Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_000552.5(VWF):c.4196G>A (p.Arg1399His)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA114133

293 (ClinVar)

Gene: VWF

Condition: hereditary von Willebrand disease

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: e970678e-3612-42d7-a192-6ae9acc6b1bc

Approved on: 2024-08-13

Published on: 2024-08-13

HGVS expressions

NM_000552.5:c.4196G>A

NM_000552.5(VWF):c.4196G>A (p.Arg1399His)

NC_000012.12:g.6019222C>T

CM000674.2:g.6019222C>T

NC_000012.11:g.6128388C>T

CM000674.1:g.6128388C>T

NC_000012.10:g.5998649C>T

NG_009072.1:g.110449G>A

NG_009072.2:g.110449G>A

ENST00000261405.10:c.4196G>A

ENST00000261405.9:c.4196G>A

ENST00000538635.5:n.421-25288G>A

NM_000552.3:c.4196G>A

NM_000552.4:c.4196G>A

Uncertain Significance

PM5_Supporting BS1 BP5 PS3 PP4 PP3

PS4 PM6

Evidence Links 0

Expert Panel

von Willebrand Disease VCEP

Criteria Specification Information

Criteria Specification: ClinGen von Willebrand Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for VWF Version 1.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

von Willebrand Disease VCEP

The NM_000552.5:c.4196G>A variant in VWF is a missense variant predicted to cause substitution of arginine by histidine at amino acid 1399. The Arg1399His variant has a relatively high Grpmax filtering allele frequency in gnomAD v4.1 of 0.01289 (based on 15410/1179858 alleles in the European non-Finnish population), which is higher than the ClinGen VWD VCEP threshold (>0.01; BS1). At least 4 patients with this variant displayed excessive mucocutaneous bleeding as well as the laboratory phenotype of an abnormal collagen binding assay, which together are consistent with VWD Type 2M (PP4, PS4_Moderate), however, all patients exhibited a VWF:RCo/VWF:Ag ratio between 0.7 and 1.5 (PMID: 22507569, PMID: 28083987, PMID: 28971901). This variant has also been observed in at least 2 patients with an alternate molecular basis for disease, one of whom exhibited VWD Type 2B phenotypes and harbored the c.3916C>T (p.Arg1306Trp) variant in cis (PMID: 1672694), which is classified as pathogenic for VWD Type 2B by the ClinGen VWD VCEP. The second patient exhibited a VWD Type 2M phenotype and harbored this variant as well as the c.4225G>T (p.Val1409Phe) variant, which is classified as likely pathogenic for VWD Type 2M by the ClinGen VWD VCEP (PMID: 28971901). The computational predictor REVEL gives a score of 0.698, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). Another missense variant in the same codon, NM_000552.5(VWF):c.4195C>T (p.Arg1399Cys), has been reported in multiple patients with VWD Type 2M (PMID: 17000885, PMID: 26988807, PMID: 28083987). This variant has been classified as likely pathogenic by the ClinGen VWD VCEP (PM5_supporting). Multiple functional studies show a deleterious effect on protein function, including a hydrodynamic mouse model showing >75% loss of both collagen 4 binding and platelet adhesion PMID: 25662333) and a knock-in mouse model showing decreased VWF binding to collagen IV but not collagen III, decreased platelet adhesion, and increased bleeding, indicating a hypomorphic effect (PMID: 30565388). Exogenous expression of the p.Arg1399His mutant in 293 cells identified undetectable binding to type VI (PMID: 22507569) and type IV collagen (PMID: 25662333) (PS3). In summary, this variant meets the criteria to be classified as a Variant of Unknown Significance for von Willebrand disease type 2M based on the ACMG/AMP criteria applied, as specified by the ClinGen von Willebrand disease Variant Curation Expert Panel: PS3, PM5_supporting, PP3, PP4, BP5, BS1. (VCEP Rule specifications for von Willebrand disease type 2A, 2B and 2M v1.0.0; date of approval 08/13/2024)

PM5_Supporting

Another missense variant in the same codon, NM_000552.5(VWF):c.4195C>T (p.Arg1399Cys), has been reported in multiple patients with VWD Type 2M (PMID: 17000885, PMID: 26988807, PMID: 28083987). This variant has been classified as likely pathogenic by the ClinGen VWD VCEP (PM5_supporting).

BS1

The Grpmax filtering allele frequency in gnomAD v4.1 is 0.01289 (based on 15410/1179858 alleles in the European non-Finnish population), which is higher than the ClinGen VWD VCEP threshold (>0.01) for BS1, and therefore meets this criterion (BS1).

BP5

This variant has been observed in at least 2 patients with an alternate molecular basis for disease. The variant has been observed in cis with the variant NM_000552.5(VWF):c.3916C>T (p.Arg1306Trp) (PMID: 1672694), which is classified as pathogenic for VWD Type 2B by the ClinGen VWD VCEP, in multiple individuals with VWD Type 2B phenotypes (moderately severe bleeding disorder, some with thrombocytopenia, prolonged bleeding time, normal to low factor VIII procoagulant activity, normal to low vWF antigen, low plasma ristocetin cofactor activity, decreased circulating high molecular weight vWF multimers, enhanced RIPA at a low concentration of ristocetin, and the absence of platelet aggregation). The phase of the variants was confirmed by Sanger sequencing of multiple restriction fragment clones from patient samples (BP5). The variant was also observed in a VWD Type 2M patient in trans with the NM_000552.5:c.4225G>T (p.Val1409Phe), which is classified as likely pathogenic for VWD Type 2M by the ClinGen VWD VCEP (PMID: 28971901).

PS3

A hydrodynamic mouse model expressing p.Arg1399His showed >75% loss of both collagen 4 binding and platelet adhesion, indicating that the variant has a damaging effect on protein function (PS3; PMID: 25662333). A mouse model with heterozygous knock-in of the variant into the endogenous gene exhibited decreased VWF binding to collagen IV but not collagen III, decreased platelet adhesion, and increased bleeding, indicating a hypomorphic effect consistent with the mild phenotype of the human patients harboring this variant (PMID: 30565388). Exogenous expression the p.Arg1399His mutant in 293 cells identified undetectable binding to type VI (PMID: 22507569) and type 4 collagen (PMID: 25662333), but no dominant negative effect on the wild-type protein (PMID: 22507569). (PMID: 30565388).

PP4

At least 4 patients with this variant displayed excessive mucocutaneous bleeding as well as the laboratory phenotype of an abnormal collagen binding assay (PP4). Please note that all patients exhibited a VWF:RCo/VWF:Ag ratio between 0.7 and 1.5 (PMID: 22507569, PMID: 28083987, PMID: 28971901).

PP3

The computational predictor REVEL gives a score of 0.698, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). The computational splicing predictor SpliceAI gives a score of 0.00 for all splicing types, indicating that the variant has no impact on splicing.

PS4

This variant has been reported in at least 4 probands meeting PP4, including 1 ineligible individual already counted for the PP4 code (PMID: 22507569, PMID: 28083987, PMID: 28971901). However the MAF is too high to consider here. These cases are not considered since the variant meets BS1.

PM6

This variant has been identified as a de novo occurrence with unconfirmed parental relationships in 1 individual with VWD, but is present in a likely compound heterozygous state and contributes to loss of collagen binding but not other laboratory phenotypes apparently caused by the other variant (PMID: 22507569).

Curation History

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