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]

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Variant: NM_000552.5(VWF):c.3485C>T (p.Pro1162Leu)

CA6402756

256669 (ClinVar)

Gene: VWF

Condition: hereditary von Willebrand disease

Inheritance Mode: Undetermined mode of inheritance

Link to MONDO

UUID: 91f15e06-4d00-4a84-a2f6-92efbc2b0707

Approved on: 2024-08-12

Published on: 2024-08-12

HGVS expressions

NM_000552.5:c.3485C>T

NM_000552.5(VWF):c.3485C>T (p.Pro1162Leu)

NC_000012.12:g.6022793G>A

CM000674.2:g.6022793G>A

NC_000012.11:g.6131959G>A

CM000674.1:g.6131959G>A

NC_000012.10:g.6002220G>A

NG_009072.1:g.106878C>T

NG_009072.2:g.106878C>T

ENST00000261405.10:c.3485C>T

ENST00000261405.9:c.3485C>T

ENST00000538635.5:n.421-28859C>T

NM_000552.3:c.3485C>T

NM_000552.4:c.3485C>T

Benign

BA1 PP3

PP4 BS3 BS2

Evidence Links 1

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

NM_000552.5(VWF):c.3485C>T is a missense variant that replaces proline with leucine at position 1162. The Grpmax filtering allele frequency in gnomAD v4.1 is 0.2036 (based on 7087/34136 alleles in the African/African-American population), which is higher than the ClinGen VWD VCEP threshold (>0.1) for BA1, and therefore meets this criterion (BA1). Heterologous expression of the variant protein revealed similarities to the wild-type VWF control in secretion, collagen binding, GPIb binding, and multimerization (PMID: 28544236). The computational predictor REVEL gives a score of 0.677, 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 Benign for hereditary von Willebrand disease based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: BA1, PP3.

BA1

The Grpmax filtering allele frequency in gnomAD v4.1 is 0.2036 (based on 7087/34136 alleles in the African/African-American population), which is higher than the ClinGen VWD VCEP threshold (>0.1) for BA1, and therefore meets this criterion (BA1).

PP3

The computational predictor REVEL gives a score of 0.677, 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 acceptor gain, indicating that the variant likely has no impact on splicing.

PP4

At least one patient of interest harbors the variant and exhibits an abnormal VWF:RCo / VWF:Ag ratio, but is otherwise clinically unaffected, so this criterion is not met (PMID: 28544236).

BS3

Heterologous expression of the variant protein in HEK-293 cells revealed similarities to the wild-type VWF control in secretion, collagen binding, GPIb binding, and multimerization (PMID: 28544236). However, this criterion is considered not applicable for this gene-disease relationship.

Heterologous expression of the variant protein revealed similarities to the wild-type VWF control (PMID: 28544236) in secretion (Fig. 2A), collagen binding (Fig. 2B), GPIb binding (Fig. 2C), and multimerization (Fig. 3). PubMed:28544236

BS2

The variant has been reported in multiple unaffected patients (PMID: 28544236), however, BS2 is considered not applicable to this gene-disease relationship due to incomplete penetrance.

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