Variant: NM_000552.5(VWF):c.3944G>T (p.Arg1315Leu)

CA228506

100312 (ClinVar)

Gene: VWF

Condition: von Willebrand disease 2

Inheritance Mode: Autosomal dominant inheritance

UUID: 7ddeefbd-1298-4aec-9490-aed9a884b76c

Approved on: 2025-04-01

Published on: 2025-04-15

HGVS expressions

NM_000552.5:c.3944G>T
NM_000552.5(VWF):c.3944G>T (p.Arg1315Leu)
NC_000012.12:g.6019474C>A
CM000674.2:g.6019474C>A
NC_000012.11:g.6128640C>A
CM000674.1:g.6128640C>A
NC_000012.10:g.5998901C>A
NG_009072.1:g.110197G>T
NG_009072.2:g.110197G>T
ENST00000261405.10:c.3944G>T
ENST00000261405.9:c.3944G>T
ENST00000538635.5:n.421-25540G>T
NM_000552.3:c.3944G>T
NM_000552.4:c.3944G>T

Likely Pathogenic

• Met criteria codes: PP3 PS4_Moderate PM2_Supporting PP4_Moderate PM5_Supporting

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

Evidence submitted by expert panel

von Willebrand Disease VCEP

The p.Arg1315Leu variant has a REVEL score of 0.854, which is above the VWD VCEP threshold of > 0.644 and therefore, the variant predicts a damaging effect on VWF function (PP3). There is at least one proband with excessive bleeding as well as low activity/VWF:Ag ratio, which together are specific for VWD type 2A (PMID: 28971901). It should be noted that this variant has been associated with both VWD type 2A (PMID: 16985174) as well as type 2M (PMID: 22329792); therefore, it has been published in the literature as VWD type “2M/2A” as it has been demonstrated to exhibit characteristics of both type 2A and 2M (PMID: 35452508). The variant is absent from gnomADv4, thus, meeting PM2_supporting criteria. The p.Arg1315His variant located in the same codon has been classified as likely pathogenic for VWD type 2M by the VWD VCEP (PM5_Supporting). Additional variants, p.Arg1315Gly and p.Arg1315Cys were found at the same codon but have not been curated by the VWD VCEP and therefore were not used in the assessment of PM5. Functional data, including simulation data is present for the variant but does not meet our specifications to be counted towards PS3. The p.Arg1315Leu variant has been reported in at least 3 additional probands meeting PP4 criteria (PS4_moderate). Taken together, the variant has been classified as likely pathogenic for VWD type 2 by the Von Willebrand Disease variant curation expert panel. PP3, PP4_moderate, PM2_suppporting, PM5_supporting, PS4_moderate.

Met criteria codes

• PP3: The computational predictor REVEL gives a score of 0.854, which is above the ClinGen VWD VCEP threshold of >0.644 and therefore predicts a damaging effect on VWF function (PP3).
• PS4_Moderate: This variant has been reported in at least 3 additional probands meeting PP4 laboratory phenotype criteria (PS4_moderate); PMIDs: 22329792, 16985174, 35452508).
• PM2_Supporting: The p.Arg1315Leu variant is missing from gnomADv4, thus meeting PM2_Supporting criteria.
• PP4_Moderate: At least one patient with this variant exhibited decreased HMWM; Bleeding score: 11; VWF:Ag = 21; VWF:RCo = 5; FVIII:C = 31; VWF:RCo/VWF:Ag = 0.24; VWF:CB = 14; VWD Type 2A (PMID:28971901).
• PM5_Supporting: The p.Arg1315His variant has been classified as likely pathogenic for VWD type 2M (PM5_Supporting). Additional variants p.Arg1315Gly and p.Arg1315Cys were found at the same codon but have not been curated by the VWD VCEP and therefore will not be used in the assessment of PM5.