.4:c.6954_6955delAG

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.6954_6955delAG​(p.Gly2319SerfsTer5) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000137 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DSP NM_004415.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 6.42

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 11 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-7584211-AAG-A is Pathogenic according to our data. Variant chr6-7584211-AAG-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 518482.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.6954_6955delAG	p.Gly2319SerfsTer5	frameshift_variant	Exon 24 of 24	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.5625_5626delAG	p.Gly1876SerfsTer5	frameshift_variant	Exon 24 of 24		NP_001305963.1
DSP	NM_001008844.3	c.5157_5158delAG	p.Gly1720SerfsTer5	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.6954_6955delAG	p.Gly2319SerfsTer5	frameshift_variant	Exon 24 of 24	1	NM_004415.4	ENSP00000369129.3
DSP	ENST00000418664.2	c.5157_5158delAG	p.Gly1720SerfsTer5	frameshift_variant	Exon 24 of 24	1		ENSP00000396591.2
DSP	ENST00000710359.1	c.5625_5626delAG	p.Gly1876SerfsTer5	frameshift_variant	Exon 24 of 24			ENSP00000518230.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461894 Hom.: 0 AF XY: 0.00000138 AC XY: 1 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Pathogenic:1

Aug 03, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.6954_6955del (p.Gly2319Serfs*5) 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 2319, leading to a premature termination codon five 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 ~19% of the coding region, with ~550 amino acids removed. This variant is absent in the general population (gnomAD). Additionally, multiple other truncating variants after the amino acid 2319 in the DSP gene have been reported in ClinVar in association with DSP-related disorders. Therefore, the c.6954_6955del (p.Gly2319Serfs*5) variant of DSP is classified as likely pathogenic. -

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

Aug 02, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the C-terminus of the DSP protein. Other variant(s) that disrupt this region (p.Gln2667*, p.Pro2719Argfs*27) have been determined to be pathogenic (PMID: 20400443, Invitae). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has not been reported in the literature in individuals with DSP-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the DSP gene (p.Gly2319Serfs*5). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 553 amino acids of the DSP protein. -

Arrhythmogenic right ventricular cardiomyopathy Pathogenic:1

Mar 29, 2021

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Gly2319SerfsX5 variant in DSP has not been previously reported in individuals with arrhythmogenic right ventricular cardiomyopathy (ARVC) or Carvajal syndrome but has been reported by other clinical laboratories in ClinVar (Variation ID: 518482). It was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 2319 and leads to a premature termination codon 5 amino acids downstream. This termination codon occurs within the last exon and is, therefore, likely to escape nonsense mediated decay (NMD) and result in a truncated protein that is missing ~19% of the coding region, with 548 amino acids removed. Additional truncating variants downstream of this variant have been reported in individuals with ARVC/ Carvajal syndrome. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant ARVC and autosomal recessive Carvajal syndrome. ACMG/AMP Criteria applied: PVS1_Strong, PM2_Supporting. -

Cardiomyopathy Pathogenic:1

Nov 18, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant deletes 2 nucleotides in exon 24 of the DSP gene, creating a frameshift and premature translation stop signal in the last exon. This variant is predicted to escape nonsense-mediated decay and be expressed as a truncated protein. Although functional studies have not been reported, this variant is expected to disrupt the plakin repeat domain B and C. Plakin repeat domains and downstream C-terminal sequence have been reported to be essential for interaction with intermediate filaments (PMID: 12101406, 12802069, 21756917). In addition, other truncating variants occurring downstream of this variant are known to be disease-causing (ClinVar variation ID: 246676, 263803). This variant has been reported in an individual affected with arrhythmogenic cardiomyopathy (PMID: 32389048). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

not provided Pathogenic:1

Dec 12, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in an individual from an exome sequencing cohort; however, patient-specific clinical details were not provided (PMID: 36129056); 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: 36129056) -

Cardiovascular phenotype Pathogenic:1

Sep 12, 2017

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.6954_6955delAG variant, located in coding exon 24 of the DSP gene, results from a deletion of two nucleotides at nucleotide positions 6954 to 6955, causing a translational frameshift with a predicted alternate stop codon (p.G2319Sfs*5). 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 occurs at the 3' terminus of DSP, is not expected to trigger nonsense-mediated mRNA decay, and removes the last 553 amino acids of the protein. While the exact functional impact of these removed amino acids is unknown at this time, the eliminated amino acids include 4 plectin domains and 6 X 4 AA tandem repeats of G-S-R-[SR], and several alterations more C-terminal than this variant have been detected in ARVC and DCM cohorts (e.g., c.8077_8080delAAG and c.8188delC in Walsh R et al. Genet. Med. 2017;19:192-203). In addition, multiple nonsense and frameshift alterations in the 3' terminus of DSP have been identified in the homozygous or compound heterozygous state in individuals with autosomal recessive Carvajal syndrome (e.g., c.7623delG in Norgett EE et al. Hum. Mol. Genet. 2000;9:2761-6). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

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: rs1554108929; hg19: chr6-7584444;