6-7581071-GAGGAG-GTTCT

Position:

• chr6-7581071-GAGGAG-GTTCT

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.4882_4886delinsTTCT​(p.Arg1628PhefsTer17) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DSP NM_004415.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 5.37

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 6-7581072-AGGAG-TTCT is Pathogenic according to our data. Variant chr6-7581072-AGGAG-TTCT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 452266.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.4882_4886delinsTTCT	p.Arg1628PhefsTer17	frameshift_variant	23/24	ENST00000379802.8	NP_004406.2
DSP	NM_001008844.3	c.3582+1300_3582+1304delinsTTCT		intron_variant			NP_001008844.1
DSP	NM_001319034.2	c.4050+832_4050+836delinsTTCT		intron_variant			NP_001305963.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.4882_4886delinsTTCT	p.Arg1628PhefsTer17	frameshift_variant	23/24	1	NM_004415.4	ENSP00000369129	P2
DSP	ENST00000418664.2	c.3582+1300_3582+1304delinsTTCT		intron_variant		1		ENSP00000396591	A2
DSP	ENST00000710359.1	c.4050+832_4050+836delinsTTCT		intron_variant				ENSP00000518230	A2

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

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

Jul 19, 2023

This variant deletes 9 nucleotides in exon 23 of the DSP gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, this variant has not been reported in individuals affected with DSP-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of DSP function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

Arrhythmogenic right ventricular cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 18, 2018

The p.Arg1628fs variant in DSP has not been previously reported in individuals w ith arrhythmogenic right ventricular cardiomyopathy (ARVC) and was absent from l arge population studies, though the ability of these studies to accurately detec t indels may be limited. This variant has been reported in ClinVar (Variation ID : 452266). This variant is located within exon 23 of DSP which undergoes alterna tive splicing resulting in two isoforms: one with a shorter and one with a longe r form of this exon. This variant is only located in the coding region of the lo nger isoform. In that transcript, this variant is predicted to cause a frameshif t, which alters the protein?s amino acid sequence beginning at position 1628 and leads to a premature termination codon 17 amino acids downstream. This alterati on is then predicted to lead to a truncated or absent protein. Loss-of-function variants in the longer form of exon 23 have been observed in individuals with AR VC and/or DCM, suggesting that loss-of-function variants in this region are like ly to be disease causing (LMM data). In summary, although additional studies are required to fully establish its clinical significance, the p.Arg1628fs variant is likely pathogenic. ACMG/AMP criteria applied: PVS1, PM2. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 05, 2024

Has been reported in an individual identified as part of the eMERGE study (PMID: 31447099); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 33684294, 34352074, 31447099) -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 06, 2021

The c.4882_4886delAGGAGinsTTCT pathogenic mutation, located in coding exon 23 of the DSP gene, results from the deletion of 5 nucleotides and insertion of 4 nucleotides causing a translational frameshift with a predicted alternate stop codon (p.R1628Ffs*17). 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. -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 26, 2021

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Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1554108410; hg19: chr6-7581305;