12-6019621-G-T
Variant summary
Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP4
This summary comes from the ClinGen Evidence Repository: The NM_000552.5:c.3797C>A variant in VWF is a missense variant predicted to cause substitution of proline by glutamine at amino acid 1266. Population and in silico predictors were between the pathogenic and benign thresholds for the respective codes. At least 1 patient with this variant displayed excessive mucocutaneous bleeding as well as a laboratory phenotype of low VWF:RCo/VWF:Ag ratio and no loss of HMW multimers (described as non-selective loss and low intensity but high molecular weight bands are still present), which is specific for VWD type 2M (PP4, PMID 23179108).The majority of reported cases were asserted as VWD type 2M but there were also assertions for type 2B and type 1. No reported case in the literature had a combination of activity/antigen ratio <0.7, documented abnormal bleeding phenotype, and enhanced platelet binding. There is conflicting evidence of altered platelet binding phenotype evidenced by in vitro assays showing both enhanced GPIb and decreased GPIb binding (PMIDs 23179108, 30488424). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal dominant VWD type 2 based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: PP4. (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/CA228441/MONDO:0013304/081
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: Uncertain_significance. The variant received 1 ACMG points.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_000552.5. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| VWF | NM_000552.5 | MANE Select | c.3797C>A | p.Pro1266Gln | missense | Exon 28 of 52 | NP_000543.3 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| VWF | ENST00000261405.10 | TSL:1 MANE Select | c.3797C>A | p.Pro1266Gln | missense | Exon 28 of 52 | ENSP00000261405.5 | ||
| VWF | ENST00000539641.1 | TSL:3 | n.595C>A | non_coding_transcript_exon | Exon 3 of 3 | ||||
| VWF | ENST00000538635.5 | TSL:4 | n.421-25687C>A | intron | N/A |
Frequencies
GnomAD3 genomes 0.000533 AC: 81AN: 152092Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.000276 AC: 69AN: 249794 AF XY: 0.000348 show subpopulations
GnomAD4 exome AF: 0.000543 AC: 793AN: 1460696Hom.: 3 Cov.: 38 AF XY: 0.000674 AC XY: 490AN XY: 726690 show subpopulations
Age Distribution
GnomAD4 genome 0.000532 AC: 81AN: 152210Hom.: 0 Cov.: 32 AF XY: 0.000591 AC XY: 44AN XY: 74412 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
not provided Pathogenic:3Uncertain:2Other:1
In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28497886, 28640903, 18315546, 23179108, 30349898, 28971901, 33711653, 33113216, 32224444, 26986123, 26827609, 23809112, 30488424, 34426522, 31589614, 34130347, 35505650, 34758185, 35452508, 34807970, 35741733, 34697415, 37647632, 37872709, 37168293, 36444397, 18805962, ShamrizR2023[Article], 21711445)
VWF: PM5, PP1:Moderate, PS4:Moderate, PS3:Supporting, BP4
The VWF c.3797C>A (p.Pro1266Gln) variant has been reported in the published literature in individuals affected with type 1, 2A, and 2B von Willebrand disease having normal multimer patterns (PMIDs: 18805962 (2009), 21711445 (2011), 34130347 (2021), and 37168293 (2023)). These patients also carried other variants due to a gene conversion event with a pseudogene in the published literature (PMIDs: 18805962 (2009), 23179108 (2013), and 28497886 (2017)). This variant has also been reported in individuals with bleeding disorders (PMIDs: 32224444 (2020), 33113216 (2020), 33711653 (2021), and 34807970 (2022)). One functional study described this variant as being associated with type 2M von Willbrand disease due to a protein defect (PMID:23179108 (2013)), however, a recent study showed no protein folding defect (PMID: 30488424 (2019)). The frequency of this variant in the general population, 0.0013 (41/30468 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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 likely pathogenic.
The VWF p.P1266Q variant was identified in the heterozygous or compound heterozygous state in multiple individuals with von Willebrand disease type 2B, including 8 individuals from 4 families; these individuals generally displayed normal multimeric protein patterns, plasma VWF levels, platelet VWF levels, and low bleeding scores (Casonato_2017_PMID:28640903; BorraÃÄs_2017_PMID:28971901; Federici_2009_PMID:18805962; Ahmad_2013_PMID:23179108; Veyradier_2016_PMID:26986123; Casonato_2016_PMID:27532107). The p.P1266Q variant usually results due to gene conversion with the VWF pseudogene and is typically found in combination with other VWF variants. The variant was identified in dbSNP (ID: rs61749370) and ClinVar (classified as pathogenic by John Hopkins Children's Hospital and as likely pathogenic by CeGat Praxis). The variant was identified in control databases in 76 of 281180 chromosomes (2 homozygous) at a frequency of 0.0002703 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: South Asian in 41 of 30468 chromosomes (freq: 0.001346), Other in 3 of 7204 chromosomes (freq: 0.000416), European (non-Finnish) in 24 of 127752 chromosomes (freq: 0.000188), Latino in 5 of 35424 chromosomes (freq: 0.000141), African in 2 of 24944 chromosomes (freq: 0.00008) and East Asian in 1 of 19948 chromosomes (freq: 0.00005), but was not observed in the Ashkenazi Jewish or European (Finnish) populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.P1266 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. Functional studies demonstrated that the p.P1266Q variant alone did not affect VWF protein expression or activity compared to wildtype, however the combination of p.V1229G-p.N1231T-p.P1266Q variants caused decreased expression and binding of VWF to GPIba (Ahmad_2018_PMID: 30488424). In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
von Willebrand disease type 2 Pathogenic:2Uncertain:1
The NM_000552.5:c.3797C>A variant in VWF is a missense variant predicted to cause substitution of proline by glutamine at amino acid 1266. Population and in silico predictors were between the pathogenic and benign thresholds for the respective codes. At least 1 patient with this variant displayed excessive mucocutaneous bleeding as well as a laboratory phenotype of low VWF:RCo/VWF:Ag ratio and no loss of HMW multimers (described as non-selective loss and low intensity but high molecular weight bands are still present), which is specific for VWD type 2M (PP4, PMID 23179108). The majority of reported cases were asserted as VWD type 2M but there were also assertions for type 2B and type 1. No reported case in the literature had a combination of activity/antigen ratio <0.7, documented abnormal bleeding phenotype, and enhanced platelet binding. There is conflicting evidence of altered platelet binding phenotype evidenced by in vitro assays showing both enhanced GPIb and decreased GPIb binding (PMIDs 23179108, 30488424). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal dominant VWD type 2 based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: PP4. (ClinGen von Willebrand Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for VWF Version 1.0.0; May 6th, 2025)
This variant is classified as Likely pathogenic. Evidence in support of pathogenic classification: This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as likely pathogenic and pathogenic, and has been identified in multiple heterozygous individuals with type 2B 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, PMID: 28971901, PMID: 30488424, PMID: 26986123, PMID: 28640903, PMID: 37168293); Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. This alternative change (p.Pro1266Leu) has been reported as likely pathogenic or pathogenic, and has been observed in multiple heterozygous individuals with type 2B von Willebrand disease (VWD), and a single homozygous individual with type 3 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 (ClinVar, PMID: 18805962, PMID: 28971901, PMID: 30817071, PMID: 28640903). Additional information: Variant is predicted to result in a missense amino acid change from proline to glutamine; This variant is heterozygous; 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); Variant is present in gnomAD (v2 and v3) >=0.001 and <0.01 for a dominant condition (132 heterozygotes, 2 homozygotes); An alternative amino acid change at the same position has been observed in gnomAD (v2) (334 heterozygotes, 1 homozygote); Functional evidence for this variant is inconclusive. Analysis of this variant, either in isolation or in conjunction with common variants found in cis, did not identify a significant decrease in protein binding (PMID: 30488424); Variant is located in the annotated D3-A1 junction of the VWA N2 domain (NCBI, PMID: 26986123); Missense variant with conflicting in silico predictions and uninformative conservation; Dominant negative, gain of function and loss of function are known mechanisms of disease in this gene and are associated with von Willebrand disease (VWD) (OMIM, PMID: 30488424); The condition associated with this gene has incomplete penetrance (PMID: 19372260); Variants in this gene are known to have variable expressivity (PMID: 19372260); This variant has been shown to be paternally inherited (by trio analysis).
The missense variant p.P1266Q in VWF (NM_000552.4) has been previously established to cause the VWD Malmo/New York variant (Batlle J et al, 2016). The p.P1266Q variant is observed in 6/978 (0.6135%) alleles from individuals of South Asian background in 1000 Genomes, including in 4 persons in homozygous state. There is a moderate physicochemical difference between proline and glutamine. The p.P1266Q missense variant is predicted to be damaging by both SIFT and PolyPhen2. The proline residue at codon 1266 of VWF is conserved in all mammalian species. The nucleotide c.3797 in VWF is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic.
Hereditary von Willebrand disease Pathogenic:2Other:1
von Willebrand disease type 1 Pathogenic:1Uncertain:1
von Willebrand disease type 1;C1264040:von Willebrand disease type 2;C1264041:von Willebrand disease type 3 Pathogenic:1
VWF-related disorder Pathogenic:1
The VWF c.3797C>A variant is predicted to result in the amino acid substitution p.Pro1266Gln. This variant, and a similar variant, p.Pro1266Leu, have been reported in patients with von Willebrand disease (VWD) type 2B (Holmberg et al. 1993. PubMed ID: 8486782; Federici et al. 2009. PubMed ID: 18805962). The p.Pro1266Gln substitution has also been reported in patients with VWD type 2M (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 have a functional consequence. This variant is reported in 0.13% of alleles in individuals of South Asian descent in gnomAD. This variant is interpreted as likely pathogenic.
not specified Uncertain:1
Variant summary: VWF c.3797C>A (p.Pro1266Gln) results in a non-conservative amino acid change located in the von Willebrand factor, 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 0.00054 in 1612906 control chromosomes, predominantly at a frequency of 0.0039 within the South Asian subpopulation in the gnomAD database (v4.0.0), including 3 homozygotes. This frequency does not allow conclusions about variant significance.. c.3797C>A has been reported in the literature in individuals affected with Von Willebrand Disease as a component of gene conversion from the VWF pseudogene resulting in multiple alterations with normal levels of VWFGPIb-alpha/BC, normal platelet count before and after stress, normal platelet morphology, and a normal multimeric pattern (example, Federici_2009, Robertson_2011, Ahmad_2013, Casonato_2017, Alzahrani_2023). These report(s) do not provide unequivocal conclusions about association of the variant with Von Willebrand Disease. At least one publication reports experimental evidence evaluating an impact on protein function in isolation (example Ahmad_2018). These results showed no damaging effect of this variant in isolation as all analysed qualitative and quantitative parameters of rVWF were comparable to WT. These results showed no damaging effect of this variant. The following publications have been ascertained in the context of this evaluation (PMID: 30488424, 23179108, 37168293, 28640903, 18805962, 20371742, 21711445, 34807970). ClinVar contains an entry for this variant (Variation ID: 100279). Based on the evidence outlined above, the variant was classified as uncertain significance.
EBV-positive nodal T- and NK-cell lymphoma Benign:1
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at