rs61749370

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM1PM5PP2PP5BP4

The NM_000552.5(VWF):c.3797C>T(p.Pro1266Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000668 in 1,612,852 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1266Q) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00088 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00065 ( 2 hom. )

Consequence

VWF
NM_000552.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:19U:1O:2

Conservation

PhyloP100: 3.40

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 Uncertain_significance. Variant got 5 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000552.5

PM5

Other missense variant is known to change same aminoacid residue: Variant chr12-6019621-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 100279.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=3, Likely_pathogenic=5, not_provided=2, Pathogenic=2}.

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.

PP5

Variant 12-6019621-G-A is Pathogenic according to our data. Variant chr12-6019621-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 314.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=9, not_provided=2, Likely_pathogenic=8, Uncertain_significance=1}. Variant chr12-6019621-G-A is described in Lovd as [Likely_pathogenic]. Variant chr12-6019621-G-A is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.09753367). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VWF	NM_000552.5 linkuse as main transcript	c.3797C>T	p.Pro1266Leu	missense_variant	28/52	ENST00000261405.10
VWF	XM_047429501.1 linkuse as main transcript	c.3797C>T	p.Pro1266Leu	missense_variant	28/52

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VWF	ENST00000261405.10 linkuse as main transcript	c.3797C>T	p.Pro1266Leu	missense_variant	28/52	1	NM_000552.5	P1	P04275-1
VWF	ENST00000539641.1 linkuse as main transcript	n.595C>T		non_coding_transcript_exon_variant	3/3	3
VWF	ENST00000538635.5 linkuse as main transcript	n.421-25687C>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes

AF:

0.000881

AC:

134

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000982

Gnomad ASJ

AF:

0.00461

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00358

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000808

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000797

AC:

199

AN:

249794

Hom.:

AF XY:

0.000755

AC XY:

102

AN XY:

135048

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.00110

Gnomad ASJ exome

AF:

0.00268

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000230

Gnomad FIN exome

AF:

0.00342

Gnomad NFE exome

AF:

0.000392

Gnomad OTH exome

AF:

0.000817

GnomAD4 exome

AF:

0.000646

AC:

943

AN:

1460608

Hom.:

Cov.:

AF XY:

0.000656

AC XY:

477

AN XY:

726638

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.00105

Gnomad4 ASJ exome

AF:

0.00314

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000418

Gnomad4 FIN exome

AF:

0.00463

Gnomad4 NFE exome

AF:

0.000426

Gnomad4 OTH exome

AF:

0.000829

GnomAD4 genome

AF:

0.000880

AC:

134

AN:

152244

Hom.:

Cov.:

AF XY:

0.000927

AC XY:

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.000217

Gnomad4 AMR

AF:

0.000981

Gnomad4 ASJ

AF:

0.00461

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00358

Gnomad4 NFE

AF:

0.000809

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000700

Hom.:

Bravo

AF:

0.000842

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ExAC

AF:

0.000741

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:19Uncertain:1Other:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

von Willebrand disease type 2

Pathogenic:6

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	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	Jun 27, 2021	The VWF c.3797C>T (p.Pro1266Leu, legacy nomenclature p.Pro503Leu) missense variant is present in the A1 domain (exon 28 of 52) of the VWF protein. Gain-of-function missense or in-frame insertion or deletion variants in this essential binding domain are causative of von Willebrand disease (VWD) type 2B (PMID:20409624). The p.Pro1266Leu missense variant is usually the result of a gene conversion with a VWF pseudogene and may be present with other variants. The p.Pro1266Leu variant has been reported in multiple studies with unrelated individuals with VWD, in homozygous (all of whom carried additional variants) and in heterozygous state with or without additional variants in cis or trans (PMIDs: 8486782; PMID:18805962; PMID: 24675615; PMID: 18485763; PMID: 20305138). The p.Pro1266Leu variant was found to co-segregate with disease in an autosomal dominant pattern in a large family study (PMID: 8486782). Federici et al. (2009) reported that patients carrying the p.Pro1266Leu variant collectively had the lowest bleeding time compared to the other 61 study subjects, as well as one of the lowest bleeding severity scores (PMID: 18805962). Individuals with the p.Pro1266Leu variant are reported to have a normal platelet count, normal platelet morphology, normal VWF protein multimers present in the plasma, but with enhanced platelet aggregation. Functional studies revealed the p.Pro1266Leu variant protein showed levels of protein expression and ability to form dimers comparable to wildtype, but demonstrated platelet aggregation at lower ristocetin concentrations than wildtype, which is consistent with the reported phenotype of the patients (PMID: 8486782; PMID:28640903). This variant is present in Gnomad v3 at an allele frequency of 0.000880 and has been reported in Clinvar as Pathogenic/ Likely Pathogenic by multiple independent submitters (Variation ID: 314). Based on this evidence, the p.Pro1266Leu variant is classified as Likely Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 01, 2022	0103 - Dominant negative, gain of function and loss of function are known mechanisms of disease in this gene and are associated with von Willebrand disease (OMIM, PMID: 30488424). (I) 0108 - This gene is associated with both recessive and dominant disease. VWD can be both dominantly and recessively inherited, and is categorised into six different types: 1 (MIM#193400), 2A, 2B, 2M, 2N (MIM#613554) and 3 (MIM#277480). (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 19372260). (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 19372260). (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to leucine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 (232 heterozygotes, 1 homozygote). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (72 heterozygotes, 2 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated D3-A1 junction of the VWA N2 domain (NCBI, PMID: 26986123). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as likely pathogenic or pathogenic, and has been observed in many heterozygous individuals with type 2B VWD. It is common for heterozygous individuals to have additional variants in cis, however these variants are often reported as VUS, likely benign and/or benign (ClinVar, PMID: 18805962, 28971901, 30817071, 28640903, 35307943). This variant has also been reported in patients with type 3 VWD in the context of a homozygous gene conversion event, where additional variants including nonsense variants are also present (PMID: 29984440, 31532876, 16115133). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Individuals with this variant have demonstrated enhanced ristocitin-induced platelet aggregation relative to wildtype (PMID: 8486782). (SP) 0703 - Another missense variant comparable to the one identified in this case has moderate previous evidence for pathogenicity. This alternative change (p.(Pro1266Gln)), has been reported as likely pathogenic and pathogenic, and has been identified in multiple heterozygous individuals with type 2B von Willebrand disease (vWD). It is common for these individuals to have additional variants in cis, however these variants are often reported as VUS, likely benign and/or benign (LOVD, ClinVar, PMID: 18805962, 28971901, 30488424, 26986123, 28640903). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	May 12, 2023	The VWF c.3797C>T variant is classified as LIKELY PATHOGENIC (PM2_supporting, PS4_moderate, PM5, PS3_moderate, PP1_Supporting, PP4) The VWF c.3797C>T variant is a single nucleotide change in exon 28/52 of the VWF gene, which is predicted to change the amino acid proline at position 1266 in the protein to leucine. The variant is rare in population databases (gnomAD allele frequency = 0.088%, 134 het and 0 hom in 152,126 sequenced alleles) (PM2_supporting). It has been reported multiple times in the literature in affected individuals (PMID: 18805962, 28971901, 30817071, 28640903, 29984440, 31532876) (PS4_moderate). This variant is a novel missense change at an amino acid residue where a different missense change (p.Pro1266Gln) has been seen before (PMID: 18805962) (PM5). Functional studies show a deleterious effect of the variant on protein function (PMID: 8486782, 28640903) (PS3_moderate). The variant has been reported in the literature to segregate with disease in autosomal dominant affected individuals (PMID: 8486782) (PP1_Supporting). The clinical features of this case are highly specific for the VWF gene (Phx of RiCOF, ratio <0.6 and high bleeding score) (PP4). The variant has been reported in dbSNP (rs61749370) and in the HGMD database (CM930727). It has been reported as Conflicting interpretations of pathogenicity by other diagnostic laboratories (ClinVar Variation ID: 314). -
Pathogenic, criteria provided, single submitter	clinical testing	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	Jun 07, 2018	This variant is a missense variant located in the A1 domain of the von Willebrand factor (VWF) protein. Gain-of-function missense variants in this essential binding domain have been previously reported as causative for von Willebrand disease type 2B (PMID: 28640903). The c.3797C>T (p.Pro1266Leu) variant was found to co-segregate with disease in an autosomal dominant pattern in a large family study (PMID: 8486782). Federici et al. reported that patients carrying the p.Pro1266Leu variant collectively had the lowest bleeding time compared to the other 61 study subjects, as well as one of the lowest bleeding severity scores (PMID: 18805962). Individuals with the p.Pro1266Leu variant are reported to have a normal platelet count, normal platelet morphology, normal VWF protein multimers present in the plasma, but with enhanced platelet aggregation. Functional studies revealed the p.Pro1266Leu variant protein showed levels of protein expression and ability to form dimers comparable to wild-type, but demonstrated platelet aggregation at lower ristocetin concentrations than wildtype (PMID: 8486782, 28640903). The variant is present in the gnomAD database at an allele frequency of 0.08% (234/281180), and includes a report of one homozygous individual. Based on the combined evidence, the variant is classified as likely pathogenic. -

not provided

Pathogenic:4Uncertain:1Other:1

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 22, 2023	The VWF c.3797C>T; p.Pro1266Leu variant (rs61749370), also known as Pro503Leu, has been described in the literature in individuals with von Willibrand disease (VWD) type 2B, though it is generally reported in individuals with normal VWF multimers (Casonato 2017, Federici 2009, Holmberg 1993, Veyradier 2016, Weiss 1986). This variant has been reported to co-segregate with disease in affected family members (Holmberg 1993, Weiss 1986), and disease is often described as mild (Federici 2009, Holmberg 1993). This variant is also commonly reported in cis to a p.Val1279Ile variant (James 2007). The p.Pro1266Leu variant is reported in ClinVar (Variation ID: 314), and it is found in the Finnish European population with an overall allele frequency of 0.37% (92/25086 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.325). However, both patient samples and purified protein with the p.Pro1266Leu variant exhibit enhanced ristocitin-induced platelet aggregation relative to wildtype, consistent with type 2B VWD (Holmberg 1993, Weiss 1986). Additionally, another variant at this codon (p.Pro1266Gln) has been described in families with VWD and is considered pathogenic (Casonato 2017, Federici 2009). Based on available information, the p.Pro1266Leu variant is considered to be pathogenic. References: Casonato A et al. Type 2B von Willebrand disease with or without large multimers: A distinction of the two sides of the disorder is long overdue. PLoS One. 2017 Jun 22;12(6):e0179566. PMID: 28640903. Federici AB et al. Clinical and molecular predictors of thrombocytopenia and risk of bleeding in patients with von Willebrand disease type 2B: a cohort study of 67 patients. Blood. 2009 Jan 15;113(3):526-34. PMID: 18805962 Holmberg L et al. von Willebrand factor mutation enhancing interaction with platelets in patients with normal multimeric structure. J Clin Invest. 1993 May;91(5):2169-77. PMID: 8486782. James PD et al. The mutational spectrum of type 1 von Willebrand disease: Results from a Canadian cohort study. Blood. 2007 Jan 1;109(1):145-54. PMID: 17190853. 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. Weiss HJ et al. A new von Willebrand variant (type I, New York): increased ristocetin-induced platelet aggregation and plasma von Willebrand factor containing the full range of multimers. Blood. 1986 Jul;68(1):149-56. PMID: 3487353. -
not provided, no classification provided	literature only	Academic Unit of Haematology, University of Sheffield	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 14, 2022	Reported (sometimes as P503L due to alternate nomenclature) in multiple unrelated patients from different ethnic backgrounds with von Willebrand disease in published literature (Holmberg et al., 1993; Federici et al., 2009; Casonato et al., 2010; Gupta et al., 2005); Published functional studies suggest this variant may be responsible for enhanced platelet reactivity to lower ristocetin concentrations; however, additional studies are needed to validate the functional effect of this variant in the absence of other VWF variants (Holmberg et al., 1993; Gupta et al., 2005); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 16889557, 28980759, 31135071, 30488424, 26827609, 22995991, 8367445, 16985174, 20801902, 18805962, 8486782, 20305138, 29388750, 29924503, 29168270, 31618753, 31980526, 26986123, 28640903, 28971901, 31107984, 29984440, 31532876, 30817071, 34426522, 33556167, 33587123, 33942438, 33807613, 34758185, 31064749, 16115133, 8096943) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 31, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	VWF: PP1:Strong, PM1, PM5, PP4, PS3:Supporting, BP4 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -

Hereditary von Willebrand disease

Pathogenic:4Other:1

Pathogenic, criteria provided, single submitter	research	NIHR Bioresource Rare Diseases, University of Cambridge	Feb 01, 2019	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The VWF c.3797C>T (p.Pro1266Leu) missens variant is present in the A1 domain of the VWF protein. Gain-of-function missense or in-frame insertion or deletion variants in this essential binding domain are the sole cause of von Willebrand disease (VWD) type 2B (Goodeve 2010). The p.Pro1266Leu missense variant is usually the result of a gene conversion with a nearby VWF pseudogene and may be present with other variants. The p.Pro1266Leu variant has been reported in at least four studies in which it is found in a total of 11 unrelated individuals with VWD, including in three patients in a homozygous state (all of whom carried additional variants), four patients in a heterozygous state (all of whom carried additional variants in cis or trans), and four in a heterozygous state (Holmberg et al. 1993; Gupta et al. 2008; Federici et al. 2009; Kasatkar et al. 2014).The p.Pro1266Leu variant was found to co-segregate with disease in an autosomal dominant pattern in a large family study (Holmberg et al. 1993). Control data are unavailable for this variant, which is reported at a frequency of 0.002572 in the European (Finnish) population of the Exome Aggregation Consortium. Federici et al. (2009) reported that patients carrying the p.Pro1266Leu variant collectively had the lowest bleeding time compared to the other 61 study subjects, as well as one of the lowest bleeding severity scores. Individuals with the p.Pro1266Leu variant are reported to have a normal platelet count, normal platelet morphology, normal VWF protein multimers present in the plasma, but with enhanced platelet aggregation. Functional studies revealed the p.Pro1266Leu variant protein showed levels of protein expression and ability to form dimers comparable to wildtype, but demonstrated platelet aggregation at lower ristocetin concentrations than wildtype, which is consistent with the reported phenotype of the patients (Holmberg et al. 1993). Based on the evidence, the p.Pro1266Leu variant is classified as likely pathogenic for von Willebrand disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 04, 2023	Variant summary: VWF c.3797C>T (p.Pro1266Leu) results in a non-conservative amino acid change located in the VWA N-terminal domain (IPR032361) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0008 in 249794 control chromosomes in the gnomAD database, including 1 homozygote. The variant c.3797C>T (legacy name: P503L) has been reported in the literature in several heterozygous individuals affected with Von Willebrand Disease (e.g. Holmberg_1993, Federici_2009, Veyradier_2016, Szederjesi_2020); in general these patients had an increased bleeding tendency, but their symptoms (when present) were considered mild. Several studies noted that the Pro1266Leu variant frequently results from a gene conversion event with a VWF pseudogene (VWFP1) and occurs together with other pseudogene derived variants. Publications reported experimental evidence evaluating an impact on protein function, including protein stability, binding kinetics, platelet reactivity, and demonstrated altered function for the variant protein (or protein domain) carrying the Pro1266Leu variant in isolation (e.g. Holmberg_1993, Legan_2022). The following publications have been ascertained in the context of this evaluation (PMID: 8486782, 18805962, 32573891, 26986123, 36580664). 14 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments. Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 04, 2022	The p.Pro1266Leu variant (also reported in the literature as Pro503Leu) in VWF has been reported in 6 individuals with von Willebrand disease and segregated with disease in 5 affected individuals from 3 families (Holmberg 1993 PMID: 8486782, Federici 2009 PMID: 18805962, Casonato 2010 PMID: 20305138, Veyradier 2016 PMID: 26986123). It has also been identified in 0.4% (16/3472) of Ashkenazi Jewish chromosomes and 0.3% (38/10620) of Finnish chromosomes by gnomAD (http://gnomad.broadinstitute.org), though this may be due to pseudogene contamination. This variant has also been reported in ClinVar (Variation ID 314). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. Patients with this variant had normal plasma and platelet VWF levels, however, had higher bleeding scores than controls (Casonato 2017 PMID: 28640903). Another study found that this variant did not alter the ability to assemble dimeric species but may increase platelet aggregation, though perhaps less than other variants (Holmberg 1993 PMID: 8486782). In summary, this variant meets criteria to be classified as likely pathogenic . ACMG/AMP Criteria applied: PP1_Moderate, PS4_Moderate, PS3_Supporting, PP4. -

von Willebrand disease type 1

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Pathogenic, criteria provided, single submitter	research	Laboratory of Hematology, Radboud University Medical Center	Mar 21, 2021	- -

Von Willebrand disease type 2B

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 2010

- -

VWF-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 08, 2023

The VWF c.3797C>T variant is predicted to result in the amino acid substitution p.Pro1266Leu. (aka VWD2B Malmo/New York). This variant, and a similar variant, p.Pro1266Gln, have been reported in patients with autosomal dominant VWD types 1 or 2 (type 2B in Veyradier et al. 2016. PubMed ID: 26986123 and Freitas. 2019. PubMed ID: 30817071; aka p.Pro503Leu, type I New York or type II Malmo in Holmberg et al. 1993. PubMed ID: 8486782; Federici et al. 2009. PubMed ID: 18805962; Ahmad et al. 2013. PubMed ID: 23179108). The p.Pro1266Leu and p.Pro1266Gln substitutions are characterized by enhanced ristocetin-induced platelet aggregation (RIPA), low bleeding severity, normal VWF multimer formation, and no thrombocytopenia in most of the patients harboring one of these two variants (Holmberg et al. 1993. PubMed ID: 8486782; Federici et al. 2009. PubMed ID: 18805962). Several patients with one of these variants were shown to have slightly elevated bleeding severity and the p.Pro1266Leu substitution was reported to enhance the VWF—GP1B protein interaction (Gupta et al. 2005. PubMed ID: 16115133) suggesting that substitutions of p.Pro1266 are unlikely to be benign and are likely to be a primary cause of disease. This variant is reported in 0.37% of alleles in individuals of European (Finnish) descent in gnomAD, however this is a region with high homology to other sites in the genome so allele frequency data may not be representative. This variant is interpreted as likely pathogenic. -

Thrombocytopenia

Pathogenic:1

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

Benign

0.10

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Uncertain

-0.020

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.65

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.85

LIST_S2

Pathogenic

0.99

M_CAP

Uncertain

0.20

MetaRNN

Benign

0.098

MetaSVM

Benign

-0.58

MutationAssessor

Uncertain

2.9

MutationTaster

Benign

0.98

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.84

REVEL

Uncertain

0.33

Sift

Benign

0.27

Sift4G

Benign

0.14

Polyphen

1.0

Vest4

0.58

MVP

0.83

MPC

0.85

ClinPred

0.040

GERP RS

5.2

Varity_R

0.27

gMVP

0.84

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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