rs61750100

chr12-6018901-G-A

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PP2 PP3_Strong PP5_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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9 O:2
• Conservation: PhyloP100: 9.77

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]

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_000552.5
• PP2: Missense variant where missense usually causes diseases, VWF
• 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	UniProt
VWF	NM_000552.5	c.4517C>T	p.Ser1506Leu	missense_variant	28/52	ENST00000261405.10
VWF	XM_047429501.1	c.4517C>T	p.Ser1506Leu	missense_variant	28/52

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 151574 Hom.: 0 Cov.: 32 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: 33 AN: 1422766 Hom.: 0 Cov.: 98 AF XY: 0.0000240 AC XY: 17 AN XY: 707010

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: 0 AN: 151574 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 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:9 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3 Other: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:3 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Likely pathogenic, no assertion criteria provided	research	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	-	- -
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, criteria provided, single submitter	research	NIHR Bioresource Rare Diseases, University of Cambridge	Feb 01, 2019	- -

von Willebrand disease type 2 Pathogenic:3

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	research	Laboratory of Hematology, Radboud University Medical Center	Dec 10, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.74	D
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.1	H
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.1	D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.82
MutPred		0.80		Gain of catalytic residue at I1509 (P = 2e-04);
MVP		0.95
MPC		0.89
ClinPred		0.99	D
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

Other links and lift over

dbSNP: rs61750100; hg19: chr12-6128067; COSMIC: COSV54611132; COSMIC: COSV54611132;