12-6019474-C-T

Position:

chr12-6019474-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PP4_ModeratePP3PM2_SupportingPS4_Moderate

This summary comes from the ClinGen Evidence Repository: The missense variant NM_000552.5(VWF):c.3944G>A (p.Arg1315His) is a rare variant which occurs at a Grpmax filtering allele frequency in gnomAD v4.1 is 0.00002255 (based on 4/60004 alleles in the Admixed American population), which is lower than the ClinGen VWD VCEP threshold of <0.0001 (PM2_supporting). The computational predictor REVEL gives a score of 0.815, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). Portuguese patient P30, with this variant, (PMID:26988807) displayed excessive mucocutaneous bleeding (bleeding score 7) as well as a laboratory phenotype of normal multimers, low VWF:RCo/VWF:Ag ratio (VWF:RCo 11%, VWF:Ag 16%, ratio 0.69) and an abnormal collagen binding assay (VWF:CB 19%), which together are highly specific for VWD type 2M (PP4_moderate). At least 3 additional probands have been reported with this variant and VWD reported as type 1 (but with VWF:RCo/VWF:Ag ratio <0.7) or type 2M (PMID:26986123, 25689060, 16985174; PS4_moderate). In summary, the variant meets the criteria to be classified as Likely Pathogenic for von Willebrand disease type 2M based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: PM2_supporting, PP3, PP4_moderate, PS4_moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA228504/MONDO:0015630/081

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

VWF
NM_000552.5 missense

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:5U:1O:1

Conservation

PhyloP100: 6.99

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:

VWF (HGNC:):

VWF links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PS4

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

PM2

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/exons	MANE	Protein	UniProt
VWF	NM_000552.5 linkuse as main transcript	c.3944G>A	p.Arg1315His	missense_variant	28/52	ENST00000261405.10	NP_000543.3	P04275-1
VWF	XM_047429501.1 linkuse as main transcript	c.3944G>A	p.Arg1315His	missense_variant	28/52		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10 linkuse as main transcript	c.3944G>A	p.Arg1315His	missense_variant	28/52	1	NM_000552.5	ENSP00000261405.5		P04275-1
VWF	ENST00000538635.5 linkuse as main transcript	n.421-25540G>A		intron_variant		4

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

250994

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135700

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000178

AC:

AN:

1461606

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

727108

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000126

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000847

Hom.:

Bravo

AF:

0.000151

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:5Uncertain:1Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:2Uncertain:1Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 28, 2023	The VWF c.3944G>A; p.Arg1315His variant (rs61749396) is reported in the literature in multiple individuals affected with Von Willebrand disease types 1, 2m and 3 (Elayaperumal 2018, Goodeve 2007, Veyradier 2016). This variant is also reported in ClinVar (Variation ID: 100311) and is found in the general population with an overall allele frequency of 0.002% (6/250,994 alleles) in the Genome Aggregation Database. Additionally, other amino acid substitutions at this codon (Cys, Gly, Leu, Pro) have been reported in individuals with VWF and are considered disease causative (Elayaperumal 2018, Goodeve 2007, Veyradier 2016). Computational analyses predict that this variant is deleterious (REVEL: 0.815). Based on available information, this variant is considered to be likely pathogenic. References: 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. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 12, 2022	The frequency of this variant in the general population, 0.000087 (3/34586 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals affected with Type 1 von Willebrand disease (vWD) (PMID: 16985174 (2007)), Type 2 vWD with a collagen binding defect (PMID: 26986123 (2016), 28083987 (2017)), and Type 3 vWD (PMID: 29984440 (2018)). 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, we are unable to determine the clinical significance of this variant. -
not provided, no classification provided	literature only	Academic Unit of Haematology, University of Sheffield	-	- -

von Willebrand disease type 2

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genetics and Molecular Pathology, SA Pathology

Jul 26, 2019

- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 14, 2024

The c.3944G>A (p.R1315H) alteration is located in exon 28 (coding exon 27) of the VWF gene. This alteration results from a G to A substitution at nucleotide position 3944, causing the arginine (R) at amino acid position 1315 to be replaced by a histidine (H). for autosomal dominant, autosomal recessive Von Willebrand disease; however, its clinical significance for autosomal dominant von Willebrand disease Type 2B is uncertain Based on data from gnomAD, the A allele has an overall frequency of 0.002% (6/250994) total alleles studied. The highest observed frequency was 0.016% (1/6124) of Other alleles. This variant has been identified in the heterozygous state or in conjunction with other VWF variants in individuals with features consistent with various forms of von Willebrand disease; in at least one instance, the variants were identified in trans (Álvarez-Laderas, 2015; Fidalgo, 2017; Elayaperumal, 2018). Two other alterations at the same codon, c.3943C>T (p.R1315C) and c.3944G>T (p.R1315L), have been detected in multiple individuals with autosomal dominant/autosomal recessive loss of function von Willebrand disease forms (Baronciani, 2006; Elayaperumal, 2018). This amino acid position is well conserved in available vertebrate species. Based on internal structural analysis, R1315H is deleterious. The variant is moderately destabilizing to the local structure. The variant is not on an interface. The variant has no nearby pathogenic variants and has no nearby benign variants (Ribba, 2001; Ambry internal data). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

von Willebrand disease type 1

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Zotz-Klimas Genetics Lab, MVZ Zotz Klimas

Oct 09, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.50

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

M_CAP

Pathogenic

0.47

MetaRNN

Pathogenic

0.87

MetaSVM

Pathogenic

0.90

MutationAssessor

Pathogenic

3.8

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-2.0

REVEL

Pathogenic

0.81

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0020

Polyphen

0.98

Vest4

0.75

MVP

0.92

MPC

1.0

ClinPred

0.97

GERP RS

5.0

Varity_R

0.60

gMVP

0.88

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