Evidence Repository - Clinical Genome Resources

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Variant: NM_000552.5(VWF):c.2561G>A (p.Arg854Gln)

CA114139

296 (ClinVar)

Gene: VWF

Condition: von Willebrand disease type 2N

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 01c59bbd-0d03-488a-94f1-fa68f3b2e083

Approved on: 2024-07-09

Published on: 2024-08-12

HGVS expressions

NM_000552.5:c.2561G>A

NM_000552.5(VWF):c.2561G>A (p.Arg854Gln)

NC_000012.12:g.6034812C>T

CM000674.2:g.6034812C>T

NC_000012.11:g.6143978C>T

CM000674.1:g.6143978C>T

NC_000012.10:g.6014239C>T

NG_009072.1:g.94859G>A

NG_009072.2:g.94859G>A

ENST00000261405.10:c.2561G>A

ENST00000261405.9:c.2561G>A

ENST00000538635.5:n.421-40878G>A

NM_000552.3:c.2561G>A

NM_000552.4:c.2561G>A

Pathogenic

PM3_Strong PS3 PP1 PP4_Moderate

BP4 PP3 PM5 PM2 BS1

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(VWF):c.2561G>A variant in VWF is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 854. The Grpmax filtering allele frequency in gnomAD v4.0 is 0.005857 (based on 7050/1180026 alleles, with 24 homozygotes) in the European non-Finnish population. This allele frequency is above the ClinGen VWD VCEP threshold for VWD Type 2N (<0.005) for PM2_Supporting but below the threshold (>0.01) for BS1 and therefore does not meet any population criterion. At least 9 patients with this variant displayed excessive mucocutaneous bleeding, low FVIII activity, and decreased VWF:FVIII binding, which is highly specific for VWD type 2N (PP4_Moderate, PMID: 28971901, PMID: 22875612). Four individuals were homozygous for the variant (PMID: 28971901, PMID: 22875612, PMID: 1832934) and one of those individuals was compound heterozygous for the variant and a pathogenic variant (p.Arg816Trp) confirmed in trans (PMID: 1832934), additional compound heterozygotes have been reported but were not considered here (PM3_Strong). In one family, the variant segregated with VWD type 2N in the proband and a second affected family member (PP1; PMID: 28971901). A hydrodynamic mouse model showed 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). 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: PS3, PM3_Strong, PP4_Moderate, PP1.

PM3_Strong

This variant has been detected in at least 9 individuals with VWD Type 2N. 4 individuals were homozygous for the variant (1 point maximum, PMID: 28971901, PMID: 22875612, PMID: 1832934). 1 of those individuals was compound heterozygous for the variant and a pathogenic variant (p.Arg816Trp) confirmed in trans (1 point, PMID: 1832934). Total 2pt (PM3_Strong) 2 additional individuals were compound heterozygous for the p.Arg854Gln variant with a second variant confirmed in trans (p.Arg324Ter and p.Pro2558GlyfsTer7, respectively, 2 points, PMID: 28971901) but quantitative VWD classification rules are not yet finalized.

PS3

A hydrodynamic mouse model with wild-type and p.Arg854Gln mutant VWF proteins was generated from the plasma of VWF/FVIII double knockout mice, and p.Arg854Gln samples showed 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).

PP1

The variant has been reported to segregate with VWD type 2N in the proband plus one affected family member (PP1; PMID: 28971901).

PP4_Moderate

At least 4 patients with this variant displayed excessive mucocutaneous bleeding (score between 6 and 16) as well as low FVIII activity (between 3 and 24) and decreased VWF:FVIII binding (between 0.02 and 0.11), which is highly specific for VWD type 2N. (PP4_Moderate, PMID: 28971901). Additional consistent phenotypes were also reported in the patients including normal HMW multimers. While NGS was used for genotyping, it is not clear whether the alternate diagnosis of Hemophilia A was successfully ruled out in these patients. Two additional homozygous affected individuals have been found in PMID: 22875612.

BP4

The computational predictor REVEL gives a score of 0.487, which is above the ClinGen VWD VCEP PP3 threshold of <0.290.

PP3

The computational predictor REVEL gives a score of 0.487, which is below the ClinGen VWD VCEP PP3 threshold of >0.644 and does not predict a damaging effect on VWF function. The computational splicing predictor SpliceAI gives a score of 0.02 for splice acceptor gain, indicating that the variant likely has no impact on splicing.

PM5

Another missense variant NM_000552.5(VWF):c.2560C>T (p.Arg854Trp) (PMID: 9684781, PMID: 20586924, ClinVar Variation ID: 100228) in the same codon has not yet been classified for VWD Type 2N by the ClinGen VWD VCEP, and PM5 will not be evaluated in this curation to avoid circularity.

PM2

The Grpmax filtering allele frequency in gnomAD v4.1 is 0.005857 (based on 7050/1180026 alleles, with 24 homozygotes) in the European non-Finnish population. This allele frequency is above the ClinGen VWD VCEP threshold (<0.005) for VWD Type 2N variants for PM2_Supporting.

BS1

The Grpmax filtering allele frequency in gnomAD v4.1 is 0.005857 (based on 7050/1180026 alleles, with 24 homozygotes) in the European non-Finnish population. This allele frequency is below the ClinGen VWD VCEP threshold (>0.01) for VWD Type 2N variants for BS1.

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