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]

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CA383495656

Gene: VWF

Condition: von Willebrand disease type 2M

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: b1e09c2b-c630-4155-985c-99ea79ede2dc

Approved on: 2024-08-13

Published on: 2024-08-13

HGVS expressions

NM_000552.5:c.5336G>T

NC_000012.12:g.6016208C>A

CM000674.2:g.6016208C>A

NC_000012.11:g.6125374C>A

CM000674.1:g.6125374C>A

NC_000012.10:g.5995635C>A

NG_009072.1:g.113463G>T

NG_009072.2:g.113463G>T

ENST00000261405.10:c.5336G>T

ENST00000261405.9:c.5336G>T

ENST00000538635.5:n.421-22274G>T

NM_000552.3:c.5336G>T

NM_000552.4:c.5336G>T

Uncertain Significance

PP4_Moderate PP3 PS4_Supporting PM2_Supporting

PP1

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.5336G>T (p.Arg1779Leu) missense variant has been reported in at least 2 unrelated probands with excessive mucocutaneous bleeding as well as a laboratory phenotype of low VWF:RCo/VWF:Ag ratio and low collagen binding, which together are specific for VWD Type 2M (PS4_Supporting, PMID: 28971901). At least 1 reported proband displayed excessive mucocutaneous bleeding as well as a laboratory phenotype of low VWF:RCo/VWF:Ag ratio, low collagen binding, and normal VWF high-MW multimers, which together are highly specific for VWD Type 2M (PP4_Moderate, PMID: 29924855). Low FVIII activity, an inconsistent phenotype, was also reported in these patients, as well as low VWF antigen, leading in two cases to a diagnosis of VWD Type 1 (PMID: 28971901). The computational predictor REVEL gives a score of 0.659, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). The Grpmax filtering allele frequency in gnomAD v4.1 is 0 (based on 1/60024 alleles in the Admixed American population), which is lower than the ClinGen VWD VCEP threshold of <0.0001 (PM2_Supporting). In summary, the variant meets the criteria to be classified as a Variant of Uncertain Significance for von Willebrand disease type 2M based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: PS4_Supporting, PP4_Moderate, PP3, and PM2_Supporting.

PP4_Moderate

At least 1 patient with this variant displayed excessive mucocutaneous bleeding as well as a laboratory phenotype of low VWF:RCo/VWF:Ag ratio, low collagen binding, and normal VWF high-MW multimers, which together are highly specific for VWD Type 2M (PP4_Moderate, PMID: 29924855). Low FVIII activity, an inconsistent phenotype, was also reported in these patients, as well as low VWF antigen. The genotyping method ruled out the presence of the p.Asp1472His variant (PMID: 29924855). Three additional probands are described, two of whom meet PP4 for VWD Type 2M (PMID: 28971901).

PP3

The computational predictor REVEL gives a score of 0.659, 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 0.02 for splice acceptor loss, indicating that the variant likely has no impact on splicing.

PS4_Supporting

This variant has been reported in at least 2 unrelated probands (1 of whom was used for PP4) with excessive mucocutaneous bleeding as well as a laboratory phenotype of low VWF:RCo/VWF:Ag ratio and low collagen binding, which together are specific for VWD Type 2M (PS4_Supporting, PMID: 28971901). An additional proband has been described (PMID: 29924855) but it is likely that the proband is related to one of those from PMID: 28971901.

PM2_Supporting

The Grpmax filtering allele frequency in gnomAD v4.1 is 0 (based on 1/60024 alleles in the Admixed American population), which is lower than the ClinGen VWD VCEP threshold of <0.0001 (PM2_Supporting).

PP1

The variant has been reported to segregate with VWD type 2M through 1 affected meiosis from each of 2 different families (PMID: 28971901). At least 2 meioses are required within a single family, so this criterion is not met.

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