rs61748477
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM3PP4_ModeratePP3PM2_SupportingPS3
This summary comes from the ClinGen Evidence Repository: The NM_000552.4(VWF):c.2372C>T variant in VWF is a missense variant predicted to cause substitution of threonine by methionine at amino acid 791. The Grpmax filtering allele frequency in gnomAD v4.1 is 0.000006150 (based on 2/64030alleles in European non-Finnish population), which is lower than the ClinGen VWD VCEP threshold <0.005 for PM2_Supporting, meeting this criterion (PM2_Supporting). At least four patients with this variant displayed excessive mucocutaneous bleeding as well as a low VWF:FVIII/VWF:Ag ratio which is highly specific for VWD type 2N (PP4_moderate, PMIDs: 2018834; 31741138; 22871923; 10706867). This variant has been detected in at least six individuals with VWD type 2N, with absent VWF:FVIII binding, compound heterozygous with a second variant (including Arg854Gln classified Pathogenic by the VWD VCEP without reported confirmation of trans phase 0.5pt PMID:22102197) and two individuals were homozygous for the variant (PMIDs: 2018834; 22871923) (PM3). Factor VIII binding assay in HEK293 expressing recombinant VWF showed decreased binding indicating that this variant has a damaging effect on protein function (PMID:19088379; PS3_supporting). The computational predictor REVEL gives a score of 0.869, 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 pathogenic for von Willebrand disease type 2N. ACMG/AMP criteria applied as specified by the ClinGen von Willebrand disease Variant Curation Expert Panel: PM2_supporting, PP4_moderate, PM3, PS3, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA114135/MONDO:0015631/090
Frequency
Consequence
NM_000552.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
VWF | NM_000552.5 | c.2372C>T | p.Thr791Met | missense_variant | 18/52 | ENST00000261405.10 | |
VWF | XM_047429501.1 | c.2372C>T | p.Thr791Met | missense_variant | 18/52 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
VWF | ENST00000261405.10 | c.2372C>T | p.Thr791Met | missense_variant | 18/52 | 1 | NM_000552.5 | P1 | |
VWF | ENST00000538635.5 | n.421-50427C>T | intron_variant, non_coding_transcript_variant | 4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152180Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251384Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135880
GnomAD4 exome AF: 0.0000185 AC: 27AN: 1461850Hom.: 0 Cov.: 61 AF XY: 0.0000193 AC XY: 14AN XY: 727232
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152180Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 74342
ClinVar
Submissions by phenotype
von Willebrand disease type 2N Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 2010 | - - |
von Willebrand disease type 2 Pathogenic:1
Pathogenic, criteria provided, single submitter | research | Laboratory of Hematology, Radboud University Medical Center | Dec 10, 2020 | - - |
Abnormal bleeding Pathogenic:1
Likely pathogenic, criteria provided, single submitter | research | NIHR Bioresource Rare Diseases, University of Cambridge | Feb 01, 2019 | - - |
not provided Other:1
not provided, no classification provided | literature only | Academic Unit of Haematology, University of Sheffield | - | - - |
Hereditary von Willebrand disease Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at