NM_004415.4(DSP):c.7214_7217del (p.Leu2405fs) AND Arrhythmogenic cardiomyopathy with wooly hair and keratoderma

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Dec 18, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV004006072.2

Allele description [Variation Report for NM_004415.4(DSP):c.7214_7217del (p.Leu2405fs)]

NM_004415.4(DSP):c.7214_7217del (p.Leu2405fs)

Gene:

DSP:desmoplakin [Gene - OMIM - HGNC]

Variant type:

Microsatellite

Cytogenetic location:

6p24.3

Genomic location:

Preferred name:

NM_004415.4(DSP):c.7214_7217del (p.Leu2405fs)

HGVS:

NC_000006.11:g.7584709_7584712del
NC_000006.12:g.7584474TC[1]
NG_008803.1:g.47838TC[1]
NM_001008844.3:c.5417_5420del
NM_001319034.2:c.5885_5888del
NM_004415.4:c.7214_7217delMANE SELECT
NP_001008844.1:p.Leu1806fs
NP_001305963.1:p.Leu1962fs
NP_004406.2:p.Leu2405Glnfs
NP_004406.2:p.Leu2405fs
LRG_423t1:c.7212_7213TC[1]
LRG_423:g.47838TC[1]
LRG_423p1:p.Leu2405Glnfs
NC_000006.11:g.7584707TC[1]
NC_000006.11:g.7584707_7584710del
NC_000006.11:g.7584709_7584712del
NM_004415.2:c.7212_7213TC[1]

Protein change:

L1806fs

Molecular consequence:

NM_001008844.3:c.5417_5420del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001319034.2:c.5885_5888del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_004415.4:c.7214_7217del - frameshift variant - [Sequence Ontology: SO:0001589]

Observations:

Condition(s)

Name:: Arrhythmogenic cardiomyopathy with wooly hair and keratoderma
Synonyms:: Palmoplantar keratoderma with left ventricular cardiomyopathy and woolly hair; Epidermolytic palmoplantar keratoderma woolly hair and dilated cardiomyopathy; Dilated cardiomyopathy with woolly hair and keratoderma; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0011581; MedGen: C1854063; Orphanet: 65282; OMIM: 605676

Recent activity

Clear Turn Off Turn On

hypothetical protein LOC113444 [Homo sapiens]
hypothetical protein LOC113444 [Homo sapiens]
gi|31377614|ref|NP_612437.2|

Protein

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004841997	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (Dec 18, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 12101406, 12802069, 21756917, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004841997

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely Pathogenic
(Dec 18, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	1	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

Structures of two intermediate filament-binding fragments of desmoplakin reveal a unique repeat motif structure.

Choi HJ, Park-Snyder S, Pascoe LT, Green KJ, Weis WI.

Nat Struct Biol. 2002 Aug;9(8):612-20.

PubMed [citation]

PMID:: 12101406

Interaction of the bullous pemphigoid antigen 1 (BP230) and desmoplakin with intermediate filaments is mediated by distinct sequences within their COOH terminus.

Fontao L, Favre B, Riou S, Geerts D, Jaunin F, Saurat JH, Green KJ, Sonnenberg A, Borradori L.

Mol Biol Cell. 2003 May;14(5):1978-92. Epub 2003 Jan 26.

PubMed [citation]

PMID:: 12802069
PMCID:: PMC165091

See all PubMed Citations (4)

Details of each submission

From All of Us Research Program, National Institutes of Health, SCV004841997.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (4)

Description

This variant deletes 4 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 with disrupted plakin repeat domain B (a.a. 2244-2446) and downstream C-terminal sequence that have been reported to be essential for interaction with intermediate filaments (PMID: 12101406, 12802069, 21756917). In addition, truncating variants occurring downstream of this variant are known to be disease-causing (ClinVar variation ID: 1326970, 432027, 246676). 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 Likely Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Sep 29, 2024

ClinVar

Relating variation to medicine