chr12-6019501-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_Moderate

The NM_000552.5(VWF):​c.3917G>A​(p.Arg1306Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1306L) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

VWF
NM_000552.5 missense

Scores

6
7
6

Clinical Significance

Pathogenic criteria provided, single submitter P:3O:1

Conservation

PhyloP100: 1.22
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 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 chr12-6019501-C-A is described in Lovd as [Likely_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, 0.933
PP5
Variant 12-6019501-C-T is Pathogenic according to our data. Variant chr12-6019501-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 100300.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-6019501-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
VWFNM_000552.5 linkc.3917G>A p.Arg1306Gln missense_variant Exon 28 of 52 ENST00000261405.10 NP_000543.3 P04275-1
VWFXM_047429501.1 linkc.3917G>A p.Arg1306Gln 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.3917G>A p.Arg1306Gln missense_variant Exon 28 of 52 1 NM_000552.5 ENSP00000261405.5 P04275-1
VWFENST00000538635.5 linkn.421-25567G>A intron_variant Intron 5 of 5 4
VWFENST00000539641.1 linkn.*27G>A downstream_gene_variant 3

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152188
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461648
Hom.:
0
Cov.:
38
AF XY:
0.00
AC XY:
0
AN XY:
727134
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:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152188
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74328
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:3Other:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Pathogenic:1Other:1
May 04, 2022
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 multiple individuals with type 2B von Willebrand disease (VWD) (PMIDs: 9198195 (1997), 9858249 (1998), 17598021 (2007), 28971901 (2017)). This variant is located in the glycoprotein Ib (GPIb)-binding site of VWF, and has been shown to allow normal VWF multimerization but cause abnormal increased affinity of plasma VWF for platelets (PMIDs: 9108394 (1997), 9858249 (1998), 20200350 (2010)). 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

- -

von Willebrand disease type 2 Pathogenic:1
Apr 26, 2022
Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

VWF-related disorder Pathogenic:1
Mar 18, 2024
PreventionGenetics, part of Exact Sciences
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

The VWF c.3917G>A variant is predicted to result in the amino acid substitution p.Arg1306Gln. This variant (aka p.Arg543Gln) has been reported in multiple individuals with von Willebrand disease (VWD) type 2B (Hilbert et al. 1998. PubMed ID: 9858249; Szántó et al. 2007. PubMed ID: 17598021; Borràs et al. 2017. PubMed ID: 28971901. Table S7; Sadler et al. 2021. PubMed ID: 33556167. Table S3). In vitro and in vivo functional studies have demonstrated that this variant increases VWF binding affinity toward platelet-bound glycoprotein 1b-alpha (GP1Ba), leading to platelet aggregation (Yago et al. 2008. PubMed ID: 18725999; Rayes et al. 2010. PubMed ID: 20200350; Tischer et al. 2014. PubMed ID: 25185554). Additional studies using an in vivo mouse model found that this variant also increases VWF binding affinity toward macrophage-bound LRP1, leading to increased clearance of mutant VWF from circulation (Wohner et al. 2015. PubMed ID: 25728415). This variant has not been reported in a large population database, indicating this variant is rare. Of note, a different missense variant at the same amino acid position (p.Arg1306Trp) is one of the most commonly reported disease-causing variants in patients with VWD type 2B (for example, see Ozeki et al. 2010. PubMed ID: 19740526; Borràs et al. 2017. PubMed ID: 28971901; Sadler et al. 2021. PubMed ID: 33556167). Taken together, the p.Arg1306Gln variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.092
BayesDel_addAF
Pathogenic
0.34
D
BayesDel_noAF
Pathogenic
0.25
CADD
Benign
22
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.39
T
Eigen
Uncertain
0.39
Eigen_PC
Uncertain
0.33
FATHMM_MKL
Benign
0.61
D
LIST_S2
Uncertain
0.94
D
M_CAP
Pathogenic
0.61
D
MetaRNN
Pathogenic
0.93
D
MetaSVM
Uncertain
0.20
D
MutationAssessor
Uncertain
2.2
M
PrimateAI
Benign
0.33
T
PROVEAN
Benign
-1.1
N
REVEL
Pathogenic
0.72
Sift
Uncertain
0.014
D
Sift4G
Uncertain
0.012
D
Polyphen
0.98
D
Vest4
0.77
MutPred
0.76
Gain of catalytic residue at R1306 (P = 0.0024);
MVP
0.74
MPC
0.96
ClinPred
0.85
D
GERP RS
4.1
Varity_R
0.51
gMVP
0.69

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: rs61749385; hg19: chr12-6128667; API