NM_004415.4(DSP):c.5745dup (p.Lys1916Ter) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 10, 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:: RCV001383704.7

Allele description [Variation Report for NM_004415.4(DSP):c.5745dup (p.Lys1916Ter)]

NM_004415.4(DSP):c.5745dup (p.Lys1916Ter)

Gene:

DSP:desmoplakin [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

6p24.3

Genomic location:

Preferred name:

NM_004415.4(DSP):c.5745dup (p.Lys1916Ter)

HGVS:

NC_000006.12:g.7583007dup
NG_008803.1:g.46371dup
NM_001008844.3:c.3948dup
NM_001319034.2:c.4416dup
NM_004415.4:c.5745dupMANE SELECT
NP_001008844.1:p.Lys1317Ter
NP_001305963.1:p.Lys1473Ter
NP_004406.2:p.Lys1916Ter
LRG_423t1:c.5745dup
LRG_423:g.46371dup
NC_000006.11:g.7583239_7583240insT
NC_000006.11:g.7583240dup
NM_004415.2:c.5745dupT

Protein change:

K1317*

Links:

dbSNP: rs1060500607

NCBI 1000 Genomes Browser:

rs1060500607

Molecular consequence:

NM_001008844.3:c.3948dup - nonsense - [Sequence Ontology: SO:0001587]
NM_001319034.2:c.4416dup - nonsense - [Sequence Ontology: SO:0001587]
NM_004415.4:c.5745dup - nonsense - [Sequence Ontology: SO:0001587]

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

Name:: Arrhythmogenic right ventricular dysplasia 8 (ARVD8)
Synonyms:: ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA, FAMILIAL, 8; Arrhythmogenic right ventricular cardiomyopathy, type 8; Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy 8
Identifiers:: MONDO: MONDO:0011831; MedGen: C1843896; OMIM: 607450

Recent activity

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Homo sapiens CCAAT enhancer binding protein delta (CEBPD), mRNA
Homo sapiens CCAAT enhancer binding protein delta (CEBPD), mRNA
gi|1653960551|ref|NM_005195.4|

Nucleotide
BMP/retinoic acid-inducible neural-specific protein 2 precursor [Homo sapiens]
BMP/retinoic acid-inducible neural-specific protein 2 precursor [Homo sapiens]
gi|23943866|ref|NP_066988.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001582954	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 10, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 11063735, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001582954

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 10, 2023)

germline

clinical testing

PubMed (2)
[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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Recessive mutation in desmoplakin disrupts desmoplakin-intermediate filament interactions and causes dilated cardiomyopathy, woolly hair and keratoderma.

Norgett EE, Hatsell SJ, Carvajal-Huerta L, Cabezas JC, Common J, Purkis PE, Whittock N, Leigh IM, Stevens HP, Kelsell DP.

Hum Mol Genet. 2000 Nov 1;9(18):2761-6.

PubMed [citation]

PMID:: 11063735

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001582954.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This variant has not been reported in the literature in individuals affected with DSP-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Lys1916*) in the DSP gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 956 amino acid(s) of the DSP protein. ClinVar contains an entry for this variant (Variation ID: 405223). For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the DSP protein in which other variant(s) (p.Thr2634Lysfs*4) have been determined to be pathogenic (PMID: 11063735). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing.

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

Last Updated: Sep 29, 2024

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