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]

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Variant: NM_000552.5(VWF):c.4195C>T (p.Arg1399Cys)

CA228555

100337 (ClinVar)

Gene: VWF

Condition: von Willebrand disease type 2M

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 807b1008-f3f9-4267-96c0-1bbbc7a587ed

Approved on: 2024-08-13

Published on: 2024-08-13

HGVS expressions

NM_000552.5:c.4195C>T

NM_000552.5(VWF):c.4195C>T (p.Arg1399Cys)

NC_000012.12:g.6019223G>A

CM000674.2:g.6019223G>A

NC_000012.11:g.6128389G>A

CM000674.1:g.6128389G>A

NC_000012.10:g.5998650G>A

NG_009072.1:g.110448C>T

NG_009072.2:g.110448C>T

ENST00000261405.10:c.4195C>T

ENST00000261405.9:c.4195C>T

ENST00000538635.5:n.421-25289C>T

NM_000552.3:c.4195C>T

NM_000552.4:c.4195C>T

Likely Pathogenic

PP4_Moderate PM2_Supporting PS4 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.4195C>T (p.Arg1399Cys) missense variant has been reported in a proband displaying excessive mucocutaneous bleeding as well as laboratory phenotypes of low VWF:RCo/VWF:Ag ratio (0.67), abnormal collagen binding assay, and normal high molecular weight multimer pattern, which together are highly specific for VWD type 2M (PP4_moderate, PMID: 28083987). Although the patient's multimer pattern did not lack high-molecular weight forms, it was visibly smeared, similar to those associated with the p.Arg1315Cys and p.Arg1374Cys variants (PMID: 26988807). At least 5 probands with phenotypes meeting at least the laboratory phenotype requirements of type 2M PP4 criteria, in addition to the proband used for the PP4_Moderate code (PS4; PMID: 17000885, PMID: 26988807, PMID: 35452508, PMID: 34758185). The computational predictor REVEL gives a score of 0.712, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). The Grpmax allele frequency in gnomAD v4.1 is 0.00005281 (8/74886 alleles) in the African/African American population, which is lower than the ClinGen VWD VCEP threshold of <0.0001 (PM2_Supporting). In summary, the variant meets the criteria to be classified as Likely Pathogenic for von Willebrand disease Type 2M based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: PS4_Strong, PP4_Moderate, PP3, and PM2_Supporting. (VCEP Rule specifications for von Willebrand disease type 2A, 2B and 2M v1.0.0; date of approval 08/13/2024)

PP4_Moderate

At least 1 patient with this variant displayed excessive mucocutaneous bleeding (bleeding score of 7) as well as laboratory phenotypes that included a normal multimer pattern, low VWF:RCo/VWF:Ag ratio (0.67), and abnormal collagen binding assay, which together are highly specific for VWD type 2M. (PP4_moderate, PMID: 28083987). Please note that the multimer pattern did not lack high-molecular weight forms, but was visibly smeary, similar to the p.Arg1315Cys and p.Arg1374Cys variants (PMID: 26988807).

PM2_Supporting

The Grpmax allele frequency in gnomAD v4.1 is 0.00005281 (8/74886 alleles) in the African/African American population, which is lower than the ClinGen VWD VCEP threshold (<0.0001), meeting this criterion (PM2_Supporting).

PS4

This variant has been reported in at least 5 probands with phenotypes meeting at least the laboratory phenotype requirements of type 2M PP4 criteria, in addition to the proband used for the PP4_Moderate code (PS4; PMID: 17000885, PMID: 26988807, PMID: 35452508, PMID: 34758185).

PP3

The computational predictor REVEL gives a score of 0.712, 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.

PP1

Affected family members of probands have been alluded to but not described in PMID: 26988807, so that this criterion is not met.

PM5

Another missense variant in the same codon, NM_000552.5(VWF):c.4196G>A (p.Arg1399His), has been reported. This variant has been classified as VUS by the ClinGen VWD VCEP and is not considered here to avoid circularity.

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