rs141211612

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP3PP1PP4_Moderate

This summary comes from the ClinGen Evidence Repository: NM_000552.5(VWF):c.4130C>T is a missense variant in VWF that replaces alanine with valine at position 1377. At least 1 patient with this variant, in combination with p.Arg1379Cys (ClinVar 100333; Pathogenic VWD type 1) in cis, displayed excessive mucocutaneous bleeding as well as laboratory phenotypes of a normal multimer pattern, low VWF:RCo/VWF:Ag ratio (0.6 to 0.7), and decreased GP1b binding assay which together are highly specific for VWD type 2M (PP4_moderate, PMID:27785872). The p.Ala1377Val and p.Arg1379Cys variants have been reported in cis in 3 additional probands with high mucocutaneous bleeding as well as laboratory phenotypes of a normal multimer pattern, low VWF:RCo/VWF:Ag ratio (0.6 to 0.7), and decreased GP1b binding assay, but the four patients from Milan show the same short tandem repeats nearby, indicating the possibility of a common ancestor. The proband of Family VIII (PMID:35452508) has 3 additional type 2M diagnosed individuals, 2 are counted here with VWF Act/ VWF:Ag ratio <=0.42 (the other is 0.75). Each individual is heterozygous for p.A1377V; p.R1379C (PP1). The Grpmax filtering allele frequency of this variant in gnomAD v4.1 is 0.001967 (based on 170/75034 alleles in the African / African-American population), which is lower than the ClinGen VWD VCEP threshold for BS1 (>0.01) and higher than the threshold for PM2_Supporting (<0.0001). GP1b-alpha binding assay performed with recombinant VWF expressed by HEK-293 cells showed severely decreased binding when p.Ala1377Val was combined with the p.Arg1379Cys variant, indicating that the combination of these two variants has a damaging effect on protein function. PS3_Supporting was not met because the individual p.Ala1377Val and p.Arg1379Arg mutants showed approximately wild-type binding to GpIb-alpha (PMID:27785872). The computational predictor REVEL gives a score of 0.805, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). In summary, this variant meets the criteria to be classified as a variant of unknown significance for hereditary von Willebrand disease based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: PP4_Moderate, PP3, PP1. (Rule specifications for von Willebrand disease type 2A, 2B and 2M v1.0.0; date of approval 08/12/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA6402597/MONDO:0019565/090

Frequency

Genomes: 𝑓 0.00060 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000072 ( 0 hom. )

Consequence

VWF
NM_000552.5 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:6

Conservation

PhyloP100: 9.22

Variant links:

Genes affected

VWF (HGNC:12726): (von Willebrand factor) This gene encodes a glycoprotein involved in hemostasis. The encoded preproprotein is proteolytically processed following assembly into large multimeric complexes. These complexes function in the adhesion of platelets to sites of vascular injury and the transport of various proteins in the blood. Mutations in this gene result in von Willebrand disease, an inherited bleeding disorder. An unprocessed pseudogene has been found on chromosome 22. [provided by RefSeq, Oct 2015]

VWF links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PP1

For more information check the summary or visit ClinGen Evidence Repository.

PP3

For more information check the summary or visit ClinGen Evidence Repository.

PP4

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VWF	NM_000552.5 link	c.4130C>T	p.Ala1377Val	missense_variant	Exon 28 of 52	ENST00000261405.10	NP_000543.3	P04275-1
VWF	XM_047429501.1 link	c.4130C>T	p.Ala1377Val	missense_variant	Exon 28 of 52		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
VWF	ENST00000261405.10 link	c.4130C>T	p.Ala1377Val	missense_variant	Exon 28 of 52	1	NM_000552.5	ENSP00000261405.5	P04275-1
VWF	ENST00000538635.5 link	n.421-25354C>T		intron_variant	Intron 5 of 5	4
VWF	ENST00000539641.1 link	n.*240C>T		downstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.000598

AC:

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000211

AC:

AN:

250788

Hom.:

AF XY:

0.000184

AC XY:

AN XY:

135634

show subpopulations

Gnomad AFR exome

AF:

0.00267

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000718

AC:

105

AN:

1461650

Hom.:

Cov.:

AF XY:

0.0000605

AC XY:

AN XY:

727134

show subpopulations

Gnomad4 AFR exome

AF:

0.00239

Gnomad4 AMR exome

AF:

0.000246

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

AF:

0.000598

AC:

AN:

152240

Hom.:

Cov.:

AF XY:

0.000497

AC XY:

AN XY:

74426

show subpopulations

Gnomad4 AFR

AF:

0.00217

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000594

Hom.:

Bravo

AF:

0.000691

ESP6500AA

AF:

0.00272

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000181

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Oct 30, 2018

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 12, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: VWF c.4130C>T (p.Ala1377Val) results in a non-conservative amino acid change located in the von Willebrand factor, type A (IPR002035) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00021 in 250788 control chromosomes. c.4130C>T has been reported in the literature in individuals affected with Von Willebrand Disease, without strong evidence for causality (example, Maas_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Von Willebrand Disease. Co-occurrences with other pathogenic variant(s) have been reported in four individuals affected with Von Willebrand Disease (in cis along with VWF c.4135C>T, p.Arg1379Cys), providing supporting evidence for a benign role (Pagliari_2016). At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in about 50% of normal VWF levels in medium and cell lysates using an ELISA assay (Pagliari_2016). The following publications have been ascertained in the context of this evaluation (PMID: 34758185, 27785872). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (VUS, n=2, Likely benign, n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided

Uncertain:2

Jun 19, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The VWF c.4130C>T; p.Ala1377Val variant (rs141211612, ClinVar Variation ID: 619750) is reported in the literature an individual with von Willebrand disease type 1 (VWD; Alzahrani 2023) and an individual with VWD type 2M that had a second VWF variant detected with a normal multimer pattern (Maas 2022). Additionally, four individuals with VWD type 2M were found to have a VWF variant (p.Arg1379Cys) in cis to p.Ala1377Val, and all had nearly normal multimer patterns (Pagliari 2016). In vitro functional analyses of the Ala1377Val mutant found slightly decreased expression but slightly increased binding to recombinant glycoprotein Iba; however, the Ala1377Val-Arg1379Cys mutant decreased recombinant glycoprotein Iba binding (Pagliari 2016). The p.Ala1377Val variant is found in the African/African-American population with an allele frequency of 0.25% (62/24,834 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses predict that this variant is deleterious (REVEL: 0.805). However, given the lack of clinical and functional data of p.Ala1377Val in isolation, the significance of this variant is uncertain at this time. References: Alzahrani FM et al. Phenotypic and genotypic (exon 28) characterization of patients diagnosed with von Willebrand disease type 1 in Eastern Saudi Arabia. J Med Life. 2023 Mar;16(3):428-433. PMID: 37168293. Maas DPMSM et al. Von Willebrand disease type 2M: Correlation between genotype and phenotype. J Thromb Haemost. 2022 Feb;20(2):316-327. PMID: 34758185. Pagliari MT et al. von Willebrand disease type 1 mutation p.Arg1379Cys and the variant p.Ala1377Val synergistically determine a 2M phenotype in four Italian patients. Haemophilia. 2016 Nov;22(6):e502-e511. PMID: 27785872. -

Oct 23, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PALB2 c.503C>A (p.Ser168*) variant causes the premature termination of PALB2 protein synthesis. This variant has been reported in the published literature in an individual with Type 1 (PMID: 37168293 (2023)) and individuals/families with Type 2M Von Willebrand Disease (PMIDs: 27785872 (2016), 34758185 (2022), 35452508 (2022), and 36754679 (2023)). Functional studies found that this variant did not compromise vWF capacity to bind the GpIba receptor, resulted in normal vWF protein levels and normal multimers (PMIDs: 27785872 (2016) and 34758185 (2022)). However, inconclusive functional evidence for the variant showed either normal (PMID: 27785872 (2016)) or reduced vWF activity (PMID: 34758185 (2022)) with enhanced VWF clearance (PMID: 36754679 (2023)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. -

von Willebrand disease type 2

Uncertain:1

Apr 26, 2022

Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hereditary von Willebrand disease

Uncertain:1

Aug 12, 2024

ClinGen von Willebrand Disease Variant Curation Expert Panel, ClinGen

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

NM_000552.5(VWF):c.4130C>T is a missense variant in VWF that replaces alanine with valine at position 1377. At least 1 patient with this variant, in combination with p.Arg1379Cys (ClinVar 100333; Pathogenic VWD type 1) in cis, displayed excessive mucocutaneous bleeding as well as laboratory phenotypes of a normal multimer pattern, low VWF:RCo/VWF:Ag ratio (0.6 to 0.7), and decreased GP1b binding assay which together are highly specific for VWD type 2M (PP4_moderate, PMID: 27785872). The p.Ala1377Val and p.Arg1379Cys variants have been reported in cis in 3 additional probands with high mucocutaneous bleeding as well as laboratory phenotypes of a normal multimer pattern, low VWF:RCo/VWF:Ag ratio (0.6 to 0.7), and decreased GP1b binding assay, but the four patients from Milan show the same short tandem repeats nearby, indicating the possibility of a common ancestor. The proband of Family VIII (PMID: 35452508) has 3 additional type 2M diagnosed individuals, 2 are counted here with VWF Act/ VWF:Ag ratio <=0.42 (the other is 0.75). Each individual is heterozygous for p.A1377V; p.R1379C (PP1). The Grpmax filtering allele frequency of this variant in gnomAD v4.1 is 0.001967 (based on 170/75034 alleles in the African / African-American population), which is lower than the ClinGen VWD VCEP threshold for BS1 (>0.01) and higher than the threshold for PM2_Supporting (<0.0001). GP1b-alpha binding assay performed with recombinant VWF expressed by HEK-293 cells showed severely decreased binding when p.Ala1377Val was combined with the p.Arg1379Cys variant, indicating that the combination of these two variants has a damaging effect on protein function. PS3_Supporting was not met because the individual p.Ala1377Val and p.Arg1379Arg mutants showed approximately wild-type binding to GpIb-alpha (PMID: 27785872). The computational predictor REVEL gives a score of 0.805, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). In summary, this variant meets the criteria to be classified as a variant of unknown significance for hereditary von Willebrand disease based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: PP4_Moderate, PP3, PP1. (Rule specifications for von Willebrand disease type 2A, 2B and 2M v1.0.0; date of approval 08/12/2024) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Uncertain

0.094

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.48

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.97

M_CAP

Pathogenic

0.83

MetaRNN

Benign

0.079

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.8

PrimateAI

Uncertain

0.48

PROVEAN

Benign

-1.9

REVEL

Pathogenic

0.81

Sift

Uncertain

0.0020

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.64

MVP

0.96

MPC

0.84

ClinPred

0.25

GERP RS

4.1

Varity_R

0.64

gMVP

0.82

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over