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_000552.4(VWF):c.1583A>G (p.Asn528Ser)

CA114178

318 (ClinVar)

Gene: VWF
Condition: von Willebrand disease type 2A
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: 9a7228cc-a4fe-4d5d-ba2a-316baa9e75a9
Approved on: 2024-08-13
Published on: 2024-08-13

HGVS expressions

NM_000552.4:c.1583A>G
NM_000552.4(VWF):c.1583A>G (p.Asn528Ser)
NC_000012.12:g.6057995T>C
CM000674.2:g.6057995T>C
NC_000012.11:g.6167161T>C
CM000674.1:g.6167161T>C
NC_000012.10:g.6037422T>C
NG_009072.1:g.71676A>G
NG_009072.2:g.71676A>G
ENST00000261405.10:c.1583A>G
ENST00000261405.9:c.1583A>G
ENST00000538635.5:n.420+52520A>G
NM_000552.3:c.1583A>G
NM_000552.5:c.1583A>G
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Pathogenic

Met criteria codes 5
PP4_Moderate PS3 PP1 PM3 PM2_Supporting
Not Met criteria codes 7
BS3 BS4 BP5 BP4 PS2 PP3 PM6

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 NM_000552.4(VWF):c.1583A>G variant in VWF is a missense variant predicted to cause substitution of asparagine by serine at amino acid 528. This variant is absent from gnomAD v4.1 (PM2_Supporting). This variant has been reported homozygous in two homozygous (PM3) probands meeting the VWD type 2A phenotypic criteria (PP4_moderate, PS4_suporting; PMID: 20335223; 9714529). The variant was found to co-segregate with disease in multiple affected family members, with 3 meioses observed in one family (PP1; PMID: 20335223). There is evidence of defective VWF storage with no response to desmopressin and very little VWF:Ag released after administration. Expression in 293 EBNA cells showed that homozygous N528S-VWF secretion was 7.5% of WT, with a multimer pattern lacking medium and HMWMs (PMID: 20335223 Fig. 4; PS3). Expression in AtT-20 cells showed that the N528S-VWF is not multimerized and is not trafficked to storage granules. In summary, this variant meets the criteria to be classified as pathogenic for von Willebrand disease type 2A. ACMG/AMP criteria applied, as specified by the ClinGen von Willebrand disease Variant Curation Expert Panel: PM2_supporting, PP4_moderate, PM3, PP1, PS3.
Met criteria codes
PP4_Moderate
At least one patient with this variant displayed activity<antigen, loss of HMWMs and abnormal RCo assay, which is highly specific for VWD type 2A PMID: 20335223 - Ag plasma: 38,30,33; CB:7,5,6; Ag platelet: <1,<1,nd; FVIII:C: 66,58,91; reduction of medium and HMWMs consistent with 2A; PMID 9714529 - FVIII:C: 25; VWF:Ag: 26; VWF:RCo: <6
PS3
defective VWF storage with no response to desmopressin and very little VWF:Ag released after administration; Expression in 293 EBNA cells showed homozygous variant secretion was 7.5% of WT, with multimer pattern lacking medium and HMWMs (PMID: 20335223 Fig. 4; PS3); AtT-20 cells showed the variant is not multimerized and is not trafficked to storage granules
PP1
The variant has been reported to segregate with VWD type 2A in 3 affected family members from 1 family, all homozygous for this variant PMIDs: 20335223
PM3
This variant has been reported in two homozygous probands meeting activity < antigen, loss of HMWMs and abnormal RCo (PMID: 20335223, PMID 9714529). 1pt PM3 An additional compound heterozygote has been reported in PMID: 35452508. Family 1 proband was compound heterozygous for N528S and p. D366LfsX16, confirmed in trans. The second variant has not yet been curated by the VWD VCEP. This could potentially increase the code to PM3_Strong but would not affect the variant classification.
PM2_Supporting
This variant is absent from gnomAD v4.1 (PM2_Supporting).
Not Met criteria codes
BS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP4
The computational predictor REVEL gives a score of 0.555, which is above the ClinGen VWD VCEP threshold of <0.290.
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP3
The computational predictor REVEL gives a score of 0.555, which is below the ClinGen VWD VCEP PP3 threshold of >0.644 and does not predict a damaging effect on VWF function. The computational splicing predictor SpliceAI gives a score of 0.08 for splice acceptor loss, indicating that the variant likely has no impact on splicing.
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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