ClinVar Genomic variation as it relates to human health
NM_000552.5(VWF):c.1625C>G (p.Ala542Gly)
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(1); Likely pathogenic(1); Uncertain significance(6)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000552.5(VWF):c.1625C>G (p.Ala542Gly)
Variation ID: 381621 Accession: VCV000381621.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12p13.31 12: 6057953 (GRCh38) [ NCBI UCSC ] 12: 6167119 (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 Mar 8, 2017 Jan 6, 2024 Jul 11, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000552.5:c.1625C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000543.3:p.Ala542Gly missense NM_000552.4:c.1625C>G NC_000012.12:g.6057953G>C NC_000012.11:g.6167119G>C NG_009072.2:g.71718C>G LRG_587:g.71718C>G LRG_587t1:c.1625C>G LRG_587p1:p.Ala542Gly - Protein change
- A542G
- Other names
- p.A542G
- Canonical SPDI
- NC_000012.12:6057952:G:C
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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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0.00040 (C)
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Allele frequency
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The frequency of the allele represented by this VCV record.
1000 Genomes Project 30x 0.00031
1000 Genomes Project 0.00040
Exome Aggregation Consortium (ExAC) 0.00045
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00062
The Genome Aggregation Database (gnomAD), exomes 0.00072
Trans-Omics for Precision Medicine (TOPMed) 0.00072
The Genome Aggregation Database (gnomAD) 0.00074
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
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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 |
1468 | 1522 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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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Uncertain significance (1) |
criteria provided, single submitter
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Oct 31, 2018 | RCV000765104.4 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Jun 22, 2023 | RCV000760113.10 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Feb 1, 2019 | RCV000852047.3 | |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 10, 2020 | RCV002264696.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 14, 2022 | RCV003147455.3 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jul 11, 2023 | RCV003323534.2 | |
Uncertain significance (1) |
criteria provided, single submitter
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Sep 9, 2022 | RCV003422399.4 |
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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Uncertain significance
(Oct 31, 2018)
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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: SCV000896324.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Likely pathogenic
(Feb 01, 2019)
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criteria provided, single submitter
Method: research
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von Willebrand disorder
Affected status: yes
Allele origin:
unknown
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NIHR Bioresource Rare Diseases, University of Cambridge
Study: ThromboGenomics
Accession: SCV000899540.1 First in ClinVar: Sep 29, 2019 Last updated: Sep 29, 2019 |
Sex: female
Ethnicity/Population group: European
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Uncertain significance
(Dec 10, 2020)
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criteria provided, single submitter
Method: research
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von Willebrand disease type 1
Affected status: yes
Allele origin:
germline
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Laboratory of Hematology, Radboud University Medical Center
Study: WIN study
Accession: SCV002546247.1 First in ClinVar: Jul 18, 2022 Last updated: Jul 18, 2022 |
Number of individuals with the variant: 2
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Pathogenic
(Apr 14, 2022)
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criteria provided, single submitter
Method: clinical testing
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von Willebrand disease type 2
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV003835603.1
First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023 |
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Uncertain significance
(Jun 22, 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: SCV000521094.6
First in ClinVar: Mar 08, 2017 Last updated: Jul 01, 2023 |
Comment:
Observed in the homozygous state in an individual with von Willebrand disease who had an additional homozygous VWF variant in cis (Corrales et al., 2010); … (more)
Observed in the homozygous state in an individual with von Willebrand disease who had an additional homozygous VWF variant in cis (Corrales et al., 2010); Observed in individuals with von Willebrand disease who have a second VWF variant, however it is unknown if these variants are in cis or trans (Sadler et al., 2021); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26986123, 28971901, 31064749, 27532107, 33556167, 20801902) (less)
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Uncertain significance
(Jul 11, 2023)
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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: SCV004028805.1
First in ClinVar: Aug 26, 2023 Last updated: Aug 26, 2023 |
Comment:
Variant summary: VWF c.1625C>G (p.Ala542Gly) results in a non-conservative amino acid change located in the von Willebrand factor, type D domain (IPR001846) of the encoded … (more)
Variant summary: VWF c.1625C>G (p.Ala542Gly) results in a non-conservative amino acid change located in the von Willebrand factor, type D domain (IPR001846) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00072 in 250426 control chromosomes (gnomAD). c.1625C>G has been reported in the literature in individuals affected with Von Willebrand Disease (Corrales_2010, Casonato_2016, Veyradier_2016, Sadler_2021, Borras_2017). One patient was reported as putatively compound heterozygous with a pathogenic variant, although other patients were found to have a likely pathogenic variant in cis or without the phase indicated. These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 20801902, 27532107, 26986123, 33556167, 28971901, 21251206, 31064749). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classified it as uncertain significance (n=4), or pathogenic/likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(Sep 09, 2022)
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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: SCV004117161.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The VWF c.1625C>G variant is predicted to result in the amino acid substitution p.Ala542Gly. This variant has been reported in patients with von Willebrand disease, … (more)
The VWF c.1625C>G variant is predicted to result in the amino acid substitution p.Ala542Gly. This variant has been reported in patients with von Willebrand disease, but has always been reported in a cis configuration with a splice site variant c.533-2A>G making it unclear whether the missense variant p.Ala542Gly is actually a cause of disease (see Corrales et al. 2010. PubMed ID: 20801902; http://www.hemobase.com/vwf/VWF_Database/Mutations/Mutations.html). This variant has also been reported in studies of VWD patients, but it is unclear whether it is a cause of disease within the studied cohort (Veyradier et al. 2016. PubMed ID: 26986123; Table S2 - Sadler et al. 2021. PubMed ID: 33556167). Additionally, the c.1625C>G (p.Ala542Gly) variant was observed in a cohort of individuals with bleeding, thrombotic and platelet disorders, and reported as likely pathogenic (TGP0672, Supplementary Table 3, Downes et al. 2019. PubMed ID: 31064749). This variant is reported in 0.14% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-6167119-G-C). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
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Uncertain significance
(May 31, 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: SCV000889895.3
First in ClinVar: Mar 14, 2019 Last updated: Jan 06, 2024 |
Comment:
In the published literature, this variant has been reported in individuals with low VWF and/or Type 1 von Willebrand disease (VWD) co-occurring with another likely … (more)
In the published literature, this variant has been reported in individuals with low VWF and/or Type 1 von Willebrand disease (VWD) co-occurring with another likely pathogenic/pathogenic variant in the VWF gene (PMID: 33556167 (2021)). It has also been reported in an individual with Type 3 VWD in the homozygous state with a homozygous canonical splice variant (PMID: 20801902 (2010), 21251206 (2011), 28971901 (2017)). This variant has also been reported individuals with Type 1, Type 1H, and Type 2A VWD (PMID: 26986123 (2016), 27532107 (2016), 28971901 (2017)), as well as in an individual with a bleeding, thrombotic, or platelet disorder (PMID: 31064749 (2019)). The frequency of this variant in the general population, 0.0015 (4/2642 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 conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant. (less)
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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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von Willebrand factor antigen levels are associated with burden of rare nonsynonymous variants in the VWF gene. | Sadler B | Blood | 2021 | PMID: 33556167 |
Diagnostic high-throughput sequencing of 2396 patients with bleeding, thrombotic, and platelet disorders. | Downes K | Blood | 2019 | PMID: 31064749 |
Molecular and clinical profile of von Willebrand disease in Spain (PCM-EVW-ES): comprehensive genetic analysis by next-generation sequencing of 480 patients. | Borràs N | Haematologica | 2017 | PMID: 28971901 |
Diagnostic Value of Measuring Platelet Von Willebrand Factor in Von Willebrand Disease. | Casonato A | PloS one | 2016 | PMID: 27532107 |
A Laboratory Phenotype/Genotype Correlation of 1167 French Patients From 670 Families With von Willebrand Disease: A New Epidemiologic Picture. | Veyradier A | Medicine | 2016 | PMID: 26986123 |
Next-generation sequencing study finds an excess of rare, coding single-nucleotide variants of ADAMTS13 in patients with deep vein thrombosis. | Lotta LA | Journal of thrombosis and haemostasis : JTH | 2013 | PMID: 23648131 |
The study of the effect of splicing mutations in von Willebrand factor using RNA isolated from patients' platelets and leukocytes. | Corrales I | Journal of thrombosis and haemostasis : JTH | 2011 | PMID: 21251206 |
Integration of molecular and clinical data of 40 unrelated von Willebrand Disease families in a Spanish locus-specific mutation database: first release including 58 mutations. | Corrales I | Haematologica | 2010 | PMID: 20801902 |
Text-mined citations for rs141649383 ...
HelpRecord last updated Mar 17, 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.