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]

Variant: NM_000552.4(VWF):c.4789C>T (p.Arg1597Trp)

Curation Version - 1.2
Curation History
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CA114117

285 (ClinVar)

Gene: VWF

Condition: von Willebrand disease type 2A

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 6c3ab7ed-575d-4fb9-b6ce-27a327fbab90

Approved on: 2024-08-13

Published on: 2024-08-19

HGVS expressions

NM_000552.4:c.4789C>T

NM_000552.4(VWF):c.4789C>T (p.Arg1597Trp)

NC_000012.12:g.6018629G>A

CM000674.2:g.6018629G>A

NC_000012.11:g.6127795G>A

CM000674.1:g.6127795G>A

NC_000012.10:g.5998056G>A

NG_009072.1:g.111042C>T

NG_009072.2:g.111042C>T

ENST00000261405.10:c.4789C>T

ENST00000261405.9:c.4789C>T

ENST00000538635.5:n.421-24695C>T

NM_000552.3:c.4789C>T

NM_000552.5:c.4789C>T

Pathogenic

PS4_Very Strong PP4_Moderate PS2_Supporting PM2_Supporting PP1_Moderate PS3 PP3

PM5

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_000552.4(VWF):c.4789C>T (p.Arg1597Trp) missense variant has been identified in at least 40 probands reported to have type 2A VWD. This variant has been reported in at least 16 probands meeting PP4 laboratory phenotype criteria. (PS4_VeryStrong; PMIDs: 31939074, 22102197, 26791163, 27214365, 22329792, 14630825, 33807613, 23702511, 25689060, 27766062, 1380739, 16961623, 19277422, 22871923, 23355534). At least one patient with this variant displayed excessive mucocutaneous bleeding as well as laboratory phenotypes of very low VWF activity (VWF:RCo 11%), low VWF:RCo/VWF:Ag ratio of 0.28, and loss of high molecular weight multimers, which together are highly specific for VWD type 2A. Additionally, a normal RIPA assay was reported for this patient (PP4_moderate, PMID: 25689060 Patient 7). The variant has been reported to segregate with VWD type 2A through >2 affected meioses in at least 2 families (PP1_moderate; PMID: 22329792, 27766062). This variant has been identified as a de novo occurrence with unconfirmed parental relationships in at least 1 individual with VWD type 2A (PS2_supporting; PMID: 27214365). The Grpmax filtering allele frequency in gnomAD v4.1 is 0 which is lower than the ClinGen VWD VCEP threshold of <0.0001 (PM2_Supporting), a single allele is present in the European (Finnish) population. ADAMTS susceptibility assay, in 293 EBNA cells and hydrodynamic mouse model, expressing recombinant R1597W VWF showed increased susceptibility indicating that this variant has a damaging effect on protein function and the hydrodynamic model is a strong recapitulation human patients with a multimer profile was skewed toward lower molecular weight multimers, reduced VWF:Ag, and reduced thrombus formation. (PMID: 16322474, 29186156, 22372972)(PS3). The computational predictor CADD gives a PHRED score of 27.4, which is above the ClinGen VWD VCEP threshold of >20 and predicts a damaging effect on VWF function (PP3). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant VWD type 2A based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: PP1_moderate, PP4_moderate, PS4_VeryStrong, PP3, PM2_supporting, PS2_supporting, PS3.

PS4_Very Strong

This variant has been reported in at least 16 probands meeting the PP4 laboratory phenotype criteria. (PS4_VeryStrong; PMIDs: 31939074, 22102197, 26791163, 27214365, 22329792, 14630825, 33807613, 23702511, 25689060, 27766062, 1380739, 16961623, 19277422, 22871923, 23355534). There are at least 24 additional probands with insufficient information reported to confirm the type 2A phenotype.

PP4_Moderate

At least 1 patient with this variant displayed excessive mucocutaneous bleeding as well as laboratory phenotypes of very low VWF activity (VWF:RCo 11%), low VWF:RCo/VWF:Ag ratio of 0.28, and loss of high molecular weight multimers, which together are highly specific for VWD type 2A (PP4_moderate, PMID: 25689060 Patient 7). Additionally, a normal RIPA assay was reported for this patient, as well as the FVIII activity consistent with VWF antigen (ratio 1.33).

PS2_Supporting

This variant has been identified as a de novo occurrence with unconfirmed parental relationships in at least 1 individual with VWD type 2A (PS2_supporting; PMID: 27214365).

PM2_Supporting

The Grpmax filtering allele frequency in gnomAD v4.1 is 0 which is lower than the ClinGen VWD VCEP threshold of <0.0001 (PM2_Supporting), a single allele is present in the European (Finnish) population.

PP1_Moderate

The variant has been reported to segregate with VWD type 2A through >2 affected meioses in at least 2 families (PP1_moderate; PMID: 22329792, 27766062). At least 6 additional families with >2 affected meioses have been reported but information was insufficient to confirm the type 2A phenotype in all affected individuals.

PS3

ADAMTS susceptibility assay, in 293 EBNA cells and hydrodynamic mouse model, expressing recombinant R1597W VWF showed increased susceptibility indicating that this variant has a damaging effect on protein function (PMID: 16322474, 29186156, 22372972). Additionally, the hydrodynamic mouse model is a strong recapitulation human patients with a multimer profile was skewed toward lower molecular weight multimers, reduced VWF:Ag, and thrombus formation was reduced. Downscoring from PS3_Strong to PS3_moderate was considered due to missing information on VWF activity (measured by VWF:RCo or VWF:GP1b assay), but PS3 was approved by the VCEP due to the overriding importance of the multimer pattern.

R1597W expressed in 293 EBNA cells was assessed for susceptibility to ADAMTS13-dependent proteolysis, by visual comparison of the multimer patterns of mutant and WT rhuVWF digested under the same conditions. R1597W caused increased proteolysis compared with rhuVWF-WT in both the presence and absence of urea and and resulted in a very pronounced loss of HMW multimers. Similar results were reported in PMID: 29186156. PubMed:16322474

PP3

The computational predictor REVEL gives a score of 0.748, 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 scores of 0.00 for all splice site types, indicating that the variant has no impact on splicing.

PM5

At least 4 different missense variants R1597G/L/Q/P (ClinVar 100389; no classification, 100392; no classification, 100391; Pathogenic, PMID: 26986123), have been reported in the same codon as R1597W but have not yet been classified by the ClinGen VWD VCEP.

Curation History

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