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.6859C>T (p.Arg2287Trp)

CA228760

100450 (ClinVar)

Gene: VWF
Condition: hereditary von Willebrand disease
Inheritance Mode: Undetermined mode of inheritance
Link to MONDO
UUID: 114e5833-f2ba-4723-af04-e42627bec89f
Approved on: 2024-08-13
Published on: 2024-08-13

HGVS expressions

NM_000552.5:c.6859C>T
NM_000552.5(VWF):c.6859C>T (p.Arg2287Trp)
NC_000012.12:g.5985605G>A
CM000674.2:g.5985605G>A
NC_000012.11:g.6094771G>A
CM000674.1:g.6094771G>A
NC_000012.10:g.5965032G>A
NG_009072.1:g.144066C>T
NG_009072.2:g.144066C>T
ENST00000261405.10:c.6859C>T
ENST00000261405.9:c.6859C>T
NM_000552.3:c.6859C>T
NM_000552.4:c.6859C>T
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Uncertain Significance

Met criteria codes 1
PS3_Supporting
Not Met criteria codes 7
BS2 BS1 BP4 BP5 PP4 PP3 PM2

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.6859C>T is a missense variant in VWF that replaces arginine with tryptophan at position 2287. The Grpmax filtering allele frequency in gnomAD v4.1 is 0.008368 (based on 670/75044 alleles in African / African-American population, with 3 homozygotes). This intermediate allele frequency is lower than the ClinGen VWD VCEP threshold for BS1 (>0.01) but higher than the threshold for PM2_Supporting (<0.0001). At least 2 patients harboring this variant displayed a laboratory phenotype that led to a diagnosis of either VWD Type 2A (PMID: 23340442) or VWD Type 2M (PMID: 16321553), with the former patient exhibiting loss of high-molecular weight VWF multimers and VWF:CB/VWF:Ag ratio <0.7. However, this phenotype was not sufficiently detailed to meet the PP4 code. This variant has been observed once in the homozygous state in gnomAD, and two other healthy controls harboring the variant have been reported with normal lab values (PMID: 22197721). However, BS2 has not been evaluated because this code is not considered applicable to VWD due to incomplete penetrance. A number of published control individuals have been found to harbor this variant, but were associated with a 35-40 IU/dL per allele decrease in VWF:Ag level and a smaller (non-significant) decrease in FVIII:C level (PMID: 23690449). Exogenous expression of the variant in COS-1 cells showed normal multimerization but subnormal levels of protein secreted into the medium (50-70% of wild-type, though evidence of abnormal retention in the cell was absent). This quantitative but not qualitative defect does not meet the requirements for use by the ClinGen VWD VCEP for functional evaluation of VWD Type 2 variants, but may be a match for VWD Type 1. 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: PS3_Supporting. While published data do not make a conclusive case that this variant is disease-causing by itself, they indicate that this variant has functional impact and raise the possibility that it may act as a risk factor.
Met criteria codes
PS3_Supporting
Exogenous expression of the variant in COS-1 cells showed normal multimerization but subnormal levels of protein secreted into the medium (50-70% of wild-type, though evidence of abnormal retention in the cell was absent). This quantitative but not qualitative defect does not meet the requirements for use by the ClinGen VWD VCEP for functional evaluation of VWD Type 2 variants, but may be a match for VWD Type 1.
Not Met criteria codes
BS2
This variant has been observed in gnomAD in an individual between 40 and 45 years of age. Two other healthy controls harboring the variant have been reported with normal lab values (PMID: 22197721). However, BS2 has not been evaluated because this code is not considered applicable to VWD due to incomplete penetrance. An unspecified number of control individuals were found to harbor this variant, but were associated with a 35-40 IU/dL per allele decrease in VWF:Ag level and a smaller (non-significant) decrease in FVIII:C level (PMID: 23690449).
BS1
The Grpmax filtering allele frequency in gnomAD v4.1 is 0.008368 (based on 670/75044 alleles in African / African-American population, with 3 homozygotes). This intermediate allele frequency is lower than the ClinGen VWD VCEP threshold for BS1 (>0.01) but higher than the threshold for PM2_Supporting (<0.0001).
BP4
The computational predictor REVEL gives a score of 0.34, which is abovethe ClinGen VWD VCEP BP4 threshold of <0.290.
BP5
The p.Arg2287Trp variant has been observed in at least 1 patient with a VWD Type 1 phenotype who harbors the p.Cys2216Phefs*9, p.His817Gln, p.Met740Ile, p.Asp1472His, and p.Arg2185Gln variants as well. These variants have not yet been evaluated, so that BP5 is not met (PMID: 35734101).
PP4
At least 2 patients harboring this variant displayed a laboratory phenotype that led to a diagnosis of either VWD Type 2A (PMID: 23340442) or VWD Type 2M (PMID: 16321553), with the former patient exhibiting loss of high-molecular weight VWF multimers and VWF:CB/VWF:Ag ratio <0.7. This phenotype is not sufficiently detailed to meet PP4.
PP3
The computational predictor REVEL gives a score of 0.34, 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 0.05 for splice donor loss, indicating that the variant likely has no impact on splicing.
PM2
The Grpmax filtering allele frequency in gnomAD v4.1 is 0.008368 (based on 670/75044 alleles in African / African-American population, with 3 homozygotes). This intermediate allele frequency is lower than the ClinGen VWD VCEP threshold for BS1 (>0.01) but higher than the threshold for PM2_Supporting (<0.0001).
Curation History
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