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.4130C>T (p.Ala1377Val)

CA6402597

619750 (ClinVar)

Gene: VWF
Condition: hereditary von Willebrand disease
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 7b5db5e9-0875-4a2d-876d-618ab52f4c15
Approved on: 2024-08-12
Published on: 2024-08-12

HGVS expressions

NM_000552.5:c.4130C>T
NM_000552.5(VWF):c.4130C>T (p.Ala1377Val)
NC_000012.12:g.6019288G>A
CM000674.2:g.6019288G>A
NC_000012.11:g.6128454G>A
CM000674.1:g.6128454G>A
NC_000012.10:g.5998715G>A
NG_009072.1:g.110383C>T
NG_009072.2:g.110383C>T
ENST00000261405.10:c.4130C>T
ENST00000261405.9:c.4130C>T
ENST00000538635.5:n.421-25354C>T
NM_000552.3:c.4130C>T
NM_000552.4:c.4130C>T
More

Uncertain Significance

Met criteria codes 3
PP4_Moderate PP1 PP3
Not Met criteria codes 6
BS1 BP2 BP5 PM2 PS4 PS3

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
NM_000552.5(VWF):c.4130C>T is a missense variant in VWF that replaces alanine with valine at position 1377. At least 1 patient with this variant, in combination with p.Arg1379Cys (ClinVar 100333; Pathogenic VWD type 1) in cis, displayed excessive mucocutaneous bleeding as well as laboratory phenotypes of a normal multimer pattern, low VWF:RCo/VWF:Ag ratio (0.6 to 0.7), and decreased GP1b binding assay which together are highly specific for VWD type 2M (PP4_moderate, PMID: 27785872). The p.Ala1377Val and p.Arg1379Cys variants have been reported in cis in 3 additional probands with high mucocutaneous bleeding as well as laboratory phenotypes of a normal multimer pattern, low VWF:RCo/VWF:Ag ratio (0.6 to 0.7), and decreased GP1b binding assay, but the four patients from Milan show the same short tandem repeats nearby, indicating the possibility of a common ancestor. The proband of Family VIII (PMID: 35452508) has 3 additional type 2M diagnosed individuals, 2 are counted here with VWF Act/ VWF:Ag ratio <=0.42 (the other is 0.75). Each individual is heterozygous for p.A1377V; p.R1379C (PP1). The Grpmax filtering allele frequency of this variant in gnomAD v4.1 is 0.001967 (based on 170/75034 alleles in the African / African-American population), which is lower than the ClinGen VWD VCEP threshold for BS1 (>0.01) and higher than the threshold for PM2_Supporting (<0.0001). GP1b-alpha binding assay performed with recombinant VWF expressed by HEK-293 cells showed severely decreased binding when p.Ala1377Val was combined with the p.Arg1379Cys variant, indicating that the combination of these two variants has a damaging effect on protein function. PS3_Supporting was not met because the individual p.Ala1377Val and p.Arg1379Arg mutants showed approximately wild-type binding to GpIb-alpha (PMID: 27785872). The computational predictor REVEL gives a score of 0.805, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). In summary, this variant meets the criteria to be classified as a variant of unknown significance for hereditary von Willebrand disease based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: PP4_Moderate, PP3, PP1. (Rule specifications for von Willebrand disease type 2A, 2B and 2M v1.0.0; date of approval 08/12/2024)
Met criteria codes
PP4_Moderate
At least 1 patient with this variant displayed excessive mucocutaneous bleeding as well as laboratory phenotypes of a normal multimer pattern, low VWF:RCo/VWF:Ag ratio (0.6 to 0.7), and decreased GP1b binding assay which together are highly specific for VWD type 2M (PP4_moderate, PMID: 27785872).
PP1
Family VIII (PMID: 35452508) has 4 type 2M diagnosed individuals, 3 are counted here with VWF Act/ VWF:Ag ratio <=0.42 (the fourth is 0.75). Each individual is heterozygous for p.A1377V; p.R1379C.
PP3
The computational predictor REVEL gives a score of 0.805, 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.
Not Met criteria codes
BS1
The Grpmax filtering allele frequency in gnomAD v4.1 is 0.001967 (based on 170/75034 alleles in the African / African-American population), which is lower than the ClinGen VWD VCEP threshold (>0.01) for BS1, failing to meet this criterion.
BP2
The additional substitution p.Arg1379Cys (ClinVar 100333; Pathogenic VWD type 1) in found in cis with this variant in all four patients. This criteria is not considered by the VWD VCEP.
BP5
The additional substitution p.Arg1379Cys (ClinVar 100333; Pathogenic VWD type 1) is found in cis with this variant in all four patients. However, the patients present with a 2M subtype so Arg1379Cys does not fully explain their phenotype.
PM2
The Grpmax filtering allele frequency in gnomAD v4.1 is 0.001967 (based on 170/75034 alleles in the African / African-American population), which is higher than the ClinGen VWD VCEP threshold for PM2_Supporting (<0.0001 for type 2A/B/M), failing to meet this criterion.
PS4
This variant has been reported in 4 probands with high mucocutaneous bleeding as well as laboratory phenotypes of a normal multimer pattern, low VWF:RCo/VWF:Ag ratio (0.6 to 0.7), and decreased GP1b binding assay. The four patients are reportedly unrelated, yet show the same short tandem repeats nearby, indicating the possibility of a common ancestor (PMID: 27785872 and PMID: 35452508).
PS3
GP1b-alpha binding assay performed with the p.Ala1377Val and p.Arg1379Cys recombinant mutant expressed by HEK-293 cells showed severely decreased binding relative to the wild-type and the individual mutants, indicating that the combination of these two variants has a damaging effect on protein function. PS3_Supporting was not met because the individual p.Ala1377Val mutant showed approximately wild-type binding to GpIb-alpha (PMID: 27785872).
Curation History
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.
¤ Powered by BCM's Genboree.