12-6019298-G-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.4120C>T​(p.Arg1374Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000031 in 1,613,796 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. R1374H) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

VWF
NM_000552.5 missense

Scores

15
2
2

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:12O:1

Conservation

PhyloP100: 5.01
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 chr12-6019297-C-T 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, 0.984
PP5
Variant 12-6019298-G-A is Pathogenic according to our data. Variant chr12-6019298-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 100329.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-6019298-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
VWFNM_000552.5 linkc.4120C>T p.Arg1374Cys missense_variant Exon 28 of 52 ENST00000261405.10 NP_000543.3 P04275-1
VWFXM_047429501.1 linkc.4120C>T p.Arg1374Cys 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.4120C>T p.Arg1374Cys missense_variant Exon 28 of 52 1 NM_000552.5 ENSP00000261405.5 P04275-1
VWFENST00000538635.5 linkn.421-25364C>T intron_variant Intron 5 of 5 4

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152152
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
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
250960
Hom.:
0
AF XY:
0.00000737
AC XY:
1
AN XY:
135690
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000882
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1461644
Hom.:
0
Cov.:
38
AF XY:
0.00000550
AC XY:
4
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:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000360
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152152
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74314
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
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:12Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:5Other:1
not provided, no classification providedliterature onlyAcademic Unit of Haematology, University of Sheffield-- -
Pathogenic, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesJul 18, 2024The VWF c.4120C>T; p.Arg1374Cys variant (rs61750071), also known as R611C, is reported in the literature in several individuals affected with von Willebrand disease type 2A or type 2M (Berber 2013, Borras 2017, Flood 2013, Goodeve 2007, Hilbert 1995, Veyradier 2016). This variant is also reported in ClinVar (Variation ID: 100329), but is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.757). Additionally, other amino acid substitutions at this codon (His, Leu, Ser) have been reported in individuals with von Willebrand disease type 2A or type 2M and are considered pathogenic (Borras 2017, Flood 2013, Goodeve 2007, Hilbert 1995, Veyradier 2016). Based on available information, this variant is considered to be pathogenic. References: Berber E et al. A common VWF exon 28 haplotype in the Turkish population. Clin Appl Thromb Hemost. 2013 Sep;19(5):550-6. PMID: 22473027. Borras N et al. Molecular and clinical profile of von Willebrand disease in Spain (PCM-EVW-ES): comprehensive genetic analysis by next-generation sequencing of 480 patients. Haematologica. 2017 Dec;102(12):2005-2014. PMID: 28971901. Corrales I et al. Rapid molecular diagnosis of von Willebrand disease by direct sequencing. Detection of 12 novel putative mutations in VWF gene. Thromb Haemost. 2009 Mar;101(3):570-6. PMID: 19277422. Flood VH et al. Collagen binding provides a sensitive screen for variant von Willebrand disease. Clin Chem. 2013 Apr;59(4):684-91. PMID: 23340442. Goodeve A et al. Phenotype and genotype of a cohort of families historically diagnosed with type 1 von Willebrand disease in the European study, Molecular and Clinical Markers for the Diagnosis and Management of Type 1 von Willebrand Disease (MCMDM-1VWD). Blood. 2007 Jan 1;109(1):112-21. PMID: 16985174. Hilbert L et al. Identification of two mutations (Arg611Cys and Arg611His) in the A1 loop of von Willebrand factor (vWF) responsible for type 2 von Willebrand disease with decreased platelet-dependent function of vWF. Blood. 1995 Aug 1;86(3):1010-8. PMID: 7620154. Veyradier A et al. A Laboratory Phenotype/Genotype Correlation of 1167 French Patients From 670 Families With von Willebrand Disease: A New Epidemiologic Picture. Medicine (Baltimore). 2016 Mar;95(11):e3038. PMID: 26986123. -
Pathogenic, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicAug 26, 2024PP1, PP3, PP5, PM2, PM5, PS3, PS4_moderate -
Pathogenic, criteria provided, single submitterclinical testingCenter for Genomic Medicine, Rigshospitalet, Copenhagen University HospitalMar 04, 2025Classification criteria: PS4_moderate, PS3, PM2_supporting, PP3_supporting, PP4_supporting -
Pathogenic, criteria provided, single submitterclinical testingGeneDxDec 07, 2023Published functional studies demonstrate a damaging effect of this variant due to decreased secretion of von Willebrand factor, decreased collagen binding, and absent platelet glycoprotein Ib binding (PMID: 28544236, 7620154); Reported in association with von Willebrand disease types 2A and 2M (PMID: 16247740, 7620154); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as p.(R611C); This variant is associated with the following publications: (PMID: 22102201, 7620154, 25185554, 28544236, 16247740, 30817071, 27414491, 23340442, 23290978, 33556167, 31064749, 34758185) -
Pathogenic, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoFeb 16, 2017- -
von Willebrand disease type 2 Pathogenic:4
Pathogenic, criteria provided, single submitterclinical testingGenetics and Molecular Pathology, SA PathologyJun 05, 2023The VWF c.4120C>T variant is classified as PATHOGENIC (PS4_Mod, PM2_supp, PM5, PS3, PP1_Moderate) The VWF c.4120C>T variant is a single nucleotide change in exon 28/52 of the VWF gene, which is predicted to change the amino acid arginine at position 1374 in the protein to cysteine. The variant has been reported in multiple individuals with a clinical presentation of bleeding disorders and low VWF activity to antigen ratios (PMID: 35307943, 34758185, 30817071, 31064749) (PS4_Mod). This variant is rare in population databases (gnomAD allele frequency = 0.00065%; 1 het and 0 hom in 152152 sequenced alleles) (PM2_Supp) and co-segregates with disease (PMID:16247740) (PP1_moderate). This variant is a missense change at an amino acid residue where different missense changes (p.Arg1374His, p.Arg1374Cys, p.Arg1374Leu, p.Arg1374Ser) have been seen before (PM5). in vitro and in vivo studies showed that the variant results in decreased VWF synthesis and impaired GPIb binding (PMID:28544236, 11150026) (PS3). The variant has been reported in dbSNP (rs61750071) and in the HGMD database: CM951304. It has also been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 100329). -
Pathogenic, no assertion criteria providedclinical testingAngelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca Granda Ospedale Maggiore PoliclinicoApr 26, 2022- -
Pathogenic, criteria provided, single submitterresearchLaboratory of Hematology, Radboud University Medical CenterJan 21, 2022- -
Pathogenic, criteria provided, single submitterclinical testingISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology-- -
Hereditary von Willebrand disease Pathogenic:3
Pathogenic, criteria provided, single submitterclinical testingVictorian Clinical Genetics Services, Murdoch Childrens Research InstituteMay 25, 2020Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0104 - Dominant Negative is a mechanism of disease for this gene. (N) 0108 - This gene is known to be associated with both recessive and dominant disease (OMIM). (N) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine (exon 28). (N) 0251 - Variant is heterozygous. (N) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (P) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (P) 0600 - Variant is located in an annotated domain or motif (VWF type A domain; NCBI, PDB). (N) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic (ClinVar) and in more than 5 unrelated patients with type 2A or 2M von Willebrand disease (PMIDs: 16247740, 27414491, 30349898). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -
Pathogenic, criteria provided, single submitterresearchNIHR Bioresource Rare Diseases, University of CambridgeFeb 01, 2019- -
Pathogenic, no assertion criteria providedclinical testingClinical Molecular Genetics Laboratory, Johns Hopkins All Children's HospitalJul 13, 2007- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.71
BayesDel_addAF
Pathogenic
0.56
D
BayesDel_noAF
Pathogenic
0.56
CADD
Pathogenic
32
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.57
D
Eigen
Pathogenic
0.84
Eigen_PC
Pathogenic
0.71
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Pathogenic
1.0
D
M_CAP
Pathogenic
0.87
D
MetaRNN
Pathogenic
0.98
D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.8
H
PrimateAI
Uncertain
0.51
T
PROVEAN
Benign
-0.14
N
REVEL
Pathogenic
0.76
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.95
MutPred
0.84
Gain of catalytic residue at K1371 (P = 2e-04);
MVP
0.94
MPC
1.1
ClinPred
0.99
D
GERP RS
5.0
Varity_R
0.51
gMVP
0.86

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: rs61750071; hg19: chr12-6128464; API