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NM_004415.4(DSP):c.3133C>T (p.Arg1045Ter) AND Cardiac arrhythmia

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Sep 5, 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:
RCV001841483.10

Allele description [Variation Report for NM_004415.4(DSP):c.3133C>T (p.Arg1045Ter)]

NM_004415.4(DSP):c.3133C>T (p.Arg1045Ter)

Gene:
DSP:desmoplakin [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
6p24.3
Genomic location:
Preferred name:
NM_004415.4(DSP):c.3133C>T (p.Arg1045Ter)
Other names:
p.Arg1045*
HGVS:
  • NC_000006.12:g.7579323C>T
  • NG_008803.1:g.42687C>T
  • NM_001008844.3:c.3133C>T
  • NM_001319034.2:c.3133C>T
  • NM_004415.4:c.3133C>TMANE SELECT
  • NP_001008844.1:p.Arg1045Ter
  • NP_001305963.1:p.Arg1045Ter
  • NP_004406.2:p.Arg1045Ter
  • LRG_423t1:c.3133C>T
  • LRG_423:g.42687C>T
  • NC_000006.11:g.7579556C>T
  • NM_004415.2:c.3133C>T
  • NM_004415.3:c.3133C>T
  • p.Arg1045X
Protein change:
R1045*
Links:
dbSNP: rs1554108012
NCBI 1000 Genomes Browser:
rs1554108012
Molecular consequence:
  • NM_001008844.3:c.3133C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001319034.2:c.3133C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_004415.4:c.3133C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:
Cardiac arrhythmia
Synonyms:
Cardiac rhythm disease
Identifiers:
EFO: EFO_0004269; MONDO: MONDO:0007263; MedGen: C0003811; Human Phenotype Ontology: HP:0011675

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001363280Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)		Pathogenic
(Sep 5, 2023) 		germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link

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Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples.

Walsh R, Thomson KL, Ware JS, Funke BH, Woodley J, McGuire KJ, Mazzarotto F, Blair E, Seller A, Taylor JC, Minikel EV, Exome Aggregation Consortium, MacArthur DG, Farrall M, Cook SA, Watkins H.

Genet Med. 2017 Feb;19(2):192-203. doi: 10.1038/gim.2016.90. Epub 2016 Aug 17.

PubMed [citation]
PMID:
27532257
PMCID:
PMC5116235

Desmoplakin missense and non-missense mutations in arrhythmogenic right ventricular cardiomyopathy: Genotype-phenotype correlation.

Castelletti S, Vischer AS, Syrris P, Crotti L, Spazzolini C, Ghidoni A, Parati G, Jenkins S, Kotta MC, McKenna WJ, Schwartz PJ, Pantazis A.

Int J Cardiol. 2017 Dec 15;249:268-273. doi: 10.1016/j.ijcard.2017.05.018. Epub 2017 May 10.

PubMed [citation]
PMID:
28527814

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001363280.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

Variant summary: DSP c.3133C>T (p.Arg1045X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. A truncation downstream of this position has been classified as pathogenic by our laboratory (c.3337C>T, p.Arg1113X). The variant was absent in 250892 control chromosomes (gnomAD). The variant, c.3133C>T, has been reported in the literature in individuals affected with dilated cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy (Walsh_2017, Castelletti_2017). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27532257, 28527814). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic or likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Apr 20, 2024