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.4105T>A (p.Phe1369Ile)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA228533

100326 (ClinVar)

Gene: VWF

Condition: von Willebrand disease type 2M

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: fca7b05f-b09b-4b73-8047-1de666ba94d8

Approved on: 2024-08-13

Published on: 2024-08-13

HGVS expressions

NM_000552.5:c.4105T>A

NM_000552.5(VWF):c.4105T>A (p.Phe1369Ile)

NC_000012.12:g.6019313A>T

CM000674.2:g.6019313A>T

NC_000012.11:g.6128479A>T

CM000674.1:g.6128479A>T

NC_000012.10:g.5998740A>T

NG_009072.1:g.110358T>A

NG_009072.2:g.110358T>A

ENST00000261405.10:c.4105T>A

ENST00000261405.9:c.4105T>A

ENST00000538635.5:n.421-25379T>A

NM_000552.3:c.4105T>A

NM_000552.4:c.4105T>A

Pathogenic

PM2_Supporting PP4_Moderate PS3 PP1 PP3 PS4_Moderate

BP5 PM5

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_000552.4(VWF):c.4105T>A (p.Phe1369Ile) missense variant has been identified in at least three unrelated heterozygous patients (PS4_Moderate), with one of the probands meeting PP4 phenotypic criteria. These phenotypes include normal multimer pattern, low VWF:RCo/VWF:Ag ratio, and reduced binding to platelets in the presence of ristocetin, which together are highly specific for VWD type 2M (PP4_moderate, PMID:9473222). A ristocetin-induced platelet binding assay performed with the F1369I recombinant mutant expressed by COS-7 cells showed ~75% decreased binding indicating that this variant has a damaging effect on protein function (PMID: 9473222; PS3). The computational predictor REVEL gives a score of 0.893, 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 0.00004370 (based on 8/91044 alleles in the South Asian 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 Pathogenic for von Willebrand disease type 2M based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: PP3, PP4_moderate, PM2_supporting, PS4_moderate, and PS3.

PM2_Supporting

The Grpmax filtering allele frequency in gnomAD v4.1 is 0.00004370 (based on 8/91044 alleles in the South Asian population), which is lower than the ClinGen VWD VCEP threshold of <0.0001 (PM2_Supporting).

PP4_Moderate

At least 1 proband with this variant displayed excessive mucocutaneous bleeding as well as laboratory phenotypes of a normal multimer pattern, low VWF:RCo/VWF:Ag ratio, and had a decreased platelet binding assay, which together are highly specific for VWD type 2M. The additional consistent phenotypes of FVIII activity consistent with VWF antigen was also reported (PP4_moderate; PMID: 9473222).

PS3

Ristocetin-induced platelet binding assay performed with the F1369I recombinant mutant or wt vWF expressed by COS-7 showed ~75% decreased binding indicating that this variant has a damaging effect on protein function. Multimer pattern was normal. (PMID: 9473222; PS3).

PP1

Patients P5, P6, and 8 with VWD type 2M and the same genotype (p.Phe1369Ile-Ser1378Phe-Arg1379Cys/WT gene conversion) are from the same family, with unspecified relationships. Family members AII-1 and AIII-1 are both heterozygous for the F1369I variant and have clinical and laboratory data confirming vWD type 2M. AI-1 is also affected but was not sequenced (PMID: 9473222). Insufficient for the required 2 meisosis.

PP3

The computational predictor REVEL gives a score of 0.893, 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_Moderate

At least 7 probands have been reported in the literature, Three, including the proband used for PP4, had sufficient phenotypic information to satisfy PP4 laboratory criteria (PMID: 37732159, PMID: 9473222; PS4_Moderate).

BP5

Some patients harbor this variant as part of a gene conversion event -- P4 p.Ile1343Val-Val1360Ala-Phe1369Ile-Ser1378Phe-Arg1379Cys/WT; P5 p.Phe1369Ile-Ser1378Phe-Arg1379Cys/WT PMID: 37732159) -- the additional variants have not been curated but BP5 would not affect the classification of this variant. ClinVar classifications Ile1343Val VUS Val1360Ala VUS Phe1369Ile Pathogenic/Likely pathogenic Ser1378Phe VUS Arg1379Cys Pathogenic/Likely pathogenic

PM5

The Phe1369Leu variant has been reported in the same codon (ClinVar Variation ID: 627303, VUS). However, this variant has not yet met the criteria to be classified as likely pathogenic by the ClinGen VWD VCEP. Phe1369Leu has not been curated at this time because it does not affect the classification of Phe1369Ile.

Curation History

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