NM_000552.5:c.3943C>T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_000552.5(VWF):c.3943C>T(p.Arg1315Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,604 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1315G) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

VWF
NM_000552.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9O:1

Conservation

PhyloP100: 5.44

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 Pathogenic. Variant got 19 ACMG points.

PM1

In a strand (size 16) in uniprot entity VWF_HUMAN there are 14 pathogenic changes around while only 0 benign (100%) in NM_000552.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr12-6019475-G-C is described in Lovd as [Pathogenic].

PP2

Missense variant in the VWF gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 149 curated pathogenic missense variants (we use a threshold of 10). The gene has 28 curated benign missense variants. Gene score misZ: 0.98969 (below the threshold of 3.09). Trascript score misZ: 3.5064 (above the threshold of 3.09). GenCC associations: The gene is linked to von Willebrand disease type 2M, hereditary von Willebrand disease, von Willebrand disease type 2B, von Willebrand disease type 2N, von Willebrand disease 2, von Willebrand disease type 2A, von Willebrand disease 3, von Willebrand disease 1.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.981

PP5

Variant 12-6019475-G-A is Pathogenic according to our data. Variant chr12-6019475-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 100310.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-6019475-G-A is described in Lovd as [Pathogenic]. Variant chr12-6019475-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VWF	NM_000552.5 link	c.3943C>T	p.Arg1315Cys	missense_variant	Exon 28 of 52	ENST00000261405.10	NP_000543.3	P04275-1
VWF	XM_047429501.1 link	c.3943C>T	p.Arg1315Cys	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.3943C>T	p.Arg1315Cys	missense_variant	Exon 28 of 52	1	NM_000552.5	ENSP00000261405.5	P04275-1
VWF	ENST00000538635.5 link	n.421-25541C>T		intron_variant	Intron 5 of 5	4
VWF	ENST00000539641.1 link	n.*53C>T		downstream_gene_variant		3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461604

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727108

show subpopulations

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3Other:1

Oct 19, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1_strong, PP3, PP5, PM2_moderate, PS3, PS4_moderate -

Academic Unit of Haematology, University of Sheffield

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Nov 14, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The VWF c.3943C>T; p.Arg1315Cys variant (rs61749395, ClinVar Variation ID: 100310) is reported in the literature in several individuals and families affected with von Willebrand disease (VWD) types 1, 2A, and 2M (selected references: Borras 2017, Casana 1998, Goodeve 2007, James 2007, Maas 2022, Ribba 2001, Robertson 2011, Seidizadeh 2024, Starke 2013). This variant is also reported in one homozygous individual and one compound heterozygous individual with VWD type 3 (Elayaperumal 2018, Zhang 1995). The p.Arg1315Cys variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Additionally, other amino acid substitutions at this codon (Gly, His, Leu, Pro) have been reported in individuals with VWD (Elayaperumal 2018, Goodeve 2007, Veyradier 2016). Computational analyses predict that the p.Arg1315Cys variant is deleterious (REVEL: 0.769). Functional analyses show decreased mRNA and protein expression, loss of high-molecular and intermediate-molecular weight multimers, significant decrease in platelet binding, and increased retention in Weibel-Palade bodies (Ribba 2001, Starke 2013). Based on available information, this variant is considered to be likely pathogenic. References: Borras N et al. Molecular and clinical profile of von Willebrand disease in Spain (PCM-EVW-ES): comprehensive genetic analysis by next-generation sequencing of 480 patients. Haematologica. 2017 Dec;102(12):2005-2014. PMID: 28971901. Casana P et al. Search for mutations in a segment of the exon 28 of the human von Willebrand factor gene: new mutations, R1315C and R1341W, associated with type 2M and 2B variants. Am J Hematol. 1998 Sep;59(1):57-63. PMID: 9723578. Elayaperumal S et al. Type-3 von Willebrand disease in India-Clinical spectrum and molecular profile. Haemophilia. 2018 Nov;24(6):930-940. PMID: 29984440. Goodeve A et al. Phenotype and genotype of a cohort of families historically diagnosed with type 1 von Willebrand disease in the European study, Molecular and Clinical Markers for the Diagnosis and Management of Type 1 von Willebrand Disease (MCMDM-1VWD). Blood. 2007 Jan 1;109(1):112-21. PMID: 16985174. James PD et al. The mutational spectrum of type 1 von Willebrand disease: Results from a Canadian cohort study. Blood. 2007 Jan 1;109(1):145-54. PMID: 17190853. 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. Ribba AN et al. The arginine-552-cysteine (R1315C) mutation within the A1 loop of von Willebrand factor induces an abnormal folding with a loss of function resulting in type 2A-like phenotype of von Willebrand disease: study of 10 patients and mutated recombinant von Willebrand factor. Blood. 2001 Feb 15;97(4):952-9. PMID: 11159522. Robertson JD et al. Expanded phenotype-genotype correlations in a pediatric population with type 1 von Willebrand disease. J Thromb Haemost. 2011 Sep;9(9):1752-60. PMID: 21711445. Seidizadeh O et al. Type 2M/2A von Willebrand disease: a shared phenotype between type 2M and 2A. Blood Adv. 2024 Apr 9;8(7):1725-1736. PMID: 38315875. Starke RD et al. Cellular and molecular basis of von Willebrand disease: studies on blood outgrowth endothelial cells. Blood. 2013 Apr 4;121(14):2773-84. PMID: 23355534. Veyradier A et al. A Laboratory Phenotype/Genotype Correlation of 1167 French Patients From 670 Families With von Willebrand Disease: A New Epidemiologic Picture. Medicine (Baltimore). 2016 Mar;95(11):e3038. PMID: 26986123 Zhang Z et al. Effects of the mutant von Willebrand factor gene in von Willebrand disease. Hum Genet. 1995 Oct;96(4):388-94. PMID: 7557958. -

Jun 26, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in affected individuals with VWD Type 1, 2A, 2M, or 3 (PMIDs: 34758185 (2022), 33556167 (2021), 30817071 (2019), 29984440 (2018), 28536718 (2017), 23355534 (2013), 21711445 (2011), 17190853 (2007), 11159522 (2001), 9723578 (1998), and 8088787 (1994)). Functional analysis of the variant showed decreased expression, abnormal folding, decrease of intermediate-molecular weight and high molecular weight multimers as well as a loss of function of vWF in the presence of either ristocetin or botrocetin (PMID: 11159522 (2001)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as likely pathogenic. -

Hereditary von Willebrand disease

Pathogenic:2

Feb 01, 2019

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

von Willebrand disorder

Pathogenic:1

Jan 03, 2025

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: VWF c.3943C>T (p.Arg1315Cys) results in a non-conservative amino acid change located in the von Willebrand factor, type A domain (IPR002035) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250994 control chromosomes (gnomAD). c.3943C>T has been reported in the literature in individuals affected with Von Willebrand Disease (Casaa_1998, Goodeve_2006, Starke_2013). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and this variant disrupted protein function (Starke_2013). The following publications have been ascertained in the context of this evaluation (PMID: 9723578, 18805962, 16985174, 23355534). ClinVar contains an entry for this variant (Variation ID: 100310). Based on the evidence outlined above, the variant was classified as pathogenic. -

von Willebrand disease type 2

Pathogenic:1

Apr 26, 2022

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

VWF-related disorder

Pathogenic:1

Aug 01, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The VWF c.3943C>T variant is predicted to result in the amino acid substitution p.Arg1315Cys. This variant has been reported in individuals with Von Willebrand Disease (VWD) of types 1, 2A, 2M or 3 (Casaña et al. 1998. PubMed ID: 9723578; James et al. 2007. PubMed ID: 17190853; Starke et al. 2013. PubMed ID: 23355534; Liang et al. 2017. PubMed ID: 28536718; Elayaperumal et al. 2018. PubMed ID: 29984440; Freitas et al. 2019. PubMed ID: 30817071). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic. -

von Willebrand disease type 1

Pathogenic:1

Dec 10, 2020

Laboratory of Hematology, Radboud University Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.69

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.62

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

1.0

M_CAP

Pathogenic

0.66

MetaRNN

Pathogenic

0.98

MetaSVM

Pathogenic

0.94

MutationAssessor

Pathogenic

3.8

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-1.4

REVEL

Pathogenic

0.77

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.96

MutPred

0.86

Gain of catalytic residue at E1320 (P = 0);

MVP

0.92

MPC

1.1

ClinPred

1.0

GERP RS

4.0

Varity_R

0.58

gMVP

0.91

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