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
  • No CSPEC computer assertion could be determined for this classification!

Variant: NM_000552.5(VWF):c.3946G>A (p.Val1316Met)

CA114127

290 (ClinVar)

Gene: VWF
Condition: von Willebrand disease type 2B
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: b78eb887-2dcf-44f2-bf99-7f0aa13fad67
Approved on: 2024-08-13
Published on: 2024-08-19

HGVS expressions

NM_000552.5:c.3946G>A
NM_000552.5(VWF):c.3946G>A (p.Val1316Met)
NC_000012.12:g.6019472C>T
CM000674.2:g.6019472C>T
NC_000012.11:g.6128638C>T
CM000674.1:g.6128638C>T
NC_000012.10:g.5998899C>T
NG_009072.1:g.110199G>A
NG_009072.2:g.110199G>A
ENST00000261405.10:c.3946G>A
ENST00000261405.9:c.3946G>A
ENST00000538635.5:n.421-25538G>A
NM_000552.3:c.3946G>A
NM_000552.4:c.3946G>A
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Pathogenic

Met criteria codes 7
PP4_Moderate PM2_Supporting PS3 PP1 PP3 PS4_Very Strong PS2_Moderate
Not Met criteria codes 1
PM6

Evidence Links 1

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
The NM_000552.5(VWF):c.3946G>A variant in VWF is a missense variant predicted to cause substitution of valine by methionine at amino acid 1316. This variant is absent from gnomADv4.1 (PM2_Supporting). This variant has been reported in at least 9 probands showing excessive mucocutaneous bleeding as well as a laboratory phenotype of loss of high molecular weight multimers and/or enhanced platelet aggregation at low doses of ristocetin (PS4_VeryStrong, PMID: 19060241, PMID: 27885890, PMID: 28640903). At least 1 patient showed excessive mucocutaneous bleeding, loss of high molecular weight multimers, and enhanced platelet aggregation at low doses of ristocetin, which together are specific for VWD type 2B, along with consistent features of thrombocytopenia and low VWF antigen/activity ratio (PP4_Moderate, PMID: 28640903). Two additional affected patients harbored the variant in an apparent de novo heterozygous state (PS2_Moderate, PMID: 7909449, PMID: 2010538). The variant has been reported to segregate with VWD type 2B through 3 affected meioses from 1 family (PP1; PMID: 19060241). The computational predictor REVEL gives a score of 0.74, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). A knock-in mouse model expressing VWF p.Val1316Met has shown prolonged bleeding time, absence of high-MW multimers, large platelet aggregates, decreased in vitro platelet adhesion to thrombin or collagen, and enhanced in vivo VWF/platelet string formation, indicating that this variant has a damaging effect on protein function that is consistent with phenotypes of VWD Type 2B (PMID: 27212476, PS3). In summary, this variant meets the criteria to be classified as Pathogenic for von Willebrand disease type 2A. ACMG/AMP criteria applied as specified by the ClinGen von Willebrand disease Variant Curation Expert Panel: PS3, PS4_VeryStrong, PP4_Moderate, PS2_Moderate, PP1, PP3, PM2_Supporting.
Met criteria codes
PP4_Moderate
At least 4 probands with this variant displayed excessive mucocutaneous bleeding as well as a laboratory phenotype of loss of high molecular weight multimers and/or enhanced platelet aggregation at low doses of ristocetin (PMID: 27885890, PMID: 19060241, PMID: 28640903). One patient in particular has excessive mucocutaneous bleeding, loss of high molecular weight multimers, and enhanced platelet aggregation at low doses of ristocetin, which together are specific for VWD type 2B. (PP4_Moderate, PMID: 28640903). The patient was also reported to have thrombocytopenia and a VWF antigen/activity ratio consistent with type 2B, and the alternate diagnosis of platelet-type VWD was not reported in this patient, which is consistent with VWD type 2B.
PM2_Supporting
This variant was not found in gnomAD v4.1 (PM2_Supporting).
PS3
A knock-in mouse model expressing VWF p.Val1316Met showed prolonged bleeding time (Figure 3A), absence of high-MW multimers (Figure 2D), large platelet aggregates (Figure 2C), decreased in vitro platelet adhesion to thrombin or collagen (Figure 4), and enhanced in vivo VWF/platelet string formation (Figure 5), indicating that this variant has a damaging effect on protein function that is consistent with phenotypes of VWD Type 2B (PMID: 27212476, PS3).
A knock-in mouse model expressing VWF p.Val1316Met showed prolonged bleeding time (Figure 3A), absence of high-MW multimers (Figure 2D), large platelet aggregates (Figure 2C), decreased in vitro platelet adhesion to thrombin or collagen (Figure 4), and enhanced in vivo VWF/platelet string formation (Figure 5), indicating that this variant has a damaging effect on protein function that is consistent with phenotypes of VWD Type 2B (PMID: 27212476, PS3). PubMed:27212476
PP1
The variant has been reported to segregate with VWD type 2B through 3 affected meioses from 1 family (PP1; PMID: 19060241).
PP3
The computational predictor REVEL gives a score of 0.74, 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_Very Strong
This variant has been reported in 9 probands showing excessive mucocutaneous bleeding as well as a laboratory phenotype of loss of high molecular weight multimers and/or enhanced platelet aggregation at low doses of ristocetin (PS4_VeryStrong, PMID: 19060241, PMID: 27885890, PMID: 28640903, PMID: 18805962, PMID: 7909449).
PS2_Moderate
This variant has been identified as a de novo occurrence with confirmed paternal but not maternal relationships in 2 individuals with VWD Type 2B (PS2_Moderate, PMID: 7909449, PMID: 2010538).
Not Met criteria codes
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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