Evidence Repository - GenboreeKB

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:c.5140G>C

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA383496428

Gene: VWF

Condition: von Willebrand disease type 2M

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 97caccf9-3bae-4a6e-945c-be9298008b62

Approved on: 2024-08-13

Published on: 2024-08-13

HGVS expressions

NM_000552.5:c.5140G>C

NC_000012.12:g.6016784C>G

CM000674.2:g.6016784C>G

NC_000012.11:g.6125950C>G

CM000674.1:g.6125950C>G

NC_000012.10:g.5996211C>G

NG_009072.1:g.112887G>C

NG_009072.2:g.112887G>C

ENST00000261405.10:c.5140G>C

ENST00000261405.9:c.5140G>C

ENST00000538635.5:n.421-22850G>C

NM_000552.3:c.5140G>C

NM_000552.4:c.5140G>C

Uncertain Significance

PM2_Supporting PP4_Moderate PP3

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.5140G>C (p.Ala1714Pro) missense variant has been reported in one patient (P9; PMID: 28083987), with excessive mucocutaneous bleeding (bleeding score = 7) as well as laboratory phenotypes of a normal multimer pattern, low VWF:RCo/VWF:Ag ratio of 0.69, and abnormal collagen binding assay (VWF:CIIIB: 11.3% and VWF:CIIIB/VWF:Ag ratio 0.31), which together are highly specific for VWD type 2M. (PP4_moderate). This variant is absent from gnomAD v4.1 (PM2_supporting). The computational predictor REVEL gives a score of 0.662, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). In summary, the variant meets the criteria to be classified as Uncertain Significance for von Willebrand disease type 2M based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: PP3, PP4_moderate, and PM2_supporting.

PM2_Supporting

This variant is absent from gnomAD v4.1 (PM2_Supporting).

PP4_Moderate

One patient (P9; PMID: 28083987) with this variant has excessive mucocutaneous bleeding (bleeding score = 7) as well as laboratory phenotypes of a normal multimer pattern, low VWF:RCo/VWF:Ag ratio of 0.69, and abnormal collagen binding assay (VWF:CIIIB: 11.3% and VWF:CIIIB/VWF:Ag ratio 0.31), which together are highly specific for VWD type 2M. (PP4_moderate).

PP3

The computational predictor REVEL gives a score of 0.662, 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 0.01 for splice donor loss, indicating that the variant likely has no impact on splicing.

PP1

As reported in the PhD thesis of T Fidalgo (https://www.proquest.com/docview/2076363788?pq-origsite=gscholar&fromopenview=true), the daughter of P9 (P48) is also affected with VWD, however P48 is compound heterozygous for Ala1714Pro and a potential splice variant c.5170+10C>T leading to a severe type 1 VWD (VWF:AG 13%, VWF:RCo 10%, ratio 1.13, VWF:CB 12%). Additionally, a single segregation within the family is insufficient to consider PP1.

Curation History

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