12-6019474-C-T

Variant names:

• chr12-6019474-C-T
• rs61749396
• NM_000552.5:c.3944G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PS4_Moderate PP4_Moderate PP3 PM2_Supporting

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
• Clinical Significance: Likely pathogenic reviewed by expert panel P:6 U:2 O:1
• Conservation: PhyloP100: 6.99
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• hereditary von Willebrand disease

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• von Willebrand disease type 2B

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• von Willebrand disease 2

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• von Willebrand disease 1

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• von Willebrand disease type 2A

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• von Willebrand disease type 2M

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• von Willebrand disease 3

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• von Willebrand disease type 2N

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000552.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VWF	NM_000552.5	MANE Select	c.3944G>A	p.Arg1315His	missense	Exon 28 of 52	NP_000543.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VWF	ENST00000261405.10	TSL:1 MANE Select	c.3944G>A	p.Arg1315His	missense	Exon 28 of 52	ENSP00000261405.5
	VWF	ENST00000538635.5	TSL:4	n.421-25540G>A		intron	N/A
	VWF	ENST00000539641.1	TSL:3	n.*54G>A		downstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152192 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.0000239 AC: 6 AN: 250994 AF XY: 0.0000295

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000178 AC: 26 AN: 1461606 Hom.: 0 Cov.: 38 AF XY: 0.0000193 AC XY: 14 AN XY: 727108

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.0000671 AC: 3 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1111818

Other (OTH) AF: 0.000116 AC: 7 AN: 60378

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152192 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74342

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41438

American (AMR) AF: 0.0000654 AC: 1 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2088

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000847 Hom.: 0

Bravo AF: 0.000151

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Likely pathogenic

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

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:2 Uncertain:2 Other:1

Apr 16, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in multiple unrelated patients with VWD types 1 or 2M in published literature (PMID: 29984440, 26988807, 25689060); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 16985174, 26986123, 34426522, 37647632, 26988807, 29984440, 25689060)

Sep 14, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The VWF c.3944G>A (p.Arg1315His) variant has been reported in the published literature in heterozygous or compound heterozygous state in individuals affected with Type 1 von Willebrand disease (vWD) (PMIDs: 16985174 (2007), 25689060 (2015) and 37845247 (2023)), Type 2 vWD with a collagen binding defect (PMIDs: 25689060 (2015), 26986123 (2016), and 28083987 (2017)), and Type 3 vWD (PMID: 29984440 (2018)). The frequency of this variant in the general population, 0.000087 (3/34586 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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.

Academic Unit of Haematology, University of Sheffield

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Sep 26, 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.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.

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Inborn genetic diseases Pathogenic:1

Jun 14, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 (&Aacute;lvarez-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 2 Pathogenic:1

Jul 26, 2019

Genetics and Molecular Pathology, SA Pathology

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

von Willebrand disease type 2M Pathogenic:1

Aug 12, 2024

ClinGen von Willebrand Disease Variant Curation Expert Panel, ClinGen

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

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.

von Willebrand disease type 1 Pathogenic:1

Oct 09, 2023

Zotz-Klimas Genetics Lab, MVZ Zotz Klimas

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.50	T
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		7.0
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-2.0	N
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.98	D
Vest4		0.75
MVP		0.92
MPC		1.0
ClinPred		0.97	D
GERP RS		5.0
Varity_R		0.60
gMVP		0.88
Mutation Taster		=8/92	disease causing

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

Other links and lift over

dbSNP: rs61749396; hg19: chr12-6128640;