NM_014000.3(VCL):c.625A>T (p.Met209Leu) AND Dilated cardiomyopathy 1W

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jan 7, 2024
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:: RCV000577945.9

Allele description [Variation Report for NM_014000.3(VCL):c.625A>T (p.Met209Leu)]

NM_014000.3(VCL):c.625A>T (p.Met209Leu)

Gene:

VCL:vinculin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

10q22.2

Genomic location:

Preferred name:

NM_014000.3(VCL):c.625A>T (p.Met209Leu)

HGVS:

NC_000010.11:g.74074745A>T
NG_008868.1:g.81632A>T
NM_003373.4:c.625A>T
NM_014000.3:c.625A>TMANE SELECT
NP_003364.1:p.Met209Leu
NP_054706.1:p.Met209Leu
NP_054706.1:p.Met209Leu
LRG_383t1:c.625A>T
LRG_383:g.81632A>T
LRG_383p1:p.Met209Leu
NC_000010.10:g.75834503A>T
NM_014000.2:c.625A>T

Protein change:

M209L

Links:

dbSNP: rs144683137

NCBI 1000 Genomes Browser:

rs144683137

Molecular consequence:

NM_003373.4:c.625A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_014000.3:c.625A>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Dilated cardiomyopathy 1W (CMD1W)
Identifiers:: MONDO: MONDO:0012667; MedGen: C1969639; Orphanet: 154; OMIM: 611407

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000679923	Phosphorus, Inc.	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Aug 1, 2017)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 26458567, 25741868
SCV001489100	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 7, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 26458567, 35284542, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000679923

Phosphorus, Inc.

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Aug 1, 2017)

germline

clinical testing

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

SCV001489100

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 7, 2024)

germline

clinical testing

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

Help

Summary from all submissions

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

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Targeted next-generation sequencing of candidate genes reveals novel mutations in patients with dilated cardiomyopathy.

Zhao Y, Feng Y, Zhang YM, Ding XX, Song YZ, Zhang AM, Liu L, Zhang H, Ding JH, Xia XS.

Int J Mol Med. 2015 Dec;36(6):1479-86. doi: 10.3892/ijmm.2015.2361. Epub 2015 Oct 7.

PubMed [citation]

PMID:: 26458567
PMCID:: PMC4678153

See all PubMed Citations (4)

Details of each submission

From Phosphorus, Inc., SCV000679923.1

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

#	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		1	not provided	not provided	not provided

From Invitae, SCV001489100.5

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

Description

This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 209 of the VCL protein (p.Met209Leu). This variant is present in population databases (rs144683137, gnomAD 0.04%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 26458567, 35284542). ClinVar contains an entry for this variant (Variation ID: 488174). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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

Last Updated: Feb 28, 2024

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