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.3797C>T (p.Pro1266Leu)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA114170

314 (ClinVar)

Gene: VWF

Condition: hereditary von Willebrand disease

Inheritance Mode: Undetermined mode of inheritance

Link to MONDO

UUID: 12343403-689c-4cf1-abc6-a2c9ff5195db

Approved on: 2025-05-06

Published on: 2025-06-26

HGVS expressions

NM_000552.5:c.3797C>T

NM_000552.5(VWF):c.3797C>T (p.Pro1266Leu)

NC_000012.12:g.6019621G>A

CM000674.2:g.6019621G>A

NC_000012.11:g.6128787G>A

CM000674.1:g.6128787G>A

NC_000012.10:g.5999048G>A

NG_009072.1:g.110050C>T

NG_009072.2:g.110050C>T

ENST00000261405.10:c.3797C>T

ENST00000261405.9:c.3797C>T

ENST00000538635.5:n.421-25687C>T

ENST00000539641.1:n.595C>T

NM_000552.3:c.3797C>T

NM_000552.4:c.3797C>T

Likely Benign

BP5

PM2 BS3 PS4 PS3 PP1 PP4 PP3

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.3797C>T variant in VWF is a missense variant predicted to cause substitution of proline by leucine at amino acid 1266 (p.Pro1266Leu). The population frequency and in silico pathogenicity predictors of this variant are between the pathogenic and benign thresholds established by the VWD VCEP. This variant has been extensively researched and published in the literature and has been associated with VWD type 2B Malmö/NY. This sub-type of VWD type 2B is characterized by very mild clinical presentation if any, typically no thrombocytopenia and normal multimers. No published case where the variant under consideration was the sole driver of disease had a combination of: activity/antigen ratio <0.7, documented abnormal bleeding phenotype, and enhanced response to ristocetin. This variant has been observed in at least 1 patient with an alternate molecular basis for disease. The patient with VWD type 2, also carried the Arg1315His variant, which has been classified likely pathogenic respectively for VWD type 2M respectively by the VWD VCEP (BP5; PMIDs 16985174). Additionally, carriers of this variant have been documented as being treated with DDAVP without subsequent thrombocytopenia in at least two reports (PMIDs 20305138, 27353798). This observation suggests that the enhanced response to ristocetin data in patients is potentially an artifact and does not represent a biologically relevant increase in binding affinity to GPIb. In summary, this variant meets the criteria to be classified as likely benign for hereditary VWD based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: BP5. (ClinGen von Willebrand Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for VWF Version 1.0.0; May 6th, 2025)

BP5

This variant has been observed in at least 1 patient with an alternate molecular basis for disease. The patient with VWD type 2, also carried the Arg1315His variant, which has been classified likely pathogenic respectively for VWD type 2M respectively by the VWD VCEP (BP5; PMIDs 16985174).

PM2

The Grpmax filtering allele frequency in gnomAD v4.1 is 0.0008265 associated with the admixed American population (62/60002 alleles). This intermediate allele frequency is lower than the ClinGen VWD VCEP threshold (>0.01) for BS1 but higher than the threshold (<0.0001) for PM2_Supporting. (1 homozygote in the European non-Finnish, and Ashkenazi Jewish populations)

BS3

This criterion is considered not applicable.

PS4

Several reports link this variant with an atypical form of VWD type 2B, the so called Malmö/NY subtype. In no cases where VWD type 2B was asserted, did that case meet the laboratory phenotype requirements of PP4. In a single report, there was one variant carrier (carried Val1279Ile in cis) that had documented abnormal bleeding and activity/antigen ratio but was an asserted VWD type 1 patient and thus no RIPA data was provided, multimers were also normal in the patient (PMID 17190853).

PS3

Platelet aggregation assay performed with the p.Pro1266Leu recombinant mutant and wild-type vWF expressed and affinity purified as a dimer showed increased binding at low doses of ristocetin, indicating that this variant has a gain of function effect on the protein (PMID 8486782). However, PMID 20305138 shows that patients carrying this variant do not have the same drop in platelet count following DDAVP treatment as those with a typical VWD 2B variant (Figure 2) and that VWF levels and multimer patterns are similar to what the authors call the normal response to DDAVP. Lastly, no cases in the literature presented with an elevated VWF:GPIbM compared to the stated reference range when available. The data then suggest that the enhanced response to ristocetin observed in some variant carriers is an artifact and does not represent a biologically relevant variant effect.

PP1

Several pedigrees can be found in the literature however, there are no reported segregations between individuals that have a documented bleeding phenotype AND activity/antigen ratio <0.7

PP4

This variant overlaps with the VWF pseudogene and often carried on the coding sequence due to a gene conversion almost always with other variants in cis and is associated with atypical VWD type 2B Malmö/New York. None of the cases found in an extensive literature search when asserted to be VWD type 2B meet the phenotype criteria of abnormal bleeding, activity/antigen ratio <0.7, and enhanced response to ristocetin. There are cases with RIPA values indicative of VWD type 2B but in many of those cases, thrombocytopenia is explicitly reported to be absent in the case. Lastly, as the variant is often present with additional variation in VWF, no individuals that meet VWD phenotype criteria have features that can be solely attributed to the variant of record, with no cases carrying the variant of record and only additional variants curated benign by the VWD VCEP.

PP3

The computational predictor REVEL gives a score of 0.325, which is below the ClinGen VWD VCEP threshold of >0.644 indicating pathogenicity and <0.29 indicating benignity. Additionally, SpliceAI does not predict an effect on splicing.

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.