NM_014000.3(VCL):c.1907A>G (p.His636Arg) AND not specified

Germline classification:: Benign/Likely benign (3 submissions)
Last evaluated:: Jan 6, 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:: RCV000038810.11

Allele description [Variation Report for NM_014000.3(VCL):c.1907A>G (p.His636Arg)]

NM_014000.3(VCL):c.1907A>G (p.His636Arg)

Gene:

VCL:vinculin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

10q22.2

Genomic location:

Preferred name:

NM_014000.3(VCL):c.1907A>G (p.His636Arg)

Other names:

p.H636R:CAT>CGT

HGVS:

NC_000010.11:g.74100982A>G
NG_008868.1:g.107869A>G
NM_003373.4:c.1907A>G
NM_014000.3:c.1907A>GMANE SELECT
NP_003364.1:p.His636Arg
NP_054706.1:p.His636Arg
NP_054706.1:p.His636Arg
LRG_383t1:c.1907A>G
LRG_383:g.107869A>G
LRG_383p1:p.His636Arg
NC_000010.10:g.75860740A>G
NM_014000.2:c.1907A>G
c.1907A>G

Protein change:

H636R

Links:

dbSNP: rs71579374

NCBI 1000 Genomes Browser:

rs71579374

Molecular consequence:

NM_003373.4:c.1907A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_014000.3:c.1907A>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

Recent activity

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monocopper oxidase-like protein SKU5 [Benincasa hispida]
monocopper oxidase-like protein SKU5 [Benincasa hispida]
gi|1955883482|ref|XP_038899769.1|

Protein
hypothetical protein SDJN02_16135, partial [Cucurbita argyrosperma subsp. argyro...
hypothetical protein SDJN02_16135, partial [Cucurbita argyrosperma subsp. argyrosperma]
gi|2053603832|gb|KAG7022404.1||gnl| DJN|SDJN02_16135

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000062488	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Likely benign (Jan 22, 2016)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 20474083, 23396983, 24033266
SCV001337887	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Benign (Jan 6, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV001919242	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

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000062488

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Likely benign
(Jan 22, 2016)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV001337887

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Benign
(Jan 6, 2020)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link,

SCV001919242

Clinical Genetics, Academic Medical Center - VKGL Data-share Consensus

See additional submitters

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	4	not provided	not provided	not provided	clinical testing

Citations

PubMed

Genetic complexity in hypertrophic cardiomyopathy revealed by high-throughput sequencing.

Lopes LR, Zekavati A, Syrris P, Hubank M, Giambartolomei C, Dalageorgou C, Jenkins S, McKenna W; Uk10k Consortium., Plagnol V, Elliott PM.

J Med Genet. 2013 Apr;50(4):228-39. doi: 10.1136/jmedgenet-2012-101270. Epub 2013 Feb 8.

PubMed [citation]

PMID:: 23396983
PMCID:: PMC3607113

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

See all PubMed Citations (3)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000062488.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	4	not provided	not provided	clinical testing	PubMed (3)

Description

p.His636Arg in exon 14 of VCL: This variant is not expected to have clinical sig nificance because it has been identified in 0.67% (44/6604) of Finnish chromosom es by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; db SNP rs71579374).

#	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, SCV001337887.1

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

Description

Variant summary: VCL c.1907A>G (p.His636Arg) 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 0.0014 in 252006 control chromosomes in the gnomAD database, including 1 homozygotes. The observed variant frequency is approximately 31 fold of the estimated maximal expected allele frequency for a pathogenic variant in VCL causing Dilated Cardiomyopathy phenotype (4.7e-05), strongly suggesting that the variant is benign. c.1907A>G has been reported in the literature in individuals affected with Dilated Cardiomyopathy (Zimmerman_2010). This report does not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. At least one co-occurrence with a pathogenic variant has been reported (MYBPC3 c.1090+1G>A, LOVD database citing Lopes_2013), providing supporting evidence for a benign role.Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (1x benign, 2x likely benign, 1x VUS). 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, SCV001919242.1

#	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 26, 2024

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