rs121917776

chr10-74112086-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2 BS2

The NM_014000.3(VCL):c.2923C>T(p.Arg975Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000471 in 1,614,168 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. R975Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000051 (0 hom.)
• Consequence: VCL NM_014000.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:2 U:3
• Conservation: PhyloP100: 7.36

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 Likely_benign. Variant got -3 ACMG points.

• PP2: Missense variant where missense usually causes diseases, VCL
• BS2: High AC in GnomAdExome at 25 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VCL	NM_014000.3	c.2923C>T	p.Arg975Trp	missense_variant	19/22	ENST00000211998.10
VCL	NM_003373.4	c.2746-2098C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VCL	ENST00000211998.10	c.2923C>T	p.Arg975Trp	missense_variant	19/22	1	NM_014000.3
VCL	ENST00000372755.7	c.2746-2098C>T		intron_variant		1		P1
VCL	ENST00000623461.3	n.5549-2098C>T		intron_variant, non_coding_transcript_variant		1
VCL	ENST00000624354.3	c.*2678C>T		3_prime_UTR_variant, NMD_transcript_variant	18/21	2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000994 AC: 25 AN: 251424 Hom.: 0 AF XY: 0.000118 AC XY: 16 AN XY: 135882

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 SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.0000506 AC: 74 AN: 1461876 Hom.: 0 Cov.: 35 AF XY: 0.0000454 AC XY: 33 AN XY: 727238

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.000393

Gnomad4 NFE exome AF: 0.0000405

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152292 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74466

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000556 Hom.: 0

Bravo AF: 0.0000113

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000132 AC: 16

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2 Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Dilated cardiomyopathy 1W Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 06, 2024	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 975 of the VCL protein (p.Arg975Trp). This variant is present in population databases (rs121917776, gnomAD 0.03%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) (PMID: 11815424, 17097056). ClinVar contains an entry for this variant (Variation ID: 12197). 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 disruptive. Experimental studies have shown that this missense change affects VCL function (PMID: 23159629, 27503891). 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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 20, 2006	- -

Hypertrophic cardiomyopathy 15 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 20, 2006

- -

Dilated cardiomyopathy 1W;C2750459:Hypertrophic cardiomyopathy 15 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 28, 2021

- -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 10, 2020

The p.R975W variant (also known as c.2923C>T), located in coding exon 19 of the VCL gene, results from a C to T substitution at nucleotide position 2923. The arginine at codon 975 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration was previously reported in a proband with dilated cardiomyopathy (DCM), an asymptomatic aunt with DCM, a daughter with ventricular dilation, and was also identified in an unaffected sibling. The same study reported this alteration to impact actin filament organization in vitro (Olson TM et al. Circulation. 2002;105:431-7). This alteration was also reported in an individual with apical variant hypertrophic cardiomyopathy (HCM) (Vasile VC et al. Biochem Biophys Res Commun. 2006;349:709-15). This variant has also been seen in exome cohorts, but cardiovascular history was not provided (Andreasen C et al. Eur J Hum Genet. 2013;21(9):918-28). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. 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	Uncertain	0.39
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.26
Cadd	Pathogenic	33
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Benign	0.012	T
MetaRNN	Uncertain	0.59	D
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.3	L
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.35
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.99	D
Vest4		0.85
MVP		0.15
MPC		0.24
ClinPred		0.44	T
GERP RS		6.2
Varity_R		0.57
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.21		Position offset: 26

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

Publications

LitVar

Other links and lift over

dbSNP: rs121917776; hg19: chr10-75871844;