rs148619523

Positions:

• chr10-74089213-C-A
• chr10-74089213-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_014000.3(VCL):​c.1040C>A​(p.Pro347Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,748 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P347L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: VCL NM_014000.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.79

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), VCL. . Gene score misZ 2.7082 (greater than the threshold 3.09). Trascript score misZ 4.2375 (greater than threshold 3.09). GenCC has associacion of gene with dilated cardiomyopathy, hypertrophic cardiomyopathy 15, hypertrophic cardiomyopathy, familial isolated dilated cardiomyopathy, dilated cardiomyopathy 1W.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VCL	NM_014000.3	c.1040C>A	p.Pro347Gln	missense_variant	9/22	ENST00000211998.10
VCL	NM_003373.4	c.1040C>A	p.Pro347Gln	missense_variant	9/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VCL	ENST00000211998.10	c.1040C>A	p.Pro347Gln	missense_variant	9/22	1	NM_014000.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461748 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727166

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 13, 2024

The p.P347Q variant (also known as c.1040C>A), located in coding exon 9 of the VCL gene, results from a C to A substitution at nucleotide position 1040. The proline at codon 347 is replaced by glutamine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	T;.
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.45	T;T
MetaSVM	Uncertain	0.25	D
MutationAssessor	Benign	1.8	L;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.8	N;N
REVEL	Uncertain	0.43
Sift	Benign	0.050	D;D
Sift4G	Benign	0.19	T;T
Polyphen		0.90	P;P
Vest4		0.58
MutPred		0.51		Gain of MoRF binding (P = 0.0302);Gain of MoRF binding (P = 0.0302);
MVP		0.18
MPC		1.1
ClinPred		0.89	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.20
gMVP		0.42

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

LitVar

Other links and lift over

dbSNP: rs148619523; hg19: chr10-75848971;