Variant: NM_000552.4(VWF):c.3929C>T (p.Ser1310Phe)

CA228494

100306 (ClinVar)

Gene: VWF

Condition: von Willebrand disease type 2B

Inheritance Mode: Autosomal dominant inheritance

UUID: 23ca549c-5557-4dbe-b8f1-c87ae80467a7

Approved on: 2024-08-12

Published on: 2024-08-12

HGVS expressions

NM_000552.4:c.3929C>T
NM_000552.4(VWF):c.3929C>T (p.Ser1310Phe)
NC_000012.12:g.6019489G>A
CM000674.2:g.6019489G>A
NC_000012.11:g.6128655G>A
CM000674.1:g.6128655G>A
NC_000012.10:g.5998916G>A
NG_009072.1:g.110182C>T
NG_009072.2:g.110182C>T
ENST00000261405.10:c.3929C>T
ENST00000261405.9:c.3929C>T
ENST00000538635.5:n.421-25555C>T
NM_000552.3:c.3929C>T
NM_000552.5:c.3929C>T

Likely Pathogenic

• Met criteria codes: PS4_Moderate PP1 PP3 PM2_Supporting PP4_Moderate

• Not Met criteria codes: PS3 PM5

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

Evidence submitted by expert panel

von Willebrand Disease VCEP

The NM_000552.4(VWF):c.3929C>T (p.Ser1310Phe) missense variant has been identified in at least three unrelated patients, with phenotypes specific to VWD type 2B (PS4_moderate; PMIDs: 27978591, 8815591). At least 2 patients with this variant displayed excessive mucocutaneous bleeding as well as laboratory phenotypes of loss of high molecular weight multimers and a GP1b assay with enhanced low-dose RIPA showing gain of function, which together are highly specific for VWD type 2B (PP4_moderate; PMID: 27978591). The variant has been reported to segregate with VWD type 2M through 3 affected siblings from 1 family (PP1; PMID: 27978591). This variant is absent from gnomAD v4.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.937, 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 Likely Pathogenic for von Willebrand disease type 2B based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: PP1, PP3, PP4_moderate, PM2_supporting, and PS4_moderate.

Met criteria codes

• PS4_Moderate: This variant has been reported in 2 additional probands with VWD type 2B phenotypes (PS4_moderate; PMIDs: 27978591, 8815591).
• PP1: The variant has been reported to segregate with VWD type 2B through 2 affected meioses from 1 family (PP1; PMID: 27978591).
• PP3: The computational predictor REVEL gives a score of 0.937, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3).
• PM2_Supporting: This variant is absent from gnomAD v4.1 (PM2_Supporting).
• PP4_Moderate: At least 2 patients with this variant displayed excessive mucocutaneous bleeding as well as laboratory phenotypes of loss of high molecular weight multimers and a GP1b assay with enhanced low-dose RIPA showing gain of function, which together are highly specific for VWD type 2B. (PP4_moderate; PMID: 27978591). The patients were also reported to have thrombocytopenia.

Not Met criteria codes

• PS3: Use of directed evolution in yeast to identify further gain-of-function mutations that enhance A1 and GPIbα interaction, identified clone 5, with high affinity for GPIbα selected by yeast surface display, as a double mutant for V1279A and S1310F (PMID: 24391089). The variants were not studied independently so V1279A variant can not be ruled out as contributing to the gain-of-function effect at this time and PS3 is not applied.
• PM5: PMID: 26986123 reports S1310P in a type 2B case. That variant occurs at the same codon but it has not yet been evaluated by the VWD VCEP.