NM_014000.3:c.3236T>C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_014000.3(VCL):c.3236T>C(p.Ile1079Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000276 in 1,448,828 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. I1079I) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 29)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

VCL
NM_014000.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 7.67

Publications

0 publications found

Variant links:

Genes affected

VCL (HGNC:12665): (vinculin) Vinculin is a cytoskeletal protein associated with cell-cell and cell-matrix junctions, where it is thought to function as one of several interacting proteins involved in anchoring F-actin to the membrane. Defects in VCL are the cause of cardiomyopathy dilated type 1W. Dilated cardiomyopathy is a disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Multiple alternatively spliced transcript variants have been found for this gene, but the biological validity of some variants has not been determined. [provided by RefSeq, Jul 2008]

VCL Gene-Disease associations (from GenCC):

dilated cardiomyopathy 1W
Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
dilated cardiomyopathy
Inheritance: AD Classification: MODERATE Submitted by: ClinGen
familial isolated dilated cardiomyopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
hypertrophic cardiomyopathy 15
Inheritance: AD Classification: LIMITED Submitted by: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)
hypertrophic cardiomyopathy
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

VCL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VCL	NM_014000.3 link	c.3236T>C	p.Ile1079Thr	missense_variant	Exon 21 of 22	ENST00000211998.10	NP_054706.1	P18206-1V9HWK2B3KXA2
VCL	NM_003373.4 link	c.3032T>C	p.Ile1011Thr	missense_variant	Exon 20 of 21		NP_003364.1	P18206-2A0A024QZN4B3KXA2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VCL	ENST00000211998.10 link	c.3236T>C	p.Ile1079Thr	missense_variant	Exon 21 of 22	1	NM_014000.3	ENSP00000211998.5		P18206-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

228144

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000276

AC:

AN:

1448828

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

719360

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33372

American (AMR)

AF:

0.00

AC:

AN:

42618

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25744

East Asian (EAS)

AF:

0.00

AC:

AN:

39394

South Asian (SAS)

AF:

0.00

AC:

AN:

83850

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52466

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

0.00000181

AC:

AN:

1105646

Other (OTH)

AF:

0.0000167

AC:

AN:

59996

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.538

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 11, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The Ile1079Thr variant in VCL has not been previously reported in individuals wi th cardiomyopathy or in large population studies. Computational prediction tools and conservation analysis do not provide strong support for or against an impac t to the protein. In summary, the clinical significance of the Ile1079Thr varian t is uncertain. -

Cardiovascular phenotype

Uncertain:1

Jan 27, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.3236T>C (p.I1079T) alteration is located in exon 21 (coding exon 21) of the VCL gene. This alteration results from a T to C substitution at nucleotide position 3236, causing the isoleucine (I) at amino acid position 1079 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.81

BayesDel_addAF

Uncertain

0.084

BayesDel_noAF

Benign

-0.12

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.079

T;.

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.96

D;D

M_CAP

Benign

0.042

MetaRNN

Uncertain

0.53

D;D

MetaSVM

Benign

-0.88

MutationAssessor

Uncertain

2.0

M;.

PhyloP100

7.7

PrimateAI

Pathogenic

0.92

PROVEAN

Benign

0.39

N;N

REVEL

Benign

0.17

Sift

Benign

0.45

T;T

Sift4G

Benign

0.34

T;T

Polyphen

0.82

P;P

Vest4

0.72

MutPred

0.53

Gain of relative solvent accessibility (P = 0.0023);.;

MVP

0.17

MPC

2.7

ClinPred

0.78

GERP RS

5.9

Varity_R

0.29

gMVP

0.79

Mutation Taster

=21/79

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over