ClinVar Genomic variation as it relates to human health
NM_000209.4(PDX1):c.418G>A (p.Ala140Thr)
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.
Uncertain significance(1); Benign(1); Likely benign(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000209.4(PDX1):c.418G>A (p.Ala140Thr)
Variation ID: 586036 Accession: VCV000586036.10
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q12.2 13: 27924267 (GRCh38) [ NCBI UCSC ] 13: 28498404 (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 Oct 20, 2018 Feb 14, 2024 Dec 28, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000209.4:c.418G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000200.1:p.Ala140Thr missense NC_000013.11:g.27924267G>A NC_000013.10:g.28498404G>A NG_008183.1:g.9237G>A - Protein change
- A140T
- Other names
- -
- Canonical SPDI
- NC_000013.11:27924266:G:A
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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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0.00020 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00014
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
The Genome Aggregation Database (gnomAD) 0.00022
Exome Aggregation Consortium (ExAC) 0.00044
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00046
- 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 | ||
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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
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. |
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PDX1 | - | - |
GRCh38 GRCh37 |
163 | 199 |
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 (5) |
criteria provided, conflicting classifications
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Dec 28, 2023 | RCV000712001.10 | |
Benign (1) |
criteria provided, single submitter
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- | RCV002464032.1 |
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 benign
(Jul 15, 2020)
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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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Athena Diagnostics
Accession: SCV000842414.2
First in ClinVar: Oct 20, 2018 Last updated: Jan 26, 2021 |
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Likely benign
(Apr 28, 2021)
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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: SCV001826082.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Comment:
This variant is associated with the following publications: (PMID: 10720084, 21569088, 15001545)
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Benign
(-)
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criteria provided, single submitter
(K & H Uppaluri Personalized Medicine Clinic Variant Classification & Assertion Criteria_Updated V.1)
Method: research
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Pancreatic hypoplasia
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
unknown
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Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic
Accession: SCV002605249.1
First in ClinVar: Dec 11, 2022 Last updated: Dec 11, 2022 |
Comment:
Potent homozygous mutations in the PDX1 gene can lead to pancreatic agenesis/pancreatic hypoplasia and neonatal diabetes mellitus. However no sufficient evidence is found to ascertain … (more)
Potent homozygous mutations in the PDX1 gene can lead to pancreatic agenesis/pancreatic hypoplasia and neonatal diabetes mellitus. However no sufficient evidence is found to ascertain the role of this particular variant rs143517122, yet. (less)
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Uncertain significance
(Dec 28, 2023)
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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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Invitae
Accession: SCV003259033.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 140 of the PDX1 protein (p.Ala140Thr). … (more)
This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 140 of the PDX1 protein (p.Ala140Thr). This variant is present in population databases (rs143517122, gnomAD 0.04%). This missense change has been observed in individual(s) with clinical features of PDX1-related conditions (PMID: 10720084, 21569088). ClinVar contains an entry for this variant (Variation ID: 586036). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PDX1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects PDX1 function (PMID: 15001545). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV002035688.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021 |
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV002038062.1 First in ClinVar: Dec 21, 2021 Last updated: Dec 21, 2021 |
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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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Iranian neonatal diabetes mellitus due to mutation in PDX1 gene: a case report. | Sahebi L | Journal of medical case reports | 2019 | PMID: 31366392 |
Genome-wide analysis of PDX1 target genes in human pancreatic progenitors. | Wang X | Molecular metabolism | 2018 | PMID: 29396371 |
PDX1 -MODY and dorsal pancreatic agenesis: New phenotype of a rare disease. | Caetano LA | Clinical genetics | 2018 | PMID: 28436541 |
PDX1 associated therapy in translational medicine. | Yu J | Annals of translational medicine | 2016 | PMID: 27386488 |
Sequencing PDX1 (insulin promoter factor 1) in 1788 UK individuals found 5% had a low frequency coding variant, but these variants are not associated with Type 2 diabetes. | Edghill EL | Diabetic medicine : a journal of the British Diabetic Association | 2011 | PMID: 21569088 |
Pdx1 (MODY4) regulates pancreatic beta cell susceptibility to ER stress. | Sachdeva MM | Proceedings of the National Academy of Sciences of the United States of America | 2009 | PMID: 19855005 |
Pdx1 and other factors that regulate pancreatic beta-cell survival. | Fujimoto K | Diabetes, obesity & metabolism | 2009 | PMID: 19817786 |
The coactivator Bridge-1 increases transcriptional activation by pancreas duodenum homeobox-1 (PDX-1). | Stanojevic V | Molecular and cellular endocrinology | 2005 | PMID: 15885879 |
Pancreas duodenum homeobox-1 transcriptional activation requires interactions with p300. | Stanojevic V | Endocrinology | 2004 | PMID: 15001545 |
Missense mutations in the human insulin promoter factor-1 gene and their relation to maturity-onset diabetes of the young and late-onset type 2 diabetes mellitus in caucasians. | Hansen L | The Journal of clinical endocrinology and metabolism | 2000 | PMID: 10720084 |
Text-mined citations for rs143517122 ...
HelpRecord last updated May 08, 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.