rs61749370
Variant summary
Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP5
This summary comes from the ClinGen Evidence Repository: The NM_000552.5(VWF):c.3797C>T variant in VWF is a missense variant predicted to cause substitution of proline by leucine at amino acid 1266 (p.Pro1266Leu). The population frequency and in silico pathogenicity predictors of this variant are between the pathogenic and benign thresholds established by the VWD VCEP. This variant has been extensively researched and published in the literature and has been associated with VWD type 2B Malmö/NY. This sub-type of VWD type 2B is characterized by very mild clinical presentation if any, typically no thrombocytopenia and normal multimers. No published case where the variant under consideration was the sole driver of disease had a combination of: activity/antigen ratio <0.7, documented abnormal bleeding phenotype, and enhanced response to ristocetin. This variant has been observed in at least 1 patient with an alternate molecular basis for disease. The patient with VWD type 2, also carried the Arg1315His variant, which has been classified likely pathogenic respectively for VWD type 2M respectively by the VWD VCEP (BP5; PMIDs 16985174). Additionally, carriers of this variant have been documented as being treated with DDAVP without subsequent thrombocytopenia in at least two reports (PMIDs 20305138, 27353798). This observation suggests that the enhanced response to ristocetin data in patients is potentially an artifact and does not represent a biologically relevant increase in binding affinity to GPIb. In summary, this variant meets the criteria to be classified as likely benign for hereditary VWD based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: BP5. (ClinGen von Willebrand Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for VWF Version 1.0.0; May 6th, 2025) LINK:https://erepo.genome.network/evrepo/ui/classification/CA114170/MONDO:0019565/081
Frequency
Consequence
NM_000552.5 missense
Scores
Clinical Significance
Conservation
Publications
- hereditary von Willebrand diseaseInheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
- von Willebrand disease type 2BInheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
- von Willebrand disease 2Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
- von Willebrand disease 1Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
- von Willebrand disease type 2AInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- von Willebrand disease type 2MInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- von Willebrand disease 3Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- von Willebrand disease type 2NInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Likely_benign. The variant received -1 ACMG points.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| VWF | ENST00000261405.10 | c.3797C>T | p.Pro1266Leu | missense_variant | Exon 28 of 52 | 1 | NM_000552.5 | ENSP00000261405.5 | ||
| VWF | ENST00000539641.1 | n.595C>T | non_coding_transcript_exon_variant | Exon 3 of 3 | 3 | |||||
| VWF | ENST00000538635.5 | n.421-25687C>T | intron_variant | Intron 5 of 5 | 4 |
Frequencies
GnomAD3 genomes 0.000881 AC: 134AN: 152126Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.000797 AC: 199AN: 249794 AF XY: 0.000755 show subpopulations
GnomAD4 exome AF: 0.000646 AC: 943AN: 1460608Hom.: 2 Cov.: 38 AF XY: 0.000656 AC XY: 477AN XY: 726638 show subpopulations ⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
Age Distribution
GnomAD4 genome 0.000880 AC: 134AN: 152244Hom.: 0 Cov.: 32 AF XY: 0.000927 AC XY: 69AN XY: 74428 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
not provided Pathogenic:5Uncertain:1Other:1
PP1_strong, PP5, PM1, PM5, PS3
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)
VWF: PP1:Strong, PM1, PM5, PP4, PS3:Supporting, BP4
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.
von Willebrand disease type 2 Pathogenic:6
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as pathogenic. The following criteria are met: 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) 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) 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) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
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.
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.
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).
Hereditary von Willebrand disease Pathogenic:4Benign:1Other:1
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.
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.
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.
The NM_000552.5(VWF):c.3797C>T variant in VWF is a missense variant predicted to cause substitution of proline by leucine at amino acid 1266 (p.Pro1266Leu). The population frequency and in silico pathogenicity predictors of this variant are between the pathogenic and benign thresholds established by the VWD VCEP. This variant has been extensively researched and published in the literature and has been associated with VWD type 2B Malmö/NY. This sub-type of VWD type 2B is characterized by very mild clinical presentation if any, typically no thrombocytopenia and normal multimers. No published case where the variant under consideration was the sole driver of disease had a combination of: activity/antigen ratio <0.7, documented abnormal bleeding phenotype, and enhanced response to ristocetin. This variant has been observed in at least 1 patient with an alternate molecular basis for disease. The patient with VWD type 2, also carried the Arg1315His variant, which has been classified likely pathogenic respectively for VWD type 2M respectively by the VWD VCEP (BP5; PMIDs 16985174). Additionally, carriers of this variant have been documented as being treated with DDAVP without subsequent thrombocytopenia in at least two reports (PMIDs 20305138, 27353798). This observation suggests that the enhanced response to ristocetin data in patients is potentially an artifact and does not represent a biologically relevant increase in binding affinity to GPIb. In summary, this variant meets the criteria to be classified as likely benign for hereditary VWD based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: BP5. (ClinGen von Willebrand Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for VWF Version 1.0.0; May 6th, 2025)
von Willebrand disease type 1 Pathogenic:2
Von Willebrand disease type 2B Pathogenic:1
VWF-related disorder Pathogenic:1
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.
von Willebrand disease type 1;C1264041:von Willebrand disease type 3 Pathogenic:1
Thrombocytopenia Pathogenic:1
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at