NM_014000.3(VCL):c.2521G>C (p.Asp841His) AND not provided

Germline classification:: Conflicting classifications of pathogenicity (4 submissions)
Last evaluated:: Jan 25, 2019
Review status:: criteria provided, conflicting classifications

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:: RCV000172506.9

Allele description [Variation Report for NM_014000.3(VCL):c.2521G>C (p.Asp841His)]

NM_014000.3(VCL):c.2521G>C (p.Asp841His)

Gene:

VCL:vinculin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

10q22.2

Genomic location:

Preferred name:

NM_014000.3(VCL):c.2521G>C (p.Asp841His)

Other names:

p.D841H:GAC>CAC

HGVS:

NC_000010.11:g.74107316G>C
NG_008868.1:g.114203G>C
NM_003373.4:c.2521G>C
NM_014000.3:c.2521G>CMANE SELECT
NP_003364.1:p.Asp841His
NP_054706.1:p.Asp841His
NP_054706.1:p.Asp841His
LRG_383t1:c.2521G>C
LRG_383:g.114203G>C
LRG_383p1:p.Asp841His
NC_000010.10:g.75867074G>C
NM_014000.2:c.2521G>C

Protein change:

D841H

Links:

dbSNP: rs150385900

Molecular consequence:

NM_003373.4:c.2521G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_014000.3:c.2521G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000051353	Biesecker Lab/Clinical Genomics Section, National Institutes of Health - ClinSeq	criteria provided, single submitter (Ng et al. (Circ Cardiovasc Genet. 2013))	Uncertain significance (Jun 24, 2013)	unknown	research	PubMed (1) [See all records that cite this PMID]
SCV000236476	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Benign (Jan 25, 2019)	germline	clinical testing	Citation Link,
SCV000699358	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Benign (Aug 2, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] LabCorp Variant Classification Summary - May 2015.docx, Citation Link,
SCV002034136	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	Likely benign	germline	clinical testing

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	unknown	1	not provided	not provided	not provided	not provided	research
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

Citations

PubMed

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

Details of each submission

From Biesecker Lab/Clinical Genomics Section, National Institutes of Health - ClinSeq, SCV000051353.1

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

From GeneDx, SCV000236476.13

#	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 associated with the following publications: (PMID: 28373245, 23861362)

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000699358.1

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

Description

Variant summary: The VCL c.2521G>C (p.Asp841His) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is not located in any known domain (InterPro, UniProt). This variant was found in 120/121210 control chromosomes, predominantly observed in the East Asian subpopulation at a frequency of 0.0132159 (114/8626). No homozygotes have been detected in general population. This frequency is about 529 times the estimated maximal expected allele frequency of a pathogenic VCL variant (0.000025), strong evidence that this is likely a benign polymorphism found primarily in the populations of East Asian origin. One of three clinical diagnostic laboratories has classified this variant as benign based on ExAC population frequency, while two other labs classify the variant as a VUS, likely due to the large ExAC database not being utalized at the time of evaluation. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and there are no published functional studies for the variant. Taken together, this variant is 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 Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus, SCV002034136.1

#	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: Apr 12, 2026

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