Variant: NM_000552.5(VWF):c.4837T>C (p.Ser1613Pro)

CA114131

292 (ClinVar)

Gene: VWF

Condition: von Willebrand disease type 2A

Inheritance Mode: Autosomal dominant inheritance

UUID: cf756b09-5a21-46f7-96ac-d8d1c3e2d497

Approved on: 2025-02-04

Published on: 2025-02-05

HGVS expressions

NM_000552.5:c.4837T>C
NM_000552.5(VWF):c.4837T>C (p.Ser1613Pro)
NC_000012.12:g.6018581A>G
CM000674.2:g.6018581A>G
NC_000012.11:g.6127747A>G
CM000674.1:g.6127747A>G
NC_000012.10:g.5998008A>G
NG_009072.1:g.111090T>C
NG_009072.2:g.111090T>C
ENST00000261405.10:c.4837T>C
ENST00000261405.9:c.4837T>C
ENST00000538635.5:n.421-24647T>C
NM_000552.3:c.4837T>C
NM_000552.4:c.4837T>C

Uncertain Significance

• Met criteria codes: PS4_Supporting PP3 PP4_Moderate PM2_Supporting

• Not Met criteria codes: PP1

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 c.4837T>C variant in VWF is a missense variant predicted to cause substitution of Serine by Proline at amino acid 1613 (p.Ser1613Pro). At least 1 patient (Patient 14 from PMID: 38053262) with this variant displayed excessive mucocutaneous bleeding as well as laboratory phenotypes of very low VWF activity as indicated by a VWF activity-to-antigen ratio <0.7, and loss of high molecular weight multimers, which together are highly specific for VWD type 2A. Additional consistent phenotypes were also reported in the patient including a FVIII activity consistent with VWF antigen (ratio >0.7) (PP4_Moderate). This variant has been reported in one additional proband (Zimmerman program) with activity/antigen ratio <0.37, abnormal multimers, and normal platelet binding (PS4_Supporting). The computational predictor REVEL gives a score of 0.7, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). This variant is absent from gnomAD v4.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as VUS for autosomal recessive von Willebrand disease type 2A based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: PS4_Supporting, PP4_Moderate, PP3 and PM2_Supporting (VCEP specifications version 1.0.0; date of approval).

Met criteria codes

• PS4_Supporting: This variant has been reported in one additional proband (Zimmerman program) with activity/antigen ratio <0.37, abnormal multimers, and normal platelet binding (PS4_supoprting).
• PP3: The computational predictor REVEL gives a score of 0.7, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3).
• PP4_Moderate: At least 1 patient (Patient 14 from PMID: 38053262) with this variant displayed excessive mucocutaneous bleeding as well as laboratory phenotypes of very low VWF activity (VWF:RCo or VWF:GPIbM 12 IU/dL), a VWF activity-to-antigen ratio <0.7, and loss of high molecular weight multimers, which together are highly specific for VWD type 2A. Additional consistent phenotypes were also reported in the patient including a FVIII activity consistent with VWF antigen (ratio >0.7) (PP4_Moderate).
• PM2_Supporting: This variant is absent from gnomAD v4.1 (PM2_Supporting).

Not Met criteria codes

• PP1: At least one family has been reported (Zimmerman program) with the proband and daughter harboring this variant and a type 2A phenotype. This is insufficient segregations to meet the PP1 criterion.