rs61749367
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP5BS1BP4
This summary comes from the ClinGen Evidence Repository: NM_000552.5(VWF):c.3686T>G is a missense variant encoding a substitution of valine by glycine at position 1229. It has been reported in at least seven probands, two of whom have a phenotype specific for VWD Type 2B and one of whom has a phenotype specific for VWD Type 2M (PMID:8134377, PMID:17190853, PMID:31064749, PMID:16115133). However, the phenotypes are not consistent, and other variants present in cis or in trans are suspected to be disease-causing. At least one patient with this variant displayed excessive mucocutaneous bleeding as well as a laboratory phenotypes of loss of high molecular weight multimers and increased ristocetin-induced platelet aggregation showing gain of function, which together are highly specific for VWD type 2B (PMID:8134377, PMID:2657729). Although three other genotype-positive family members were similarly affected with a VWD Type 2B phenotype, the patients harbored other variants in cis, including p.Arg1306Trp, which has been classified as Pathogenic by the ClinGen VWD VCEP (BP5). The variant has also been observed in at least three control individuals (PMID:22197721). The computational predictor REVEL gives a score of 0.149, which is below the ClinGen VWD VCEP threshold of <0.290 and does not predict a damaging effect on VWF function (BP4). Additionally, the computational splicing predictor SpliceAI indicated that the variant has no impact on splicing. RIPA studies indicate that this variant does not contribute to enhanced ristocetin-induced platelet aggregation and that another variant found in the same patient was responsible instead (PMID:16115133). The Grpmax filtering allele frequency in gnomAD v4.1 is 0.01529 (based on 1200/74796 alleles, with 10 homozygotes) in the African/African-American population, which is above the ClinGen VWD VCEP threshold (>0.01) for BS1. In summary, the variant meets the criteria to be classified as likely benign based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: BS1, BP5, BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA228433/MONDO:0019565/090
Frequency
Consequence
NM_000552.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
VWF | NM_000552.5 | c.3686T>G | p.Val1229Gly | missense_variant | 28/52 | ENST00000261405.10 | |
VWF | XM_047429501.1 | c.3686T>G | p.Val1229Gly | missense_variant | 28/52 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
VWF | ENST00000261405.10 | c.3686T>G | p.Val1229Gly | missense_variant | 28/52 | 1 | NM_000552.5 | P1 | |
VWF | ENST00000539641.1 | n.484T>G | non_coding_transcript_exon_variant | 3/3 | 3 | ||||
VWF | ENST00000538635.5 | n.421-25798T>G | intron_variant, non_coding_transcript_variant | 4 |
Frequencies
GnomAD3 genomes ? AF: 0.00638 AC: 971AN: 152206Hom.: 6 Cov.: 32
GnomAD3 exomes AF: 0.00157 AC: 380AN: 241848Hom.: 2 AF XY: 0.00158 AC XY: 208AN XY: 131946
GnomAD4 exome AF: 0.00180 AC: 2626AN: 1458030Hom.: 11 Cov.: 38 AF XY: 0.00196 AC XY: 1421AN XY: 725198
GnomAD4 genome ? AF: 0.00641 AC: 977AN: 152324Hom.: 6 Cov.: 32 AF XY: 0.00608 AC XY: 453AN XY: 74492
ClinVar
Submissions by phenotype
not provided Benign:3Other:1
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Aug 18, 2017 | - - |
not provided, no classification provided | literature only | Academic Unit of Haematology, University of Sheffield | - | - - |
Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Apr 30, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Apr 03, 2021 | See Variant Classification Assertion Criteria. - |
not specified Benign:2
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Aug 03, 2018 | - - |
von Willebrand disease type 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Laboratory of Hematology, Radboud University Medical Center | Apr 21, 2021 | - - |
von Willebrand disease type 3 Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Laboratory of Hematology, Radboud University Medical Center | Apr 21, 2021 | - - |
Abnormality of coagulation Uncertain:1
Uncertain significance, criteria provided, single submitter | research | NIHR Bioresource Rare Diseases, University of Cambridge | Feb 01, 2019 | - - |
von Willebrand disease type 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Laboratory of Hematology, Radboud University Medical Center | Apr 21, 2021 | - - |
Hereditary von Willebrand disease Uncertain:1
Uncertain significance, no assertion criteria provided | research | ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at