chr12-6019297-C-A

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_000552.5(VWF):​c.4121G>T​(p.Arg1374Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1374C) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

VWF
NM_000552.5 missense

Scores

14
2
3

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5O:1

Conservation

PhyloP100: 6.75
Variant links:
Genes affected
VWF (HGNC:12726): (von Willebrand factor) This gene encodes a glycoprotein involved in hemostasis. The encoded preproprotein is proteolytically processed following assembly into large multimeric complexes. These complexes function in the adhesion of platelets to sites of vascular injury and the transport of various proteins in the blood. Mutations in this gene result in von Willebrand disease, an inherited bleeding disorder. An unprocessed pseudogene has been found on chromosome 22. [provided by RefSeq, Oct 2015]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 19 ACMG points.

PM1
In a disulfide_bond (size 186) in uniprot entity VWF_HUMAN there are 58 pathogenic changes around while only 4 benign (94%) in NM_000552.5
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr12-6019298-G-A is described in Lovd as [Pathogenic].
PP2
Missense variant in the VWF gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 149 curated pathogenic missense variants (we use a threshold of 10). The gene has 28 curated benign missense variants. Gene score misZ: 0.98969 (below the threshold of 3.09). Trascript score misZ: 3.5064 (above the threshold of 3.09). GenCC associations: The gene is linked to von Willebrand disease type 2M, hereditary von Willebrand disease, von Willebrand disease type 2B, von Willebrand disease type 2N, von Willebrand disease 2, von Willebrand disease type 2A, von Willebrand disease 3, von Willebrand disease 1.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.984
PP5
Variant 12-6019297-C-A is Pathogenic according to our data. Variant chr12-6019297-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 100331.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-6019297-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
VWFNM_000552.5 linkc.4121G>T p.Arg1374Leu missense_variant Exon 28 of 52 ENST00000261405.10 NP_000543.3 P04275-1
VWFXM_047429501.1 linkc.4121G>T p.Arg1374Leu missense_variant Exon 28 of 52 XP_047285457.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
VWFENST00000261405.10 linkc.4121G>T p.Arg1374Leu missense_variant Exon 28 of 52 1 NM_000552.5 ENSP00000261405.5 P04275-1
VWFENST00000538635.5 linkn.421-25363G>T intron_variant Intron 5 of 5 4

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
6.84e-7
AC:
1
AN:
1461642
Hom.:
0
Cov.:
38
AF XY:
0.00
AC XY:
0
AN XY:
727132
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:2Other:1
Mar 29, 2023
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals affected with von Willebrand Disease, Types 2A or 2M (PMIDs: 30046717 (2017), 26986123 (2016), 19277422 (2009), 17408416 (2007), 9198195 (1997)), and 2 other known pathogenic variants affect the same amino acid (PMID: 11843298 (2002)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic. -

-
Academic Unit of Haematology, University of Sheffield
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

- -

Aug 16, 2024
Mayo Clinic Laboratories, Mayo Clinic
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PP3, PP5, PM2, PM5, PS4_moderate -

Hereditary von Willebrand disease Pathogenic:2
Sep 12, 2023
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: VWF c.4121G>T (p.Arg1374Leu) results in a non-conservative amino acid change located in a type A domain (IPR002035) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250960 control chromosomes (gnomAD). c.4121G>T has been reported in the literature in multiple individuals affected with Von Willebrand Disease (e.g., Meyer_1997, Veyradier_2007, Gadisseur_2009, Veyradier_2016, Borras_2017, Kim_2019). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 28971901, 19506361, 9198195, 17408416, 26986123, 31240882). Two submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

-
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

von Willebrand disease type 2 Pathogenic:1
Dec 10, 2020
Laboratory of Hematology, Radboud University Medical Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.74
BayesDel_addAF
Pathogenic
0.57
D
BayesDel_noAF
Pathogenic
0.57
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.64
D
Eigen
Pathogenic
0.92
Eigen_PC
Pathogenic
0.79
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Pathogenic
0.99
D
M_CAP
Pathogenic
0.89
D
MetaRNN
Pathogenic
0.98
D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
3.8
H
PrimateAI
Benign
0.46
T
PROVEAN
Benign
-1.9
N
REVEL
Pathogenic
0.91
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.96
MutPred
0.81
Gain of catalytic residue at K1371 (P = 9e-04);
MVP
0.95
MPC
0.99
ClinPred
0.99
D
GERP RS
5.0
Varity_R
0.76
gMVP
0.88

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs61750072; hg19: chr12-6128463; API