Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
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Variant: NM_000552.5(VWF):c.5235G>T (p.Trp1745Cys)

CA228706

100421 (ClinVar)

Gene: VWF
Condition: von Willebrand disease type 2M
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: bf32ce38-6e86-4b38-a00c-1b86f6b15de8
Approved on: 2024-08-13
Published on: 2024-08-13

HGVS expressions

NM_000552.5:c.5235G>T
NM_000552.5(VWF):c.5235G>T (p.Trp1745Cys)
NC_000012.12:g.6016592C>A
CM000674.2:g.6016592C>A
NC_000012.11:g.6125758C>A
CM000674.1:g.6125758C>A
NC_000012.10:g.5996019C>A
NG_009072.1:g.113079G>T
NG_009072.2:g.113079G>T
ENST00000261405.10:c.5235G>T
ENST00000261405.9:c.5235G>T
ENST00000538635.5:n.421-22658G>T
NM_000552.3:c.5235G>T
NM_000552.4:c.5235G>T
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Likely Pathogenic

Met criteria codes 4
PM2_Supporting PS3 PP4 PP3
Not Met criteria codes 2
PS4 PP1

Evidence Links 3

Expert Panel

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
NM_000552.5(VWF):c.5235G>T is a missense variant in VWF predicted to cause substitution of tryptophan by cysteine at amino acid 1745 in the collagen-binding A3 domain. The Grpmax filtering allele frequency in gnomAD v4.1 is 0 (based on 1/1180040 alleles in European non-Finnish population), which is lower than the ClinGen VWD VCEP threshold of <0.0001 (PM2_Supporting). The computational predictor REVEL gives a score of 0.757, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). At least 1 patient with this variant was diagnosed with VWD Type 2M and displayed excessive mucocutaneous bleeding as well as a laboratory phenotype of normal high-MW multimer pattern and abnormal collagen binding assay (Reduced VWF:CB / VWF:Ag ratio of 0.3 VWF to both type III and type I collagen), which together are specific for VWD type 2M. (PP4, PMID: 19687512). However, the patient's VWF:RCo was impaired in proportion to the decreased amount of VWF:Ag, so that VWF:RCo / VWF:Ag ratio was 0.9 (approximately normal). A hydrodynamic mouse model expressing p.Trp1745Cys showed decreased expression of the variant (VWF:Ag), but did not test other parameters relevant to the VWD Type 2M phenotype (Figure 4, PMID: 25051961). Collagen binding assay performed with the p.Trp1745Cys recombinant mutant and wild-type vWF expressed by HEK-293 cells showed decreased binding to both Type I and Type III collagens in an ELISA-based format, indicating that this variant has a damaging effect on protein function (PS3; PMID: 19687512, PMID: 20345715, PMID: 25051961). In summary, this variant meets the criteria to be classified as likely pathogenic for von Willebrand disease type 2M. ACMG/AMP criteria applied as specified by the ClinGen von Willebrand disease Variant Curation Expert Panel: PS3, PP4, PM2_Supporting, PP3.
Met criteria codes
PM2_Supporting
The Grpmax filtering allele frequency in gnomAD v4.1 is 0 (based on 1/1180040 alleles in European non-Finnish population), which is lower than the ClinGen VWD VCEP threshold of <0.0001 (PM2_Supporting).
PS3
A hydrodynamic mouse model expressing p.Trp1745Cys showed decreased expression, but did not test other parameters relevant to the VWD Type 2M phenotype (Figure 4, PMID: 25051961). Collagen binding assay performed with the p.Trp1745Cys recombinant mutant and wild-type vWF expressed by HEK-293 cells showed decreased binding to both Type I and Type III collagens in an ELISA-based format, indicating that this variant has a damaging effect on protein function (PMID: 19687512, PMID: 20345715, PMID: 25051961; PS3).
The recombinant variant exhibits barely detectable binding to type I and type III collagen, at <5% of wild-type (Figure 1B). PubMed:20345715
ELISA-based collagen binding assay performed with the p.Trp1745Cys recombinant mutant and wild-type vWF expressed by HEK-293 cells showed decreased binding to both Type I collagen (Figure 4A) and Type III collagen (Figure 4B), indicating that this variant has a damaging effect on protein function (PMID: 19687512). PubMed:19687512
A flow chamber system measuring the ability of immobilized recombinant mouse VWF proteins to mediate platelet adhesion to collagen under physiological high shear detected decreased platelet adhesion to collagen I and collagen III surfaces mediated by the variant (Figure 3). Mice hydrodynamically injected with VWF expression plasmids showed decreased VWF:Ag levels associated with the variant (Figure 4). PubMed:25051961
PP4
At least 1 patient with this variant displayed excessive mucocutaneous bleeding as well as a laboratory phenotype of normal high-MW multimer pattern and abnormal collagen binding assay (Reduced VWF:CB / VWF:Ag ratio of 0.3 VWF to both type III and type I collagen), which together are specific for VWD type 2M. (PP4, PMID: 19687512). The patient's VWF:RCo was impaired in proportion to the decreased amount of VWF:Ag, so that VWF:RCo / VWF:Ag ratio was 0.9 (approximately normal). Genotyping included all coding exons of VWF and would have been sufficient to rule out the presence of the p.Asp1472His variant.
PP3
The computational predictor REVEL gives a score of 0.757, 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.
Not Met criteria codes
PS4
At least 1 reported patient with this variant has a phenotype specific for VWD type 2M, which is not a sufficient proband number to meet this criterion (PMID: 19687512).
PP1
The variant has been reported to segregate with VWD type 2M through 1 affected meiosis from 1 family, which is not sufficient to meet this criterion (PMID: 19687512).
Curation History
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