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_000552.5(VWF):c.3971G>C (p.Gly1324Ala)

CA228508

100313 (ClinVar)

Gene: VWF (HGNC:7450)

Condition: von Willebrand disease type 2M (MONDO:0015630)

Inheritance Mode: Autosomal dominant inheritance

UUID: 57dada4b-031c-4efd-b870-6f4f6fa2a1b3

Approved on: 2024-08-13

Published on: 2024-08-13

HGVS expressions

NM_000552.5(VWF):c.3971G>C (p.Gly1324Ala)

NM_000552.5:c.3971G>C

NC_000012.12:g.6019447C>G

CM000674.2:g.6019447C>G

NC_000012.11:g.6128613C>G

CM000674.1:g.6128613C>G

NC_000012.10:g.5998874C>G

NG_009072.1:g.110224G>C

NG_009072.2:g.110224G>C

ENST00000261405.10:c.3971G>C

ENST00000261405.9:c.3971G>C

ENST00000538635.5:n.421-25513G>C

NM_000552.3:c.3971G>C

NM_000552.4:c.3971G>C

Pathogenic

PM2_Supporting PP1 PP3 PM5 PS4_Supporting PS3

PP4

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.3971G>C (p.Gly1324Ala) missense variant has been reported in at least one type 2M patient with VWF:RCo/VWF:Ag ratio of 0.44 (PMID: 12008946; PS4_supporting). The variant segregated with VWD type 2M through 3 affected meioses from this family (PP1; PMID:12008946). Another missense variant in the same codon has been reported in a patient with VWD type 2 Gly1324Ser, which has been classified likely pathogenic by the ClinGen VWD VCEP (PM5). The computational predictor REVEL gives a score of 0.719, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). Platelet/GP1b binding assays performed with the Gly1324Ala recombinant mutant vWF expressed by COS-7 showed no binding indicating that this variant has a damaging effect on protein function (PMIDs: 12008946, 10845912; PS3). This variant is absent from gnomAD v4.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal dominant VWD type 2M based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: PS3, PM2_supporting, PM5, PP1, PP3, PS4_supporting.

PM2_Supporting

This variant is absent from gnomAD v4.1 (PM2_Supporting).

PP1

The variant has been reported to segregate with VWD type 2M through 3 affected meioses from 1 family (PP1; PMID:12008946).

PP3

The computational predictor REVEL gives a score of 0.719, 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 a score of 0.00 for all splicing types, indicating that the variant has no impact on splicing.

PM5

Another missense variant in the same codon has been reported in a patient with VWD type 2 Gly1324Ser, which has been classified pathogenic by the ClinGen VWD VCEP (PM5).

PS4_Supporting

At least one type 2M patient has been reported with VWF:RCo/VWF:Ag ratio of 0.44 (PMID: 12008946; PS4_supporting).

PS3

Platelet/GP1b binding assays performed with the Gly1324Ala recombinant mutant vWF expressed by COS-7 showed no binding indicating that this variant has a damaging effect on protein function (PMIDs: 12008946, 10845912; PS3).

PP4

At least one patient has been reported with this variant with VWF:RCo 25 IU/dl, VWF:Ag 57 IU/dl (ratio 0.44), normal multimers, normal RIPA, and normal platelet count, however they do not exhibit bleeding symptoms (PP4_NotMet).

Curation History

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