NM_004415.4(DSP):c.8605A>G (p.Ile2869Val) AND not specified

Germline classification:: Benign (6 submissions)
Last evaluated:: May 29, 2018
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:: RCV000172750.18

Allele description [Variation Report for NM_004415.4(DSP):c.8605A>G (p.Ile2869Val)]

NM_004415.4(DSP):c.8605A>G (p.Ile2869Val)

Gene:

DSP:desmoplakin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

6p24.3

Genomic location:

Preferred name:

NM_004415.4(DSP):c.8605A>G (p.Ile2869Val)

Other names:

p.I2869V:ATT>GTT

HGVS:

NC_000006.12:g.7585867A>G
NG_008803.1:g.49231A>G
NM_001008844.3:c.6808A>G
NM_001319034.2:c.7276A>G
NM_004415.4:c.8605A>GMANE SELECT
NP_001008844.1:p.Ile2270Val
NP_001305963.1:p.Ile2426Val
NP_004406.2:p.Ile2869Val
LRG_423t1:c.8605A>G
LRG_423:g.49231A>G
NC_000006.11:g.7586100A>G
NM_004415.2:c.8605A>G

Protein change:

I2270V

Links:

dbSNP: rs28763971

NCBI 1000 Genomes Browser:

rs28763971

Molecular consequence:

NM_001008844.3:c.6808A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001319034.2:c.7276A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_004415.4:c.8605A>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

Recent activity

Clear Turn Off Turn On

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
SCV000051540	Biesecker Lab/Clinical Genomics Section, National Institutes of Health - ClinSeq	criteria provided, single submitter (Ng et al. (Circ Cardiovasc Genet. 2013))	Benign (Jun 24, 2013)	unknown	research	PubMed (1) [See all records that cite this PMID]
SCV000168273	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Benign (Jan 13, 2013)	germline	clinical testing	Citation Link,
SCV000269040	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Benign (Mar 23, 2015)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000919285	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Benign (May 29, 2018)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 23861362, 24125834 Citation Link,
SCV001923207	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
SCV001932622	Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	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	unknown	unknown	2	not provided	not provided	not provided	not provided	research
not provided	germline	not provided	4	4	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

Interpreting secondary cardiac disease variants in an exome cohort.

Ng D, Johnston JJ, Teer JK, Singh LN, Peller LC, Wynter JS, Lewis KL, Cooper DN, Stenson PD, Mullikin JC, Biesecker LG; NIH Intramural Sequencing Center (NISC) Comparative Sequencing Program.

Circ Cardiovasc Genet. 2013 Aug;6(4):337-46. doi: 10.1161/CIRCGENETICS.113.000039. Epub 2013 Jul 16.

PubMed [citation]

PMID:: 23861362
PMCID:: PMC3887521

See all PubMed Citations (3)

Details of each submission

From Biesecker Lab/Clinical Genomics Section, National Institutes of Health - ClinSeq, SCV000051540.1

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

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

From GeneDx, SCV000168273.11

#	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 Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000269040.2

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

Description

p.Ile2869Val in exon 24 of DSP: This variant is not expected to have clinical si gnificance because it has been identified in 2.7% (228/8370) of East Asian chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs28763971).

#	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		4	not provided	4	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000919285.1

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

Description

Variant summary: DSP c.8605A>G (p.Ile2869Val) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0021 in 275770 control chromosomes, predominantly at a frequency of 0.027 within the East Asian subpopulation in the gnomAD database, including 6 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 1080-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in DSP causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. The variant, c.8605A>G, has been reported in the literature in individuals affected with ARVC and sudden death (Bao_2013, Neubauer_2016, Suktitipat_2017, Ng_2013). These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple ClinVar submissions from clinical diagnostic laboratories cite the variant as "likely benign/benign." 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, SCV001923207.1

#	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 Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus, SCV001932622.1

#	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: Nov 24, 2024

ClinVar

Relating variation to medicine