Variant: NM_000552.5(VWF):c.3568T>C (p.Cys1190Arg)

Version: 1.0
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CA228423

100269 (ClinVar)

Gene: VWF (HGNC:7450)

Condition: von Willebrand disease type 2A

Inheritance Mode: Autosomal dominant inheritance

UUID: 5a79774e-87e4-4c34-ad00-5a1de8248e31

Approved on: 2025-05-06

Published on: 2025-05-09

HGVS expressions

NM_000552.5:c.3568T>C
NM_000552.5(VWF):c.3568T>C (p.Cys1190Arg)
NC_000012.12:g.6022006A>G
CM000674.2:g.6022006A>G
NC_000012.11:g.6131172A>G
CM000674.1:g.6131172A>G
NC_000012.10:g.6001433A>G
NG_009072.1:g.107665T>C
NG_009072.2:g.107665T>C
ENST00000261405.10:c.3568T>C
ENST00000261405.9:c.3568T>C
ENST00000538635.5:n.421-28072T>C
NM_000552.3:c.3568T>C
NM_000552.4:c.3568T>C

Pathogenic

• Met criteria codes: PP1_Moderate PP4_Moderate PP3 PM2_Supporting PS4_Very Strong

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_000552.5:c.3568T>C variant in VWF is a missense variant predicted to cause substitution of cysteine by arginine at amino acid 1190. At least 1 patient with this variant displayed excessive mucocutaneous bleeding as well as laboratory phenotypes of very low VWF activity measured by VWF:Collagen binding assay, low activity/VWF:Ag ratio, and loss of high molecular weight multimers, which together are highly specific for VWD type 2A. (PP4_moderate, PMID 34532631). An additional consistent phenotype was also reported in the patient specifically, a normal platelet count. This variant has been reported in 12 additional probands meeting PP4 laboratory phenotype criteria (PS4_Moderate; WiN Study - Personal Communication). The variant has been reported to segregate with VWD type 2A through >2 affected meioses in 2 families (PP1_moderate; WiN Study Database personal communication). This variant is absent from gnomAD v4.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.982, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant VWD type 2A based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: PP4_Moderate, PS4_VeryStrong, PP1_Moderate, PM2_Supporting, PP3. (ClinGen von Willebrand Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for VWF Version 1.0.0)

Met criteria codes

• PP1_Moderate: The variant has been reported to segregate with VWD type 2A through >2 affected meioses in 2 families (PP1_moderate; WiN Study Database personal communication).
• PP4_Moderate: At least 1 patient with this variant displayed excessive mucocutaneous bleeding as well as laboratory phenotypes of very low VWF activity measured by VWF:Collagen binding assay, low activity/VWF:Ag ratio, and loss of high molecular weight multimers, which together are highly specific for VWD type 2A. (PP4_moderate, PMID 34532631). An additional consistent phenotype was also reported in the patient specifically, a normal platelet count.
• PP3: The computational predictor REVEL gives a score of 0.982, 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).
• PS4_Very Strong: This variant has been reported in 12 additional probands meeting PP4 laboratory phenotype criteria (PS4_Moderate; WiN Study - Personal Communication).