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.4141A>G (p.Thr1381Ala)

CA6402593

256678 (ClinVar)

Gene: VWF
Condition: hereditary von Willebrand disease
Inheritance Mode: Undetermined mode of inheritance
UUID: b2887324-0582-4b18-97ee-8a0cf5ef41d4
Approved on: 2024-08-13
Published on: 2024-08-13

HGVS expressions

NM_000552.5:c.4141A>G
NM_000552.5(VWF):c.4141A>G (p.Thr1381Ala)
NC_000012.12:g.6019277T>C
CM000674.2:g.6019277T>C
NC_000012.11:g.6128443T>C
CM000674.1:g.6128443T>C
NC_000012.10:g.5998704T>C
NG_009072.1:g.110394A>G
NG_009072.2:g.110394A>G
ENST00000261405.10:c.4141A>G
ENST00000261405.9:c.4141A>G
ENST00000538635.5:n.421-25343A>G
NM_000552.3:c.4141A>G
NM_000552.4:c.4141A>G
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Benign

Met criteria codes 3
BA1 BP4 BP5
Not Met criteria codes 3
BS2 BS3 BP2

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
The missense variant NM_000552.5(VWF):c.4141A>G (p.Thr1381Ala) is common in the general population with a Grpmax filtering allele frequency of 0.8925 (based on 67313/74942 alleles in the African/African American population) in gnomAD v4.1 (BA1). Several probands have been reported (PMID: 30817071, PMID: 30762591) with Thr1381Ala in cis or trans with additional vWF variants, including the type 2B Arg1308Cys variant (ClinVar 289, classified Pathogenic by the ClinGen VWD VCEP; BP5). and therefore meets criteria to be classified as benign for von Willebrand disease based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD: BA1, BP4, BP5 (VCEP Rule specifications for von Willebrand disease type 2A, 2B and 2M v1.0.0; 08/12/2024).
Met criteria codes
BA1
This variant is common in the general population with a Grpmax allele frequency in gnomAD v4.1 of 0.8925 (67313/74942 alleles) in the African/African American population. This is above the threshold of >0.1 (BA1).
BP4
The computational predictor REVEL gives a score of 0.187, 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.
BP5
Several probands have been reported (PMID: 30817071, PMID: 30762591) with T1381A in cis or trans with additional vWF variants, including the type 2B R1308C variant (ClinVar 289, classified Pathogenic by the ClinGen VWD VCEP).
Not Met criteria codes
BS2
Control individuals harboring the Thr1381Ala variant (30 heterozygotes and 21 homozygotes) were identified. Laboratory values were reported for 4 homozygotes, all in the normal range: VWF:Ag 0.82 +/- 0.02 IU/dL, VWF:RCo 1.11 +/- 0.07 IU/dL, VWF:RCo/VWF:Ag ratio of 1.35, and RIPA in PRP was induced at 1.2 mg/ml (but not lower concentrations). However, BS2 is not considered due to incomplete penetrance.
BS3
The Thr1381Ala variant, expressed in COS-7 cells, has not been shown to have a significant impact on platelet binding (PMID: 17598011). WT vWF cDNA pNUT-VWF was used to derive the Thr1381Ala variant by site-directed mutagenesis before transient expression in COS-7 cells. The extent of rGPIbα binding was evaluated at increasing concentrations of ristocetin. Binding did not occur in the absence of ristocetin and no increased binding was seen with Ala1381 (Thr1381 had 149% and 139% binding relative to Ala1381 at 0.125 and 0.2 mg/ml respectively, with equivalent binding at 0.3-0.8 mg/ml). BS3 is not considered as this assay may not test for all possible deleterious effects of the variant.
BP2
Several probands have been reported (PMID: 30817071, PMID: 30762591) with Thr1381Ala in cis or trans with additional vWF variants, including the type 2B Arg1308Cys variant (ClinVar 289, classified Pathogenic by the ClinGen VWD VCEP). BP2 is considered not applicable due to incomplete penetrance.
Curation History
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