Evidence Repository
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.7997C>T (p.Thr2666Met)

CA6401422

235639 (ClinVar)

Gene: VWF
Condition: hereditary von Willebrand disease
Inheritance Mode: Undetermined mode of inheritance
Link to MONDO
UUID: 06a9f663-3943-45b9-bcca-82acc975c902
Approved on: 2024-08-13
Published on: 2024-08-13

HGVS expressions

NM_000552.5:c.7997C>T
NM_000552.5(VWF):c.7997C>T (p.Thr2666Met)
NC_000012.12:g.5952509G>A
CM000674.2:g.5952509G>A
NC_000012.11:g.6061675G>A
CM000674.1:g.6061675G>A
NC_000012.10:g.5931936G>A
NG_009072.1:g.177162C>T
NG_009072.2:g.177162C>T
ENST00000261405.10:c.7997C>T
ENST00000261405.9:c.7997C>T
ENST00000612016.1:n.406C>T
ENST00000621700.1:n.315C>T
NM_000552.3:c.7997C>T
NM_000552.4:c.7997C>T

Likely Benign

Met criteria codes 2
BS1 BP4
Not Met criteria codes 3
PP3 BA1 BS2

Evidence Links 0

Expert Panel

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.7997C>T is a missense variant that substitutes threonine for methionine at position 2666. The Grpmax filtering allele frequency in gnomAD v4.0 is 0.06826 (based on 5238/74998 alleles in the African/African American population) which is higher than the ClinGen VWD VCEP threshold (>0.01) for BS1, and therefore meets this criterion (BS1). While this variant has been observed in healthy control individuals (PMID: 22197721), BS2 is not being used due to penetrance issues. The computational predictor REVEL gives a score of 0.027, which is below the ClinGen VWD VCEP threshold of <0.290 and does not predict a damaging effect on VWF function (BP4). Additionally, the computational splicing predictor SpliceAI indicated that the variant has no impact on splicing. In summary, this variant meets the criteria to be classified as likely benign for von Willebrand disease based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: BS1, BP4.
Met criteria codes
BS1
The Grpmax filtering allele frequency in gnomAD v4.0 is 0.06826 (based on 5238/74998 alleles in the African/African American population) which is higher than the ClinGen VWD VCEP threshold (>0.01) for BS1, and therefore meets this criterion (BS1).
BP4
The computational predictor REVEL gives a score of 0.027, which is below the ClinGen VWD VCEP threshold of <0.290 and does not predict a damaging effect on VWF function (BP4). Additionally, the computational splicing predictor SpliceAI gives a score of 0.00 for all splicing types, indicating that the variant has no impact on splicing.
Not Met criteria codes
PP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS2
Not using due to penetrance issues.
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