NM_004415.4(DSP):c.7916G>A (p.Arg2639Gln) AND not specified

Germline classification:: Benign (5 submissions)
Last evaluated:: Aug 17, 2020
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:: RCV000150581.11

Allele description [Variation Report for NM_004415.4(DSP):c.7916G>A (p.Arg2639Gln)]

NM_004415.4(DSP):c.7916G>A (p.Arg2639Gln)

Gene:

DSP:desmoplakin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

6p24.3

Genomic location:

Preferred name:

NM_004415.4(DSP):c.7916G>A (p.Arg2639Gln)

Other names:

p.R2639Q:CGG>CAG

HGVS:

NC_000006.12:g.7585178G>A
NG_008803.1:g.48542G>A
NM_001008844.3:c.6119G>A
NM_001319034.2:c.6587G>A
NM_004415.4:c.7916G>AMANE SELECT
NP_001008844.1:p.Arg2040Gln
NP_001305963.1:p.Arg2196Gln
NP_004406.2:p.Arg2639Gln
LRG_423t1:c.7916G>A
LRG_423:g.48542G>A
NC_000006.11:g.7585411G>A
NM_004415.2:c.7916G>A
NM_004415.3:c.7916G>A

Protein change:

R2040Q

Links:

dbSNP: rs116888866

NCBI 1000 Genomes Browser:

rs116888866

Molecular consequence:

NM_001008844.3:c.6119G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001319034.2:c.6587G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_004415.4:c.7916G>A - 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
SCV000197849	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Benign (Jan 18, 2016)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 18632414, 24125834, 24033266
SCV000280096	Stanford Center for Inherited Cardiovascular Disease, Stanford University	no assertion criteria provided	Uncertain significance (Jul 30, 2014)	germline	clinical testing
SCV000698448	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Benign (Aug 17, 2020)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 18632414, 20738328, 23911551, 24125834, 19924139, 25225338, 25693453, 26585738, 30354334 Citation Link,
SCV001919134	Clinical Genetics, Academic Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Benign	germline	clinical testing
SCV001963172	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus	no assertion criteria provided	Benign	germline	clinical testing

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	4	2	not provided	not provided	not provided	clinical testing

Citations

PubMed

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

Arrhythmogenic right ventricular dysplasia: clinical characteristics and identification of novel desmosome gene mutations.

Yu CC, Yu CH, Hsueh CH, Yang CT, Juang JM, Hwang JJ, Lin JL, Lai LP.

J Formos Med Assoc. 2008 Jul;107(7):548-58. doi: 10.1016/S0929-6646(08)60168-0. Erratum in: J Formos Med Assoc. 2009 Mar;108(3):265.

PubMed [citation]

PMID:: 18632414

See all PubMed Citations (10)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000197849.4

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

Description

Arg2639Gln in exon 24 of DSP: This variant is not expected to have clinical sign ificance because it has been identified in 1.2% (105/8630) of East Asian chromos omes by the by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitut e.org). In one study this variant has been identified in 4 Taiwanese individuals with ARVC, but was also identified in 1.3% (8/600) control chromosomes (Bao 201 3).

#	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 Stanford Center for Inherited Cardiovascular Disease, Stanford University, SCV000280096.1

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

Description

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. We consider this a variant of uncertain significance, probably benign, based on the weak case data, the mismatch with the phenotype, and that the variant is common in Asians. The variant has been seen in one Taiwanese patient with ARVC (Yu et al 2008) and one Chinese patient with ARVC (Bao et al 2013). However, it is also seen in Asian controls (reviewed below). In silico analysis predicts the variant to be probably damaging. The arginine at codon 2639 is conserved across species. The GeneDx report notes that another variant of uncertain significance has been reported in association with ARVC at this codon (p.Arg2639Trp), but that no other nearby variants are listed in HGMD. There are no nearby variants listed in www.arvcdatabase.info. In total the variant has been seen in 30 of 7179 published controls and individuals from publicly available population datasets, with ~5% of Asians in two different samples having the variant. There is no variation at codon 2639 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of April 23rd, 2014). Note that this dataset does not match the patient's ancestry (Japanese). Per the GeneDx report, the variant was observed in 14 of 279 Asian individuals in the 1000 genomes sample and 16 of 300 Chinese individuals studied by Bao et al (2013). The variant was not observed in 100 Tawainese individuals studied by Yu et al (2008).

#	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	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000698448.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

Variant summary: DSP c.7916G>A (p.Arg2639Gln) results in a conservative amino acid change located in a plectin repeat (IPR001101) of 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 0.00092 in 252300 control chromosomes, predominantly at a frequency of 0.011 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 1100-fold of the estimated maximal expected allele frequency for a pathogenic variant in DSP causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.7916G>A has been reported in the literature in East Asian individuals affected with Arrhythmia (Yu_2008, Bao_2013, Sato_2015, Zhao_2016), but it was also found in several controls (Bao_2013). These reports do not provide unequivocal conclusions about association of the variant with Arrhythmia. At least one publication reports experimental evidence evaluating an impact on protein function, and demonstrated a weak impact on the binding of the DSP C-terminus to the tested intermediate filaments (IF) proteins (Favre_2018). Nine other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. 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

From Clinical Genetics, Academic Medical Center - VKGL Data-share Consensus, SCV001919134.1

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

#	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 Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus, SCV001963172.1

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

#	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

Last Updated: Oct 8, 2024

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