NM_004415.4(DSP):c.4489C>T (p.Arg1497Trp) AND not specified

Germline classification:: Benign/Likely benign (4 submissions)
Last evaluated:: Dec 9, 2019
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000038045.20

Allele description [Variation Report for NM_004415.4(DSP):c.4489C>T (p.Arg1497Trp)]

NM_004415.4(DSP):c.4489C>T (p.Arg1497Trp)

Gene:

DSP:desmoplakin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

6p24.3

Genomic location:

Preferred name:

NM_004415.4(DSP):c.4489C>T (p.Arg1497Trp)

Other names:

p.R1497W:CGG>TGG

HGVS:

NC_000006.12:g.7580679C>T
NG_008803.1:g.44043C>T
NM_001008844.3:c.3582+907C>T
NM_001319034.2:c.4050+439C>T
NM_004415.4:c.4489C>TMANE SELECT
NP_004406.2:p.Arg1497Trp
LRG_423t1:c.4489C>T
LRG_423:g.44043C>T
NC_000006.11:g.7580912C>T
NM_004415.2:c.4489C>T
NM_004415.3:c.4489C>T
c.4489C>T

Protein change:

R1497W

Links:

dbSNP: rs148041814

NCBI 1000 Genomes Browser:

rs148041814

Molecular consequence:

NM_001008844.3:c.3582+907C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001319034.2:c.4050+439C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_004415.4:c.4489C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000061711	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Likely benign (Feb 9, 2012)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 16628197, 11063735, 24033266
SCV000168266	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Benign (Apr 25, 2014)	germline	clinical testing	Citation Link,
SCV000333271	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Likely benign (Aug 10, 2015)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV001363279	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Benign (Dec 9, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

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	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	2	2	not provided	not provided	not provided	clinical testing

Citations

PubMed

Early death from cardiomyopathy in a family with autosomal dominant striate palmoplantar keratoderma and woolly hair associated with a novel insertion mutation in desmoplakin.

Norgett EE, Lucke TW, Bowers B, Munro CS, Leigh IM, Kelsell DP.

J Invest Dermatol. 2006 Jul;126(7):1651-4. Epub 2006 Apr 20. No abstract available. Erratum in: J Invest Dermatol. 2006 Dec;126(12):2735.

PubMed [citation]

PMID:: 16628197

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

See all PubMed Citations (4)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000061711.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (3)

Description

Arg1497Trp in exon 23 of DSP: This variant is not expected to have clinical sign ificance because it has been identified in 0.4% (17/3738) of African American ch romosomes by the NHLBI Exome Sequencing Project in a broad population (http://ev s.gs.washington.edu/EVS; dbSNP rs148041814). Arg1497Trp in exon 23 of DSP (rs14 8041814; allele frequency = 0.4%, 17/3738) **

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		2	not provided	2	not provided

From GeneDx, SCV000168266.10

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

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

From Eurofins Ntd Llc (ga), SCV000333271.4

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

#	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		1	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001363279.1

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

Description

Variant summary: DSP c.4489C>T (p.Arg1497Trp) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00033 in 250336 control chromosomes, predominantly at a frequency of 0.0047 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 24-folds over the estimated maximal expected allele frequency for a pathogenic variant in DSP causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy phenotype (0.0002), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. Six ClinVar submissions (evaluation after 2014) cites the variant five times as likely benign and once as uncertain significance. Based on the evidence outlined above, the variant was classified as benign.

#	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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