Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computer assertion could be determined for this classification!

Variant: NM_000552.5(VWF):c.3944G>A (p.Arg1315His)

CA228504

100311 (ClinVar)

Gene: VWF
Condition: von Willebrand disease type 2M
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 3f1b7c21-b628-4132-bfd2-98c7ea579e22
Approved on: 2024-08-12
Published on: 2024-08-12

HGVS expressions

NM_000552.5:c.3944G>A
NM_000552.5(VWF):c.3944G>A (p.Arg1315His)
NC_000012.12:g.6019474C>T
CM000674.2:g.6019474C>T
NC_000012.11:g.6128640C>T
CM000674.1:g.6128640C>T
NC_000012.10:g.5998901C>T
NG_009072.1:g.110197G>A
NG_009072.2:g.110197G>A
ENST00000261405.10:c.3944G>A
ENST00000261405.9:c.3944G>A
ENST00000538635.5:n.421-25540G>A
NM_000552.3:c.3944G>A
NM_000552.4:c.3944G>A
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Likely Pathogenic

Met criteria codes 4
PP3 PS4_Moderate PM2_Supporting PP4_Moderate
Not Met criteria codes 4
BP5 BP2 PP1 PM5

Evidence Links 0

Expert Panel

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 missense variant NM_000552.5(VWF):c.3944G>A (p.Arg1315His) is a rare variant which occurs at a Grpmax filtering allele frequency in gnomAD v4.1 is 0.00002255 (based on 4/60004 alleles in the Admixed American population), which is lower than the ClinGen VWD VCEP threshold of <0.0001 (PM2_supporting). The computational predictor REVEL gives a score of 0.815, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). Portuguese patient P30, with this variant, (PMID: 26988807) displayed excessive mucocutaneous bleeding (bleeding score 7) as well as a laboratory phenotype of normal multimers, low VWF:RCo/VWF:Ag ratio (VWF:RCo 11%, VWF:Ag 16%, ratio 0.69) and an abnormal collagen binding assay (VWF:CB 19%), which together are highly specific for VWD type 2M (PP4_moderate). At least 3 additional probands have been reported with this variant and VWD reported as type 1 (but with VWF:RCo/VWF:Ag ratio <0.7) or type 2M (PMID: 26986123, 25689060, 16985174; PS4_moderate). 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: PM2_supporting, PP3, PP4_moderate, PS4_moderate.
Met criteria codes
PP3
The computational predictor REVEL gives a score of 0.815, 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.
PS4_Moderate
At least 3 additional probands have been reported with this variant and VWD reported as type 1 (but with VWF:RCo/VWF:Ag ratio <0.7 consistent with type 2M) or type 2M (PMID: 26986123, 25689060, 16985174; PS4_moderate).
PM2_Supporting
The Grpmax filtering allele frequency in gnomAD v4.1 is 0.00002255 (based on 4/60004 alleles in the Admixed American population), which is lower than the ClinGen VWD VCEP threshold of <0.0001 (PM2_supporting).
PP4_Moderate
Portuguese patient P30 (PMID: 26988807) displayed excessive mucocutaneous bleeding (bleeding score 7) as well as a laboratory phenotype of normal multimers, low VWF:RCo/VWF:Ag ratio (VWF:RCo 11%, VWF:Ag 16%, ratio 0.69) and an abnormal collagen binding assay (VWF:CB 19%), which together are highly specific for VWD type 2M. (PP4_moderate).
Not Met criteria codes
BP5
Patient IDs 7 and 8 (PMID: 25689060) are reported to have type 2B and are heterozygous for both R1341Q (considered the causative variant; classified Pathogenic by the VWD VCEP) and R1315H, without comment on cis/trans phase.
BP2
Several of the patients with this variant have additional VWF variants reported however BP2 is not considered.
PP1
The variant has been reported to segregate with VWD type 1 through 2 affected meioses from 1 family (Family F3, PMID: 16985174). Laboratory values for the additional affected family members were not provided to confirm their affected status.
PM5
Additional variants have been described in VWD patients at Arg1315, including R1315C, R1315G, R1315L, and R1315P but are not yet classified by the VWD VCEP.
Curation History
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