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.2446C>T (p.Arg816Trp)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA114137

295 (ClinVar)

Gene: VWF

Condition: von Willebrand disease type 2N

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 70363cd6-3c5e-4b06-8b9d-206168fc402f

Approved on: 2024-07-09

Published on: 2024-08-12

HGVS expressions

NM_000552.5:c.2446C>T

NM_000552.5(VWF):c.2446C>T (p.Arg816Trp)

NC_000012.12:g.6036488G>A

CM000674.2:g.6036488G>A

NC_000012.11:g.6145654G>A

CM000674.1:g.6145654G>A

NC_000012.10:g.6015915G>A

NG_009072.1:g.93183C>T

NG_009072.2:g.93183C>T

ENST00000261405.10:c.2446C>T

ENST00000261405.9:c.2446C>T

ENST00000538635.5:n.421-42554C>T

NM_000552.3:c.2446C>T

NM_000552.4:c.2446C>T

Pathogenic

PP1_Moderate PP4_Moderate PM2_Supporting PS3 PM3 PP3

BP2

Evidence Links 1

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.2446C>T variant in VWF is a missense variant predicted to cause substitution of arginine by tryptophan at amino acid 816. The Grpmax filtering allele frequency in gnomAD v4.1 is 0.00009000 (based on 10/59984 alleles in the Admixed American population), which is lower than the ClinGen VWD VCEP threshold of <0.005 (PM2_Supporting). At least 8 patients with this variant displayed excessive mucocutaneous bleeding as well as low FVIII activity (1.3% or 9.8%) and decreased VWF:FVIII binding (0.00 to 0.1), which is highly specific for VWD type 2N (PMID: 28536718, PMID: 1832934, PMID: 28971901), (PP4_Moderate). Five individuals were homozygous for the variant (PM3) and three were compound heterozygous (PMID: 28536718, PMID: 28971901, PMID: 1832934). The variant has been reported to segregate with VWD type 2N in a proband plus two affected family members (PP1_moderate; PMID: 1832934). A hydrodynamic mouse model showed prolonged bleeding time, reduced factor VIII stability, and impaired binding of factor VIII to VWF, indicating that this variant has a damaging effect on protein function (PMID: 28581694)(PS3). The computational predictor REVEL gives a score of 0.756, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). In summary, this variant meets the criteria to be classified as Pathogenic for von Willebrand disease type 2N. ACMG/AMP criteria applied as specified by the ClinGen von Willebrand disease Variant Curation Expert Panel: PM3, PP1_Moderate, PP3, PP4_Moderate, PS3, PM2_Supporting.

PP1_Moderate

The variant has been reported to segregate with VWD type 2N in the proband plus two affected family members (PP1_moderate; PMID: 1832934).

PP4_Moderate

At least 8 patients with this variant displayed excessive mucocutaneous bleeding as well as low FVIII activity (1.3% or 9.8%) and decreased VWF:FVIII binding (0.00 to 0.1), which is highly specific for VWD type 2N (PMID: 28536718, PMID: 1832934, PMID: 28971901), (PP4_Moderate).

PM2_Supporting

The Grpmax filtering allele frequency in gnomAD v4.1 is 0.00009000 (based on 10/59984 alleles in the Admixed American population), which is lower than the ClinGen VWD VCEP threshold of <0.005 (PM2_Supporting).

PS3

A hydrodynamic mouse model with tail-vein injections of plasma-derived p.Arg816Trp showed prolonged bleeding time, reduced factor VIII stability, and impaired binding of factor VIII to VWF, indicating that this variant has a damaging effect on protein function (PMID: 28581694)(PS3).

A hydrodynamic mouse model with tail-vein injections of plasma-derived p.Arg816Trp showed prolonged bleeding time (Figure 4A), reduced factor VIII stability (Figure 2B), and impaired binding of factor VIII to VWF (1D), recapitulating the key phenotypes of VWD Type 2N. PubMed:28581694

PM3

This variant has been detected in at least 7 individuals with VWD Type 2N. 5 individuals were homozygous for the variant (1 point, PMID: 28536718, PMID: 28971901, PM3). 1 individual was compound heterozygous for the variant and an established pathogenic variant associated with VWD Type 2A/2M, p.Arg1315Cys (PMID: 28971901), but was too ambiguous phenotypically to include in the evaluation of this code. 1 of those individuals was compound heterozygous for the variant and a pathogenic variant (p.Val638Cysfs*13, Canonical Allele Identifier: CA2573105978) without confirmation in trans (NGS-based genotyping but 2 variants are distant from one another), (not scored at this time since quantitative rules are not yet finalized, PMID: 28536718). 1 of those individuals was compound heterozygous for the variant and a pathogenic variant (p.Arg854Gln) confirmed in trans (not counted here to avoid circularity, PMID: 1832934).

PP3

The computational predictor REVEL gives a score of 0.756, 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 0.11 for acceptor loss, indicating an inconclusive impact on splicing.

BP2

1 individual diagnosed with VWD Type 2A/2M was compound heterozygous for the variant and an established pathogenic variant associated with VWD Type 2A, p.Arg1315Cys (PMID: 28971901), but had phenotypes consistent with both VWD Type 2A and Type 2N and was too ambiguous phenotypically to include in the evaluation of this code.

Curation History

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.