rs779488376

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 9P and 4B. PVS1PP5BS2

The NM_014000.3(VCL):​c.1713delA​(p.Ala573HisfsTer8) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000018 in 1,613,948 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A571A) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

VCL
NM_014000.3 frameshift

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1

Conservation

PhyloP100: -2.26

Publications

1 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
Variant 10-74095824-CA-C is Pathogenic according to our data. Variant chr10-74095824-CA-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 468811.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
BS2
High AC in GnomAdExome4 at 28 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
VCLNM_014000.3 linkc.1713delA p.Ala573HisfsTer8 frameshift_variant Exon 12 of 22 ENST00000211998.10 NP_054706.1 P18206-1V9HWK2B3KXA2
VCLNM_003373.4 linkc.1713delA p.Ala573HisfsTer8 frameshift_variant Exon 12 of 21 NP_003364.1 P18206-2A0A024QZN4B3KXA2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
VCLENST00000211998.10 linkc.1713delA p.Ala573HisfsTer8 frameshift_variant Exon 12 of 22 1 NM_014000.3 ENSP00000211998.5 P18206-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152180
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.000288
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000398
AC:
10
AN:
251308
AF XY:
0.0000368
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.000695
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000264
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000192
AC:
28
AN:
1461768
Hom.:
0
Cov.:
31
AF XY:
0.0000124
AC XY:
9
AN XY:
727186
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33480
American (AMR)
AF:
0.00
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.000689
AC:
18
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86256
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53338
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5738
European-Non Finnish (NFE)
AF:
0.00000540
AC:
6
AN:
1112006
Other (OTH)
AF:
0.0000662
AC:
4
AN:
60390
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.477
Heterozygous variant carriers
0
2
3
5
6
8
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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
AF:
0.00000657
AC:
1
AN:
152180
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74328
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41456
American (AMR)
AF:
0.00
AC:
0
AN:
15274
Ashkenazi Jewish (ASJ)
AF:
0.000288
AC:
1
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5186
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4830
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10622
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68018
Other (OTH)
AF:
0.00
AC:
0
AN:
2094
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.425
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.000153
Hom.:
0

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Primary dilated cardiomyopathy Pathogenic:1
Apr 10, 2016
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The p.Ala573HisfsX8 variant in VCL has not been previously reported in individua ls with cardiomyopathy though it was identified in 3/121052 of chromosomes by th e Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). This vari ant is predicted to cause a frameshift, which alters the protein?s amino acid se quence beginning at position 573 and leads to a premature termination codon 8 am ino acids downstream. This alteration is then predicted to lead to a truncated o r absent protein. Current evidence suggests that loss of function of the VCL gen e is associated with dilated cardiomyopathy (DCM). This understanding is based u pon approximately 10 patients with infantile- or childhood- onset DCM that were identified with loss-of-function variants in VCL that also segregated with disea se in five additional family members (LMM, unpublished data). Mouse models have also shown that loss of function of the VCL gene leads to cardiac dysfunction, i ncluding dilated cardiomyopathy (DCM) (Zemljic-Harpf 2007). In summary, although additional studies are required to fully establish its clinical significance, t he p.Ala573HisfsX8 variant is likely pathogenic for dilated cardiomyopathy in an autosomal dominant manner. Data from six families tested in our laboratory sugg est over 50% penetrance of the disease in individuals with a loss-of-function va riant. -

Dilated cardiomyopathy 1W Uncertain:1
Dec 30, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Ala573Hisfs*8) in the VCL gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in VCL cause disease. This variant is present in population databases (rs779488376, gnomAD 0.07%). This premature translational stop signal has been observed in individual(s) with clinical features of VCL-related conditions (PMID: 32516855). ClinVar contains an entry for this variant (Variation ID: 468811). 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
PhyloP100
-2.3
Mutation Taster
=1/199
disease causing (ClinVar)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

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

Publications

Other links and lift over

dbSNP: rs779488376; hg19: chr10-75855582; API