ClinVar Genomic variation as it relates to human health
NM_000552.5(VWF):c.3797C>A (p.Pro1266Gln)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic(2); Likely pathogenic(5); Uncertain significance(3)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000552.5(VWF):c.3797C>A (p.Pro1266Gln)
Variation ID: 100279 Accession: VCV000100279.31
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12p13.31 12: 6019621 (GRCh38) [ NCBI UCSC ] 12: 6128787 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Feb 25, 2014 May 12, 2024 Apr 4, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000552.5:c.3797C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000543.3:p.Pro1266Gln missense NM_000552.3:c.3797C>A NC_000012.12:g.6019621G>T NC_000012.11:g.6128787G>T NG_009072.2:g.110050C>A LRG_587:g.110050C>A LRG_587t1:c.3797C>A LRG_587p1:p.Pro1266Gln - Protein change
- P1266Q
- Other names
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- Canonical SPDI
- NC_000012.12:6019620:G:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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0.00180 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 30x 0.00172
1000 Genomes Project 0.00180
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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VWF | - | - |
GRCh38 GRCh37 |
1476 | 1530 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Conflicting interpretations of pathogenicity (6) |
criteria provided, conflicting classifications
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Feb 6, 2024 | RCV000086675.22 | |
Pathogenic/Likely pathogenic (3) |
no assertion criteria provided
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Mar 26, 2014 | RCV000678765.6 | |
Likely pathogenic (1) |
criteria provided, single submitter
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- | RCV001823113.4 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Apr 4, 2024 | RCV002247493.3 | |
Uncertain significance (1) |
criteria provided, single submitter
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Feb 14, 2024 | RCV002281924.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 4, 2022 | RCV002490753.2 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Oct 13, 2023 | RCV004549528.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Likely pathogenic
(Oct 13, 2023)
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criteria provided, single submitter
Method: clinical testing
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VWF-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004108912.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
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 … (more)
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 (http://gnomad.broadinstitute.org/variant/12-6128787-G-T). This variant is interpreted as likely pathogenic. (less)
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Likely pathogenic
(Apr 28, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV004221518.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
The frequency of this variant in the general population, 0.0013 (41/30468 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the … (more)
The frequency of this variant in the general population, 0.0013 (41/30468 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals affected with type 1 and 2B von Willebrand disease having normal multimer patterns (PMIDs: 18805962 (2009), 21711445 (2011)). 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), 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)). 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, the variant is predicted to be likely pathogenic. (less)
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Likely pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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von Willebrand disease type 2
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV002072872.1
First in ClinVar: Feb 04, 2022 Last updated: Feb 04, 2022 |
Comment:
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 … (more)
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. (less)
Clinical Features:
Recurrent spontaneous abortion (present)
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Pathogenic
(May 04, 2022)
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criteria provided, single submitter
Method: clinical testing
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von Willebrand disease type 1
Affected status: unknown
Allele origin:
germline
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Mendelics
Accession: SCV002519961.1
First in ClinVar: May 28, 2022 Last updated: May 28, 2022 |
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Pathogenic
(Jan 04, 2022)
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criteria provided, single submitter
Method: clinical testing
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von Willebrand disease type 1
von Willebrand disease type 3 von Willebrand disease type 2
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002789273.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Uncertain significance
(Jan 09, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV002820421.1
First in ClinVar: Jan 21, 2023 Last updated: Jan 21, 2023 |
Comment:
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, 18805962, … (more)
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, 18805962, 18315546, 23179108, 30349898, 28971901, 33711653, 33113216, 32224444, 26986123, 26827609, 23809112, 30488424, 34426522, 31589614, 34130347, 35505650, 34758185, 35452508, 34807970, 35741733, 34697415) (less)
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Likely pathogenic
(Feb 06, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV004243461.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
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Uncertain significance
(Apr 04, 2024)
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criteria provided, single submitter
Method: clinical testing
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von Willebrand disease type 1
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004809365.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
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Uncertain significance
(Feb 14, 2024)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002570652.2
First in ClinVar: Sep 17, 2022 Last updated: Apr 15, 2024 |
Comment:
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 … (more)
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. (less)
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Likely pathogenic
(Feb 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001148586.22
First in ClinVar: Feb 03, 2020 Last updated: May 12, 2024 |
Comment:
VWF: PM5, PP1:Moderate, PS4:Moderate, PS3:Supporting, BP4
Number of individuals with the variant: 4
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Pathogenic
(Mar 26, 2014)
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no assertion criteria provided
Method: clinical testing
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von Willebrand disorder
Affected status: yes
Allele origin:
germline
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Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital
Accession: SCV000804944.1
First in ClinVar: Sep 14, 2018 Last updated: Sep 14, 2018 |
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001554036.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
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 … (more)
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. (less)
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Likely pathogenic
(-)
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no assertion criteria provided
Method: research
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Hereditary von Willebrand disease
Affected status: yes
Allele origin:
unknown
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ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology
Accession: SCV002515784.1
First in ClinVar: May 21, 2022 Last updated: May 21, 2022
Comment:
Submitted to GoldVariant by Dr Karyn Mégy from NIHR Bioresource - Cambridge University, UK
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not provided
(-)
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no classification provided
Method: not provided
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not provided
Affected status: not provided
Allele origin:
not provided
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Academic Unit of Haematology, University of Sheffield
Accession: SCV000118879.1
First in ClinVar: Feb 25, 2014 Last updated: Feb 25, 2014 |
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not provided
(-)
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no classification provided
Method: literature only
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von Willebrand disorder
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV002507245.2
First in ClinVar: May 11, 2022 Last updated: Oct 01, 2022 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Phenotypic and genotypic (exon 28) characterization of patients diagnosed with von Willebrand disease type 1 in Eastern Saudi Arabia. | Alzahrani FM | Journal of medicine and life | 2023 | PMID: 37168293 |
Whole-exome analysis of adolescents with low VWF and heavy menstrual bleeding identifies novel genetic associations. | Sadler B | Blood advances | 2022 | PMID: 34807970 |
Lessons learned from unsolicited findings in clinical exome sequencing of 16,482 individuals. | van der Schoot V | European journal of human genetics : EJHG | 2022 | PMID: 34697415 |
The genetic structure of the Turkish population reveals high levels of variation and admixture. | Kars ME | Proceedings of the National Academy of Sciences of the United States of America | 2021 | PMID: 34426522 |
Mutations in RASGRP2 gene identified in patients misdiagnosed as Glanzmann thrombasthenia patients. | Rosenberg N | Blood cells, molecules & diseases | 2021 | PMID: 33711653 |
Gastrointestinal bleeding from angiodysplasia in von Willebrand disease: Improved diagnosis and outcome prediction using videocapsule on top of conventional endoscopy. | Rauch A | Journal of thrombosis and haemostasis : JTH | 2021 | PMID: 33113216 |
Molecular genetic diagnosis by next-generation sequencing in a cohort of Mexican patients with haemophilia and report of novel variants. | Villarreal-Martínez L | Blood cells, molecules & diseases | 2020 | PMID: 32224444 |
Characterization of VWF gene conversions causing von Willebrand disease. | Ahmad F | British journal of haematology | 2019 | PMID: 30488424 |
Type 2B von Willebrand disease with or without large multimers: A distinction of the two sides of the disorder is long overdue. | Casonato A | PloS one | 2017 | PMID: 28640903 |
Acquired von Willebrand syndrome in haematologic malignancies - how the clinical-laboratory correlation improves a challenging diagnosis - a case series. | Fidalgo T | Haemophilia : the official journal of the World Federation of Hemophilia | 2017 | PMID: 28497886 |
von Willebrand Disease. | Adam MP | - | 2017 | PMID: 20301765 |
Characterisation of mutations and molecular studies of type 2 von Willebrand disease. | Ahmad F | Thrombosis and haemostasis | 2013 | PMID: 23179108 |
Expanded phenotype-genotype correlations in a pediatric population with type 1 von Willebrand disease. | Robertson JD | Journal of thrombosis and haemostasis : JTH | 2011 | PMID: 21711445 |
Mutation-specific hemostatic variability in mice expressing common type 2B von Willebrand disease substitutions. | Golder M | Blood | 2010 | PMID: 20371742 |
Clinical and molecular predictors of thrombocytopenia and risk of bleeding in patients with von Willebrand disease type 2B: a cohort study of 67 patients. | Federici AB | Blood | 2009 | PMID: 18805962 |
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Text-mined citations for rs61749370 ...
HelpRecord last updated May 19, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.