NM_000552.5(VWF):c.3797C>T (p.Pro1266Leu) AND Hereditary von Willebrand disease

Germline classification:: Pathogenic/Likely pathogenic (5 submissions)
Last evaluated:: Oct 4, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000314989.11

Allele description [Variation Report for NM_000552.5(VWF):c.3797C>T (p.Pro1266Leu)]

NM_000552.5(VWF):c.3797C>T (p.Pro1266Leu)

Gene:

VWF:von Willebrand factor [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

12p13.31

Genomic location:

Preferred name:

NM_000552.5(VWF):c.3797C>T (p.Pro1266Leu)

Other names:

p.P1266L

HGVS:

NC_000012.12:g.6019621G>A
NG_009072.2:g.110050C>T
NM_000552.5:c.3797C>TMANE SELECT
NM_000552.5:c.3797C>T
NP_000543.2:p.Pro1266Leu
NP_000543.3:p.Pro1266Leu
LRG_587t1:c.3797C>T
LRG_587:g.110050C>T
LRG_587p1:p.Pro1266Leu
NC_000012.11:g.6128787G>A
NC_000012.12:g.6019621G>A
NG_009072.1:g.110050C>T
NM_000552.2:c.3797C>T
NM_000552.3:c.3797C>T
NM_000552.4:c.3797C>T
P04275:p.Pro1266Leu

Protein change:

P1266L; PRO1266LEU

Links:

UniProtKB: P04275#VAR_005791; OMIM: 613160.0033; dbSNP: rs61749370

NCBI 1000 Genomes Browser:

rs61749370

Molecular consequence:

NM_000552.5:c.3797C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hereditary von Willebrand disease
Identifiers:: MONDO: MONDO:0019565; MeSH: D014842; MedGen: C5703318

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000380604	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Likely pathogenic (Apr 27, 2017)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 20409624, 18805962, 8486782, 24675615, 18485763 Citation Link,
SCV000540666	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (Nov 4, 2022)	germline	clinical testing	PubMed (13) [See all records that cite these PMIDs] 8486782, 26986123, 18485763, 23401895, 18315546, 27683759, 16985174, 18805962, 26827609, 16115133, 28640903, 28971901, 25741868
SCV000899695	NIHR Bioresource Rare Diseases, University of Cambridge - ThromboGenomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 1, 2019)	unknown	research	PubMed (2) [See all records that cite these PMIDs] 25741868, 31064749
SCV002507244	GeneReviews	no classification provided	not provided	germline	literature only
SCV004122478	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Oct 4, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 26986123, 18805962, 8486782, 36580664, 32573891 Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, literature only
European	unknown	yes	1	not provided	not provided	1	not provided	research

Citations

PubMed

The genetic basis of von Willebrand disease.

Goodeve AC.

Blood Rev. 2010 May;24(3):123-34. doi: 10.1016/j.blre.2010.03.003. Epub 2010 Apr 20. Review.

PubMed [citation]

PMID:: 20409624

Genetic heterogeneity in a large cohort of Indian type 3 von Willebrand disease patients.

Kasatkar P, Shetty S, Ghosh K.

PLoS One. 2014;9(3):e92575. doi: 10.1371/journal.pone.0092575.

PubMed [citation]

PMID:: 24675615
PMCID:: PMC3967998

See all PubMed Citations (18)

Details of each submission

From Illumina Laboratory Services, Illumina, SCV000380604.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000540666.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (13)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From NIHR Bioresource Rare Diseases, University of Cambridge - ThromboGenomics, SCV000899695.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	European	1	not provided	not provided	research	PubMed (2)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	1	not provided	not provided		1	not provided	not provided	not provided

From GeneReviews, SCV002507244.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004122478.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 26, 2024

ClinVar

Relating variation to medicine