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]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computer assertion could be determined for this classification!

Variant: NM_000552.5(VWF):c.2900G>A (p.Gly967Asp)

CA6402913

619932 (ClinVar)

Gene: VWF
Condition: hereditary von Willebrand disease
Inheritance Mode: Undetermined mode of inheritance
Link to MONDO
UUID: 60315f0e-4ac0-4fd7-aef6-b14531657bd1
Approved on: 2024-08-12
Published on: 2024-08-12

HGVS expressions

NM_000552.5:c.2900G>A
NM_000552.5(VWF):c.2900G>A (p.Gly967Asp)
NC_000012.12:g.6029409C>T
CM000674.2:g.6029409C>T
NC_000012.11:g.6138575C>T
CM000674.1:g.6138575C>T
NC_000012.10:g.6008836C>T
NG_009072.1:g.100262G>A
NG_009072.2:g.100262G>A
ENST00000261405.10:c.2900G>A
ENST00000261405.9:c.2900G>A
ENST00000538635.5:n.421-35475G>A
NM_000552.3:c.2900G>A
NM_000552.4:c.2900G>A
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Likely Benign

Met criteria codes 2
PP4 BS1
Not Met criteria codes 4
BP4 PP3 PM5 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:c.2900G>A is a missense variant in VWF that replaces glycine with aspartic acid at position 967. The Grpmax filtering allele frequency in gnomAD v4.1 is 0.02526 (based on 967/75012 alleles in the African / African-American population, with 34 homozygotes), which is higher than the ClinGen VWD VCEP threshold of >0.01 (BS1). This variant has been reported in at least 1 patient with a diagnosis of VWD Type 3 and a phenotype including reduced quantity of VWF antigen. However, PP4 was not met due to the absence of other phenotype details and the presence of two additional variants (p.C350AfsX107 and p.C2774W) without reported confirmation of phase (PMID:23777763). This variant has also been reported in the heterozygous state in at least 7 reported healthy control individuals with no bleeding history and normal lab values (PMID: 22197721). However, BS2 has not been considered since this code is not applicable to the gene-disease relationship due to incomplete penetrance. In summary, this variant meets the criteria to be classified as a variant of unknown significance for hereditary von Willebrand disease based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: BS1, PP4.
Met criteria codes
PP4
At least 1 patient with this variant displayed reduced quantity of VWF antigen and received a diagnosis of VWD Type 3. PP4 is met because of the phenotypic match despite the absence of other phenotype details and the presence of two additional variants (p.C350AfsX107 and p.C2774W) without reported confirmation of phase (PMID:23777763).
BS1
The Grpmax filtering allele frequency in gnomAD v4.1 is 0.02526 (based on 967/75012 alleles in the African / African-American population, with 34 homozygotes), which is higher than the ClinGen VWD VCEP BS1 threshold of >0.01 (BS1).
Not Met criteria codes
BP4
The computational predictor REVEL gives a score of 0.306, which is above the ClinGen VWD VCEP BP4 threshold of <0.290.
PP3
The computational predictor REVEL gives a score of 0.306, which is below the ClinGen VWD VCEP PP3 threshold of >0.644 and does not predict a damaging effect on VWF function. The computational splicing predictor SpliceAI gives a score of 0.00 for all splicing types, indicating that the variant has no impact on splicing.
PM5
An additional missense substitution at the same residue in VWF, p.Gly967Val, has been reported in association with von Willebrand disease (PMID: 28971901), but has not yet been classified by the ClinGen VWD VCEP, so PM5 has not yet been met.
BS2
At least 7 reported healthy control individuals with no bleeding history and normal lab values harbored the variant in the heterozygous state (PMID: 22197721). BS2 has not been considered since this code is not applicable to the gene-disease relationship due to incomplete penetrance.
Curation History
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