In silico analysis supports that this missense variant does not alter protein structure/function; Observed in healthy controls in the published literature (Bellissimo et al., 2012; Sadler et al., 2021); This variant is associated with the following publications: (PMID: 26420797, 33556167, 22197721)
ClinVar Genomic variation as it relates to human health
NM_000552.5(VWF):c.8378T>C (p.Val2793Ala)
Germline
Classification
Help
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.
(8)
Help
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.
Uncertain significance
8
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000552.5(VWF):c.8378T>C (p.Val2793Ala)
Variation ID: 437264 Accession: VCV000437264.20
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 12p13.31 12: 5949079 (GRCh38) [ NCBI UCSC ] 12: 6058245 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Aug 28, 2017 Nov 24, 2024 May 9, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000552.5:c.8378T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000543.3:p.Val2793Ala missense NC_000012.12:g.5949079A>G NC_000012.11:g.6058245A>G NG_009072.2:g.180592T>C LRG_587:g.180592T>C LRG_587t1:c.8378T>C LRG_587p1:p.Val2793Ala - Protein change
- V2793A
- Other names
- -
- Canonical SPDI
- NC_000012.12:5949078:A:G
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
-
0.00160 (G)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Exome Aggregation Consortium (ExAC) 0.00046
The Genome Aggregation Database (gnomAD), exomes 0.00047
1000 Genomes Project 30x 0.00156
1000 Genomes Project 0.00160
The Genome Aggregation Database (gnomAD) 0.00168
Trans-Omics for Precision Medicine (TOPMed) 0.00195
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00208
- Links
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 | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
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. |
|||
| VWF | - | - |
GRCh38 GRCh37 |
1594 | 1648 | |
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. |
|---|---|---|---|---|
| Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Feb 22, 2024 | RCV000500840.9 | |
| Uncertain significance (5) |
criteria provided, multiple submitters, no conflicts
|
May 9, 2024 | RCV000756906.13 | |
|
VWF-related disorder
|
Uncertain significance (1) |
criteria provided, single submitter
|
May 18, 2023 | RCV004551638.1 |
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. |
|
|---|---|---|---|---|---|
|
Uncertain significance
(Jan 19, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: no
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV000597931.1
First in ClinVar: Aug 28, 2017 Last updated: Aug 28, 2017 |
|
|
|
Uncertain significance
(Dec 31, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000884883.1
First in ClinVar: Feb 18, 2019 Last updated: Feb 18, 2019 |
|
|
|
Uncertain significance
(May 02, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV002513266.2
First in ClinVar: May 21, 2022 Last updated: Mar 04, 2023 |
Comment:
In silico analysis supports that this missense variant does not alter protein structure/function; Observed in healthy controls in the published literature (Bellissimo et al., 2012; … (more)
In silico analysis supports that this missense variant does not alter protein structure/function; Observed in healthy controls in the published literature (Bellissimo et al., 2012; Sadler et al., 2021); This variant is associated with the following publications: (PMID: 26420797, 33556167, 22197721) (less)
|
|
|
Uncertain significance
(Dec 06, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000602323.3
First in ClinVar: Aug 28, 2017 Last updated: Jan 06, 2024 |
Comment:
In the published literature, this variant has been reported in healthy individuals (PMID: 22197721 (2012), 33556167 (2022)). The frequency of this variant in the general … (more)
In the published literature, this variant has been reported in healthy individuals (PMID: 22197721 (2012), 33556167 (2022)). The frequency of this variant in the general population, 0.0058 (145/24922 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 benign. Based on the available information, we are unable to determine the clinical significance of this variant. (less)
|
|
|
Uncertain significance
(Feb 22, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002570648.2
First in ClinVar: Sep 17, 2022 Last updated: Apr 15, 2024 |
Comment:
Variant summary: VWF c.8378T>C (p.Val2793Ala) results in a non-conservative amino acid change located in the Cystine knot, C-terminal domain (IPR006207) of the encoded protein sequence. … (more)
Variant summary: VWF c.8378T>C (p.Val2793Ala) results in a non-conservative amino acid change located in the Cystine knot, C-terminal domain (IPR006207) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00047 in 250990 control chromosomes. c.8378T>C has been reported in the literature in healthy control individuals and Haemolytic uraemic syndrome patients (example, Bellissimo_2012, Sadler_2021, Connaughton_2023) but to our knowledge it has not been reported in individuals affected with Von Willebrand Disease. These report(s) do not provide unequivocal conclusions about association of the variant with Von Willebrand Disease. 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: 22197721, 37466676, 33556167). ClinVar contains an entry for this variant (Variation ID: 437264). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
|
|
|
Uncertain significance
(May 18, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
VWF-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004108965.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The VWF c.8378T>C variant is predicted to result in the amino acid substitution p.Val2793Ala. This variant has been reported in healthy controls (Bellissimo et al. … (more)
The VWF c.8378T>C variant is predicted to result in the amino acid substitution p.Val2793Ala. This variant has been reported in healthy controls (Bellissimo et al. 2011. PubMed ID: 22197721; Sadler et al. 2021. PubMed ID: 33556167. Table S2). This variant is reported in 0.58% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-6058245-A-G). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
|
|
|
Uncertain significance
(-)
|
criteria provided, single submitter
Method: not provided
|
not provided
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Breakthrough Genomics, Breakthrough Genomics
Accession: SCV005191625.1
First in ClinVar: Aug 18, 2024 Last updated: Aug 18, 2024 |
|
|
|
Uncertain significance
(May 09, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV005408208.1
First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024 |
Comment:
BP4, PM1_supporting
Number of individuals with the variant: 3
|
Comment:
Comment:
In the published literature, this variant has been reported in healthy individuals (PMID: 22197721 (2012), 33556167 (2022)). The frequency of this variant in the general population, 0.0058 (145/24922 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 benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Comment:
Variant summary: VWF c.8378T>C (p.Val2793Ala) results in a non-conservative amino acid change located in the Cystine knot, C-terminal domain (IPR006207) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00047 in 250990 control chromosomes. c.8378T>C has been reported in the literature in healthy control individuals and Haemolytic uraemic syndrome patients (example, Bellissimo_2012, Sadler_2021, Connaughton_2023) but to our knowledge it has not been reported in individuals affected with Von Willebrand Disease. These report(s) do not provide unequivocal conclusions about association of the variant with Von Willebrand Disease. 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: 22197721, 37466676, 33556167). ClinVar contains an entry for this variant (Variation ID: 437264). Based on the evidence outlined above, the variant was classified as uncertain significance.
Comment:
The VWF c.8378T>C variant is predicted to result in the amino acid substitution p.Val2793Ala. This variant has been reported in healthy controls (Bellissimo et al. 2011. PubMed ID: 22197721; Sadler et al. 2021. PubMed ID: 33556167. Table S2). This variant is reported in 0.58% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-6058245-A-G). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Comment:
BP4, PM1_supporting
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. |
Comment:
In silico analysis supports that this missense variant does not alter protein structure/function; Observed in healthy controls in the published literature (Bellissimo et al., 2012; Sadler et al., 2021); This variant is associated with the following publications: (PMID: 26420797, 33556167, 22197721)
Comment:
In the published literature, this variant has been reported in healthy individuals (PMID: 22197721 (2012), 33556167 (2022)). The frequency of this variant in the general population, 0.0058 (145/24922 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 benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Comment:
Variant summary: VWF c.8378T>C (p.Val2793Ala) results in a non-conservative amino acid change located in the Cystine knot, C-terminal domain (IPR006207) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00047 in 250990 control chromosomes. c.8378T>C has been reported in the literature in healthy control individuals and Haemolytic uraemic syndrome patients (example, Bellissimo_2012, Sadler_2021, Connaughton_2023) but to our knowledge it has not been reported in individuals affected with Von Willebrand Disease. These report(s) do not provide unequivocal conclusions about association of the variant with Von Willebrand Disease. 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: 22197721, 37466676, 33556167). ClinVar contains an entry for this variant (Variation ID: 437264). Based on the evidence outlined above, the variant was classified as uncertain significance.
Comment:
The VWF c.8378T>C variant is predicted to result in the amino acid substitution p.Val2793Ala. This variant has been reported in healthy controls (Bellissimo et al. 2011. PubMed ID: 22197721; Sadler et al. 2021. PubMed ID: 33556167. Table S2). This variant is reported in 0.58% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-6058245-A-G). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Comment:
BP4, PM1_supporting
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Genotypic analysis of a large cohort of patients with suspected atypical hemolytic uremic syndrome. | Connaughton DM | Journal of molecular medicine (Berlin, Germany) | 2023 | PMID: 37466676 |
| von Willebrand factor antigen levels are associated with burden of rare nonsynonymous variants in the VWF gene. | Sadler B | Blood | 2021 | PMID: 33556167 |
| VWF mutations and new sequence variations identified in healthy controls are more frequent in the African-American population. | Bellissimo DB | Blood | 2012 | PMID: 22197721 |
Text-mined citations for rs143743709 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 25, 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.