rs61750603

Positions:

chr12-6016636-A-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP4_StrongBS2_Supporting

The ENST00000261405.10(VWF):c.5191T>A(p.Ser1731Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00116 in 1,614,210 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1731L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00099 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 3 hom. )

Consequence

VWF
ENST00000261405.10 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:6B:2O:1

Conservation

PhyloP100: 1.07

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 Likely_benign. Variant got -4 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), VWF. . Gene score misZ 0.98969 (greater than the threshold 3.09). Trascript score misZ 3.5064 (greater than threshold 3.09). GenCC has associacion of gene with 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.

BP4

Computational evidence support a benign effect (MetaRNN=0.017343968).

BS2

High AC in GnomAd4 at 151 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VWF	NM_000552.5 linkuse as main transcript	c.5191T>A	p.Ser1731Thr	missense_variant	30/52	ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1 linkuse as main transcript	c.5191T>A	p.Ser1731Thr	missense_variant	30/52		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10 linkuse as main transcript	c.5191T>A	p.Ser1731Thr	missense_variant	30/52	1	NM_000552.5	ENSP00000261405	P1	P04275-1
VWF	ENST00000538635.5 linkuse as main transcript	n.421-22702T>A		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes

AF:

0.000992

AC:

151

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.0199

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000955

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.00157

AC:

394

AN:

251490

Hom.:

AF XY:

0.00162

AC XY:

220

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000925

Gnomad ASJ exome

AF:

0.0210

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000196

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00110

Gnomad OTH exome

AF:

0.00261

GnomAD4 exome

AF:

0.00118

AC:

1719

AN:

1461894

Hom.:

Cov.:

AF XY:

0.00122

AC XY:

887

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.000939

Gnomad4 ASJ exome

AF:

0.0211

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000174

Gnomad4 FIN exome

AF:

0.0000749

Gnomad4 NFE exome

AF:

0.000864

Gnomad4 OTH exome

AF:

0.00195

GnomAD4 genome

AF:

0.000991

AC:

151

AN:

152316

Hom.:

Cov.:

AF XY:

0.000886

AC XY:

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.000457

Gnomad4 ASJ

AF:

0.0199

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.000955

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00328

Hom.:

Bravo

AF:

0.00125

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00198

AC:

ExAC

AF:

0.00119

AC:

145

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:6Benign:2Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:2Benign:1Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 25, 2024	Published functional studies including in vitro collagen binding assays showed a reduction in binding to both type I and type III collagen (PMID: 20345715, 25051961); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21967679, 25662333, 25051961, 19506356, 19687512, 26986123, 16870550, 30046704, 31605304, 32394456, 24385719, 23406206, 18036186, 23216583, 32998182, 19630771, 34426522, 30792900, 29924855, 34758185, 34708896, 37163579, 20345715, 11583318, 38762018, 38968155) -
not provided, no classification provided	literature only	Academic Unit of Haematology, University of Sheffield	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 20, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 23, 2022	The p.Ser1731Thr variant in VWF has been reported in at least 3 individuals with clinical features of Von Willebrand disease and 1 homozygous individual with Glanzmann thrombasthenia, and segregated with disease in 2 affected relatives from 2 families. However, it was also identified in 1 individual with an alternate molecular cause of disease and 4 asymptomatic relatives (Ribba 2001 PMID: 11583318, Riddell 2009 PMID: 19687512, Veyradier 2016 PMID: 26986123, Owaidah 2019 PMID: 30792900, Al-Doory 2020). This variant has been identified in 2.1% (217/10370) of Ashkenazi Jewish chromosomes and 0.11% (136/129190) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org) and is reported in ClinVar (Variation ID: 100420). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In vitro functional studies provide some evidence that the p.Ser1731Thr variant may have a partial impact to protein function (Flood 2009 PMID: 20345715, Riddell 2009 PMID: 19687512, Flood 2015 PMID: 25662333); however, these in vitro results may not be biologically relevant. In summary, while the clinical significance of this variant is uncertain, its frequency suggests that it is more likely to be benign. ACMG/AMP Criteria applied: PS3_Supporting, BS1. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	VWF: PS3:Supporting, BS1 -

not specified

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 18, 2021	DNA sequence analysis of the VWF gene demonstrated a sequence change, c.5191T>A, in exon 30 that results in an amino acid change, p.Ser1731Thr. This sequence change has been described in the gnomAD database with a frequency of 2.1% in Ashkenazi Jewish subpopulation (dbSNP rs61750603). This sequence change has been previously described in the heterozygous states in individuals and families with von Willebrand disease (PMIDs: 11583318, 26986123, 19687512, 28971901). The p.Ser1731Thr change affects a highly conserved amino acid residue located in the A3 domain of the VWF protein. Functional studies show p.Ser1731Thr disrupts the binding of VWF to collagen (PMIDs: 11583318, 19687512, 20345715). Due to the lack of sufficient evidence, the clinical significance of the p.Ser1731Thr change remains unknown at this time. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 16, 2024	Variant summary: VWF c.5191T>A (p.Ser1731Thr) results in a conservative amino acid change located in the third VWF type A (A3) domain (IPR002035), which is the main binding site for collagens type I and III (UniProt) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0012 in 1614210 control chromosomes in the gnomAD database, including 5 homozygotes. However, in certain subpopulations, e.g. in the Ashkenazi Jewish the variant was found at a much higher allele frequency. The observed relatively high frequency, together with the homozygous occurrences, might indicate a benign nature for the variant, or alternatively the variant might represent a hypomorphic allele associated with a milder phenotype / reduced penetrance.The variant, c.5191T>A, has been reported in the literature in multiple heterozygous individuals affected with Von Willebrand Disease (e.g. Ribba_2001, Riddell_2009, Veyradier_2016, Borras_2017, Maas_2022), and in a homozygous individual with Glanzmann thrombasthenia (Owaidah 2019). However, in at least one family the variant was also observed in asymptomatic younger family members (Riddell_2009), although they also displayed the biochemical phenotype (i.e. decresed VWF binding to type I collagen; see below). Furthermore, in one of these reported cases a co-occurring pathogenic variant could explain the phenotype (Borras_2017). Several publications reported experimental evidence evaluating an impact on protein function, and in general demonstrated reduced binding to collagen type I, with mostly unaffected binding to collagen type III (e.g. Ribba_2001, Riddell_2009, Flood_2010, Shida_2014, Posch_2018). This finding was confirmed by utilizing a knock-in mouse model (Shida_2014), however authors of the study concluded that mice were still able to initiate platelet adhesion and thrombus formation in their model, demonstrating an important role for collagen-independent pathway(s) of primary hemostasis that likely contribute to the mild bleeding phenotype in patients with VWF collagen-binding mutations. The following publications have been ascertained in the context of this evaluation (PMID: 11583318, 19687512, 26986123, 28971901, 30792900, 20345715, 25051961, 29604837, 34758185, 34708896). ClinVar contains an entry for this variant (Variation ID: 100420). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -

VWF-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 23, 2024

The VWF c.5191T>A variant is predicted to result in the amino acid substitution p.Ser1731Thr. This variant has been reported previously to reduce binding between VWF protein and different collagen types (including collagen I and III) and has been reported, with variable expressivity, in several patients with von Willebrand Disease (Ribba et al. 2001. PubMed ID: 11583318; Flood et al. 2010. PubMed ID: 20345715; Riddell et al. 2009. PubMed ID: 19687512; Veyradier et al. 2016. PubMed ID: 26986123, see figure 6). However, several unaffected family members, who displayed only mildly altered biochemical findings, also harbored this variant, suggesting incomplete penetrance (see, for example, Riddell et al. 2009. PubMed ID: 19687512). This variant was also reported in the homozygous state in an individual with suspected Glanzmann thrombasthenia (Owaidah et al. 2019. PubMed ID: 30792900). This variant is reported in 2.1% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. A different missense change impacting the same amino acid (p.Ser1731Leu) was reported in two siblings with significantly reduced values for von Willebrand factor collagen-binding activity (Fels et al. 2022. PubMed ID: 35104900). Taken together, the VWF c.5191T>A (p.Ser1731Thr) variant is interpreted as likely pathogenic with reduced penetrance and variable expressivity. -

Hereditary von Willebrand disease

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

The c.5191T>A (p.Ser1731Thr) variant has been reported in three studies in which it is found in at least four patients in a heterozygous state (Ribba et al. 2001, Riddell et al. 2009, Veyradier et al. 2016). Control data are unavailable for this variant, which is reported at a frequency of 0.00205 in the European (Non-Finnish) population from the Exome Sequencing Project. This frequency is high in comparison to disease prevalence, but may be explained by a milder phenotype or reduced penetrance. Functional studies including expression of the variant in COS-7 cells demonstrated significantly decreased binding of the variant protein to collagen. Analysis in HEK293T cells showed the p.Ser1731Thr variant affects binding to collagen type I but not type III. Additional functional studies utilizing mouse models, HEK293T cell constructs, flow chamber analysis, and collagen thin films in flow assays support normal expression but reduced collagen binding of the p.Ser1731Thr variant (Flood et al. 2010; Shida et al. 2014; Hansen et al. 2011). Based on the limited number of cases but with supporting functional data, the p.Ser1731Thr variant is classified as a variant of unknown significance but suspicious for pathogenicity for von Willebrand disease. -

von Willebrand disease type 2

Benign:1

Benign, no assertion criteria provided

clinical testing

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

Apr 26, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.096

BayesDel_noAF

Uncertain

0.040

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.39

Eigen

Benign

0.035

Eigen_PC

Benign

-0.046

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.76

M_CAP

Pathogenic

0.40

MetaRNN

Benign

0.017

MetaSVM

Uncertain

0.015

MutationAssessor

Pathogenic

3.0

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-1.1

REVEL

Uncertain

0.64

Sift

Uncertain

0.0050

Sift4G

Pathogenic

0.0010

Polyphen

0.94

Vest4

0.83

MVP

0.71

MPC

0.73

ClinPred

0.059

GERP RS

1.8

Varity_R

0.70

gMVP

0.68

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

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