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.4022G>A (p.Arg1341Gln)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA114129

291 (ClinVar)

Gene: VWF

Condition: von Willebrand disease type 2B

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 35a463a2-9b33-4b91-9aab-41a0a8c96b57

Approved on: 2024-08-13

Published on: 2024-08-13

HGVS expressions

NM_000552.4:c.4022G>A

NM_000552.4(VWF):c.4022G>A (p.Arg1341Gln)

NC_000012.12:g.6019396C>T

CM000674.2:g.6019396C>T

NC_000012.11:g.6128562C>T

CM000674.1:g.6128562C>T

NC_000012.10:g.5998823C>T

NG_009072.1:g.110275G>A

NG_009072.2:g.110275G>A

ENST00000261405.10:c.4022G>A

ENST00000261405.9:c.4022G>A

ENST00000538635.5:n.421-25462G>A

NM_000552.3:c.4022G>A

NM_000552.5:c.4022G>A

Pathogenic

PP4_Moderate PM2_Supporting PS4 PS3 PP3

PP1 PM5

Evidence Links 0

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

The NM_000552.5(VWF):c.4022G>A (p.Arg1341Gln) variant in VWF has been reported in several dozen vWD type 2B patients. At least one (P8 of PMID: 20118404) has sufficient information reported to meet the PP4_moderate criteria, including mucocutaneous bleeding, positive GOF assay, and loss of HMW multimers. An additional four have been curated for inclusion based on at least a LD-RIPA response (PMIDs: 20118404, 8292729; PS4_strong). In vitro studies have shown increased platelet binding in COS-7 cells and a VWF -/- mouse with R1306-vWF hydrodynamic expression recapitulated patient phenotypes (PS3). The Grpmax filtering allele frequency in gnomAD v4.1 is 2.800e-7 (based on 2/1179864 alleles in the European non-Finnish population), which is lower than the ClinGen VWD VCEP threshold of <0.0001 (PM2_Supporting). This variant is predicted deleterious by REVEL gives a score of 0.792, which is above the ClinGen VWD VCEP threshold of >0.644 (PP3). This variant has been observed segregating in multiple families, however insufficient phenotypic information has been reported on those individuals. In summary, this variant meets criteria to be classified as pathogenic for vWD type 2B with specified criteria PS3, PS4, PM2_supporting, PP3, and PP4_moderate.

PP4_Moderate

Several dozen vWD type 2B patients have been described with the R1341Q variant. At least one (P8 of PMID: 20118404) has sufficient information reported to meet the PP4_moderate criteria, including mucocutaneous bleeding, positive GOF assay, and loss of HMW multimers.

PM2_Supporting

The Grpmax filtering allele frequency in gnomAD v4.1 is 2.800e-7 (based on 2/1179864 alleles in the European non-Finnish population), which is lower than the ClinGen VWD VCEP threshold of <0.0001 (PM2_Supporting).

PS4

Several dozen additional vWD type 2B patients have been described with the R1341Q variant, at least four have been curated for inclusion based on at least a LD-RIPA response (PMIDs: 20118404, 8292729; PS4)

PS3

The R1341Q variant, expressed in COS-7 cells, has been shown to have increased platelet binding by PMIDs: 8630394, 1400429, 9858249, and 10845912. Additionally a VWF -/- mouse with R1341Q-vWF hydrodynamic expression recapitulated patient phenotypes including increased platelet binding, reduced VWF:Ag, thrombocytopenia, and loss of HMW multimers (PMID: 20371742).

PP3

The computational predictor REVEL gives a score of 0.792, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3).

PP1

At least 2 unrelated families have been reported with at least 2 informative meiosis, where the R1341Q variant cosegregates with disease. In each case only 1 family member has sufficient information to meet the PP4 phenotypic criteria so the additional family members have not been considered to be well documented as having vWD type 2B.

PM5

Additional missense changes at this amino acid residue include R1341L (PMID: 9858249), R1341P (PMID: 19506361), and R1341W (PMID: 9723578). These have not been included in the analysis of R1306W to avoid circularity.

Curation History

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