ClinVar Miner

Submissions for variant NM_000552.4(VWF):c.3797C>T (p.Pro1266Leu) (rs61749370)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000314989 SCV000380604 likely pathogenic von Willebrand disorder 2017-04-27 criteria provided, single submitter clinical testing 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.
GeneDx RCV000086676 SCV000491028 likely pathogenic not provided 2018-08-02 criteria provided, single submitter clinical testing The P1266L variant in the VWF gene has been reported previously, using alternate nomenclature of P503L, in the heterozygous state in multiple unrelated individuals with atypical type 2B von Willebrand disease, which was previously called type New York/type Malmo von Willebrand disease (Holmberg et al., 1993; Federici et al., 2009; Casonato et al., 2010). The P1266L variant is often observed in cis with additional VWF variants due to gene conversion (Holmberg et al., 1993; Eikenboom et al., 1993; Gupta et al., 2005; Federici et al., 2009). The P1266L variant has also been observed in the homozygous state, along with other VWF variants due to gene conversion, in one patient with von Willebrand disease type 3 (Gupta et al., 2005); no additional segregation or phenotypic information was provided for this family. Functional assays indicate that when in the presence of other VWF variants in cis or when P1266L is present alone, this variant is responsible for enhanced platelet reactivity to lower ristocetin concentrations (Holmberg et al., 1993; Gupta et al., 2005). The P1266L variant is observed in 94/25,748 (0.365%) alleles from individuals of European Finnish background, including one homozygous individual, in the ExAC dataset (Lek et al., 2016). The P1266L variant is a semi-conservative amino acid substitution, which occurs at a position that is conserved across mammalian species. We interpret P1266L as a strong candidate for a pathogenic variant; however, the possibility it may be a rare benign variant cannot be completely excluded.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000454456 SCV000540666 uncertain significance not specified 2016-03-28 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in 3 patients with von Willebrand disease and segregated in 1 affected sibling (Holmberg 1993). Variant occurs in the pseudogene, but authors demonstrate that this variant likely occurs in the functional gene. 0.25% frequency in ExAC.
NIHR Bioresource Rare Diseases, University of Cambridge RCV000314989 SCV000899695 pathogenic von Willebrand disorder 2019-02-01 criteria provided, single submitter research
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV000853236 SCV000996153 likely pathogenic von Willebrand disease type 2 2018-06-07 criteria provided, single submitter clinical testing 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000086676 SCV001134898 pathogenic not provided 2018-11-16 criteria provided, single submitter clinical testing The best available variant frequency is uninformative. Statistically enriched in patients compared to ethnically matched controls. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. One other pathogenic or likely pathogenic variant affects the same amino acid. Assessment of experimental evidence suggests this variant results in abnormal protein function.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000454456 SCV001160172 pathogenic not specified 2018-12-26 criteria provided, single submitter clinical testing 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 as pathogenic/likely pathogenic by several laboratories 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. The proline at codon 1266 is moderately conserved but computational programs (PolyPhen2, SIFT) do not reach a consensus as to the effect of this variant on protein function. 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. 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. 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. 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. 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 Weiss HJ and Sussman II. 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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000086676 SCV001246255 pathogenic not provided 2019-04-01 criteria provided, single submitter clinical testing
OMIM RCV000000342 SCV000020486 pathogenic von Willebrand disease, type 2b 2010-05-01 no assertion criteria provided literature only
Academic Unit of Haematology, University of Sheffield RCV000086676 SCV000118880 not provided not provided no assertion provided not provided

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