12-6018901-G-A

Position:

chr12-6018901-G-A

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PP2PP3_StrongPP5_Very_Strong

The NM_000552.5(VWF):c.4517C>T(p.Ser1506Leu) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000023 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

VWF
NM_000552.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11O:2

Conservation

PhyloP100: 9.77

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]

VWF links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 15 ACMG points.

PM1

In a domain VWFA 2 (size 167) in uniprot entity VWF_HUMAN there are 14 pathogenic changes around while only 2 benign (88%) in NM_000552.5

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), VWF. . Gene score misZ 0.98969 (greater than the threshold 3.09). Trascript score misZ 3.5064 (greater than threshold 3.09). GenCC has associacion of gene with 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 12-6018901-G-A is Pathogenic according to our data. Variant chr12-6018901-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 100369.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VWF	NM_000552.5 linkuse as main transcript	c.4517C>T	p.Ser1506Leu	missense_variant	28/52	ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1 linkuse as main transcript	c.4517C>T	p.Ser1506Leu	missense_variant	28/52		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10 linkuse as main transcript	c.4517C>T	p.Ser1506Leu	missense_variant	28/52	1	NM_000552.5	ENSP00000261405	P1	P04275-1
VWF	ENST00000538635.5 linkuse as main transcript	n.421-24967C>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

151574

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000232

AC:

AN:

1422766

Hom.:

Cov.:

AF XY:

0.0000240

AC XY:

AN XY:

707010

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000236

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000261

Gnomad4 SAS exome

AF:

0.0000237

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000185

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

151574

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74014

Gnomad4 AFR

AF:

0.00

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

Alfa

AF:

0.505

Hom.:

212

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

von Willebrand disease type 2

Pathogenic:4

Likely pathogenic, no assertion criteria provided	clinical testing	Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico	Apr 26, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Immunology and Genetics Kaiserslautern	Jan 06, 2023	ACMG Criteria: PS3, PM2, PP1, PP3, PP4, PP5; Variant was found in heterozygous state. -
Likely pathogenic, criteria provided, single submitter	clinical testing	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	-	- -
Pathogenic, criteria provided, single submitter	research	Laboratory of Hematology, Radboud University Medical Center	Dec 10, 2020	- -

not provided

Pathogenic:3Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 04, 2021	PS2, PS3, PS4_moderate, PM1, PM2, PM6, PP3, PP5 -
not provided, no classification provided	literature only	Academic Unit of Haematology, University of Sheffield	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 10, 2017	The S1506L variant in the VWF gene has been reported previously in the heterozygous state in multiple unrelated individuals with von Willebrand disease type 2A (Culpan et al., 1998; Hassenpflug et al., 2006; Jacobi et al., 2012; Berber et al., 2013; Vayradier et al., 2016). The S1506L variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The S1506L variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals. Functional studies of the S1506L variant demonstrate a damaging effect with decreased expression of high- and intermediate-molecular-weight multimers of von Willebrand factor and severely impaired secretion of von Willebrand factor (Hassenpflug et al., 2006; Jacobi et al., 2012). Missense variants in nearby residues (L1503P, L1503R, L1503Q, G1505R, G1505E, I1509V) have been reported in the Human Gene Mutation Database in association with von Willebrand disease (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret S1506L as a likely pathogenic variant. -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 08, 2023	In the published literature, the variant has been reported in multiple individuals with Type 2A von Willebrand disease (vWD), including three de novo patients (PMIDs: 1380739 (1992), 7906590 (1993), 25477497 (2015), 27766062 (2016), 28536718 (2017), 31249928 (2018), 31939074 (2020), and 36226571 (2022)). In vitro functional studies, as well as laboratory testing performed on vWD patients, showed this variant results in a deleterious effect on VWD protein function (PMIDs: 1537829 (1992), 16322474 (2006), 22431572 (2012), and 27443694 (2016)). It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). However, it is reported with a frequency of 3% in a population of apparently healthy Japanese individuals, and as a polymorphism (1%) in the French population (see rs61750100 at HGVD (http://www.hgvd.genome.med.kyoto-u.ac.jp) and PMID: 22473027 (2013)).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. -

Hereditary von Willebrand disease

Pathogenic:3Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 01, 2023	Variant summary: VWF c.4517C>T (p.Ser1506Leu) 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 frequency data for this variant in gnomAD (versions 2 and 4) is considered unreliable, as metrics indicate poor data quality at this position. c.4517C>T has been reported in the literature in many heterozygous individuals affected with Von Willebrand Disease Type 2A (e.g., Jacobi_2012, Berber_2013, Fidalgo_2016, Leinoe_2017, Boender_2018, Chen_2022), including as a de novo variant with confirmed maternity/paternity (Chen_2022). These data indicate that the variant is likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function, finding that the variant results in severely impaired secretion (e.g., Jacobi_2012, Hassenpflug_2006). The following publications have been ascertained in the context of this evaluation (PMID: 22473027, 30358069, 36226571, 26988807, 16322474, 22431572, 28748566). Six 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. -
Likely pathogenic, no assertion criteria provided	research	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	-	- -
Likely pathogenic, criteria provided, single submitter	research	NIHR Bioresource Rare Diseases, University of Cambridge	Feb 01, 2019	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

Von Willebrand disease type 2A

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Versiti Diagnostic Laboratories, Versiti, Inc

Apr 10, 2024

The missense variant VWF c.4517C>T, p.Ser1506Leu (p.S1506L; legacy p.S743L) in exon 28 changes amino acid serine at codon 1506 to leucine. The serine at this residue is highly conserved among species. This amino acid change occurs in the A2 domain, a functional domain that is cleaved by ADAMTS13 (PMID:24928861); variants in this domain that cause increased VWF susceptibility for ADAMTS13 proteolysis are a known cause of type 2A VWD (PMID:16322474). Pathogenic variants in VWF are associated with autosomal dominant or autosomal recessive von Willebrand disease (VWD), characterized by quantitative or qualitative deficiencies in von Willebrand factor and resulting in prolonged bleeding. This sequence variant has been previously reported in patients with type 2A von Willebrand disease including a de novo report (PMID:1324533; PMID:22329792; PMID: 22431572; PMID:26986123; PMID:28971901; PMID:36226571). This variant was observed in 20 patients within our laboratory cohort. All patients were heterozygous for this variant; only 1 patient out of 20 had an additional known VWF variant classified as a variant of uncertain significance. 14 of the 20 patients had a clinical diagnosis of type 2A VWD prior to genetic testing. For all 13 patients in which multimer analysis results were provided, results were abnormal showing absence of the high molecular weight multimers (MWM) in 10, absence of higher and intermediate MWM in 2, and absence of highest MWM in 1 patient. 5 patients with this variant and a clinical diagnosis of type 2A had negative VWF inhibitor studies and normal 2B Binding testing performed through our institution. To date, this variant has not been reported in the general population (GnomAD v2, GnomAD v3, ExAC, Variation Viewer). Functional studies of the variant in mammalian cells demonstrated defective multimerization, impaired VWF secretion, and loss of regulated storage of VWF in Weibel-Palade body-like granules (PMID:16322474; PMID:22431572). In summary, the collective evidence supports VWF c.4517C>T, p.Ser1506Leu as a pathogenic variant for type 2A von Willebrand disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.81

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.46

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.74

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

M_CAP

Pathogenic

0.85

MetaRNN

Pathogenic

0.98

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.1

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-3.1

REVEL

Pathogenic

0.80

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.0050

Polyphen

1.0

Vest4

0.82

MutPred

0.80

Gain of catalytic residue at I1509 (P = 2e-04);

MVP

0.95

MPC

0.89

ClinPred

0.99

GERP RS

4.0

Varity_R

0.87

gMVP

0.92

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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