ClinVar Genomic variation as it relates to human health
NM_000209.4(PDX1):c.716C>A (p.Pro239Gln)
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(8); Likely benign(4)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000209.4(PDX1):c.716C>A (p.Pro239Gln)
Variation ID: 129881 Accession: VCV000129881.26
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q12.2 13: 28498702 (GRCh37) [ NCBI UCSC ] 13: 27924565 (GRCh38) [ 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 May 17, 2014 May 1, 2024 Jan 25, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000209.4:c.716C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000200.1:p.Pro239Gln missense NC_000013.11:g.27924565C>A NC_000013.10:g.28498702C>A NG_008183.1:g.9535C>A - Protein change
- P239Q
- Other names
- -
- Canonical SPDI
- NC_000013.11:27924564:C: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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0.00639 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00562
1000 Genomes Project 0.00639
1000 Genomes Project 30x 0.00796
The Genome Aggregation Database (gnomAD) 0.00993
Trans-Omics for Precision Medicine (TOPMed) 0.01035
Exome Aggregation Consortium (ExAC) 0.01048
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 |
159 | 194 |
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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Benign/Likely benign (5) |
criteria provided, multiple submitters, no conflicts
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Jan 25, 2024 | RCV000117899.14 | |
Benign (1) |
criteria provided, single submitter
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Aug 14, 2018 | RCV000445403.4 | |
Benign/Likely benign (4) |
criteria provided, multiple submitters, no conflicts
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Aug 7, 2023 | RCV000515153.10 | |
Likely benign (1) |
criteria provided, single submitter
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May 28, 2019 | RCV000988972.2 | |
Uncertain significance (1) |
criteria provided, single submitter
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- | RCV002250564.2 | |
Benign (1) |
criteria provided, single submitter
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May 5, 2016 | RCV002371951.2 |
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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Benign
(Oct 01, 2019)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
unknown
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Athena Diagnostics
Accession: SCV001476619.1
First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021 |
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Likely benign
(Aug 07, 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: SCV004038279.1
First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023 |
Comment:
Variant summary: PDX1 c.716C>A (p.Pro239Gln) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign … (more)
Variant summary: PDX1 c.716C>A (p.Pro239Gln) results in a non-conservative amino acid change in 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 0.006 in 109586 control chromosomes in the gnomAD database, including 6 homozygotes. The observed variant frequency significantly exceeds the estimated maximal expected allele frequency for a pathogenic variant in PDX1 causing Familial Monogenic Diabetes (Maturity Onset Diabetes Of The Young 4)/Neonatal Diabetes Mellitus phenotype (1.3e-06), strongly suggesting that the variant is benign. c.716C>A has been reported in the literature in individuals affected with Familial Monogenic Diabetes (Maturity Onset Diabetes Of The Young 4)/Neonatal Diabetes Mellitus (example, Weng_2001, Weng_2002, Lindgren_2002, Haaland_2009, Huang_2002, Zhang_2004). In our ascertainment of families with this variant, 10 transmissions of the variant allele and 6 transmissions of the reference allele to affected individuals was reported supporting lack of segregation with a disease phenotype. In our ascertainment, the penetrance of Familial Monogenic Diabetes (Maturity Onset Diabetes Of The Young 4)/Neonatal Diabetes Mellitus (0.53) due to this variant appears to be lower than expected (0.8), therefore, no conclusions can be drawn from these data. At least one publication reports experimental evidence evaluating an impact on protein function (example, Weng_2001). The most pronounced variant effect results in normal expression and binding activity to the insulin gene promoter but reduced activation of the insulin-gene transcription in response to increased glucose concentrations compared with the wild-type IPF1 protein. The following publications have been ascertained in the context of this evaluation (PMID: 11270685, 11772903, 11978663, 15111508, 19228875, 12099699, 15028942, 12677187). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign. (less)
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Benign
(May 05, 2016)
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criteria provided, single submitter
Method: clinical testing
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Maturity onset diabetes mellitus in young
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002665601.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more)
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
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Likely benign
(Feb 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
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Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Accession: SCV000610490.1
First in ClinVar: May 17, 2014 Last updated: May 17, 2014 |
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Likely benign
(Mar 29, 2016)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: no
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV000152173.2
First in ClinVar: Nov 14, 2017 Last updated: Nov 14, 2017 |
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Benign
(Jan 10, 2019)
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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: SCV001847059.1
First in ClinVar: Sep 10, 2021 Last updated: Sep 10, 2021 |
Comment:
This variant is associated with the following publications: (PMID: 11270685, 27884173, 24097065)
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Uncertain significance
(-)
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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 dominant inheritance)
Affected status: unknown
Allele origin:
somatic
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Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic
Accession: SCV002520727.1
First in ClinVar: Jun 05, 2022 Last updated: Jun 05, 2022 |
Comment:
Potent homozygous mutations in the PDX1 gene can lead to pancreatic agenesis/pancreatic hypoplasia and neonatal diabetes mellitus. However, the role of this particular variant (rs199644078) … (more)
Potent homozygous mutations in the PDX1 gene can lead to pancreatic agenesis/pancreatic hypoplasia and neonatal diabetes mellitus. However, the role of this particular variant (rs199644078) of PDX1 in pancreatic agenesis/hypoplasia and neonatal diabetes mellitus remains uncertain. (less)
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Benign
(Jan 25, 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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Invitae
Accession: SCV002410122.3
First in ClinVar: Apr 08, 2022 Last updated: Feb 20, 2024 |
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Benign
(Oct 14, 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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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV004564115.1
First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024 |
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Benign
(Nov 09, 2021)
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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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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004848598.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The p.Pro239Gln variant in PDX1 is classified as benign because it has been identified in 2.8% (351/12426) of African/African-American chromosomes, including 9 homozygotes, by gnomAD … (more)
The p.Pro239Gln variant in PDX1 is classified as benign because it has been identified in 2.8% (351/12426) of African/African-American chromosomes, including 9 homozygotes, by gnomAD (http://gnomad.broadinstitute.org). ACMG/AMP Criteria applied: BA1. (less)
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Likely benign
(May 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Maturity-onset diabetes of the young type 4
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001138927.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Benign
(Aug 14, 2018)
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criteria provided, single submitter
Method: research
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Monogenic diabetes
Affected status: unknown
Allele origin:
unknown
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Personalized Diabetes Medicine Program, University of Maryland School of Medicine
Accession: SCV000537094.2
First in ClinVar: Mar 14, 2017 Last updated: Jun 13, 2020 |
Comment:
ACMG criteria: BA1 (2.8% in gnomAD African)= benign (REVEL score 0.221 + PP3 (3 predictors) + BP4 (8 predictors)= conflicting evidence, not using)
Number of individuals with the variant: 6
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Benign
(Apr 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: SCV004132940.4
First in ClinVar: Nov 20, 2023 Last updated: Apr 15, 2024 |
Comment:
PDX1: BS1, BS2
Number of individuals with the variant: 1
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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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First Japanese Family With PDX1-MODY (MODY4): A Novel PDX1 Frameshift Mutation, Clinical Characteristics, and Implications. | Yoshiji S | Journal of the Endocrine Society | 2021 | PMID: 34988346 |
Identification and Clinical Characterization of Adult Patients with Multigenerational Diabetes Mellitus. | Ludovico O | PloS one | 2015 | PMID: 26287533 |
Identification of low-frequency and rare sequence variants associated with elevated or reduced risk of type 2 diabetes. | Steinthorsdottir V | Nature genetics | 2014 | PMID: 24464100 |
Assessing the phenotypic effects in the general population of rare variants in genes for a dominant Mendelian form of diabetes. | Flannick J | Nature genetics | 2013 | PMID: 24097065 |
A-beta-subtype of ketosis-prone diabetes is not predominantly a monogenic diabetic syndrome. | Haaland WC | Diabetes care | 2009 | PMID: 19228875 |
Genome-wide scans reveal quantitative trait Loci on 8p and 13q related to insulin action and glucose metabolism: the San Antonio Family Heart Study. | Cai G | Diabetes | 2004 | PMID: 15111508 |
PDX-1 and the pancreas. | Ashizawa S | Pancreas | 2004 | PMID: 15028942 |
The Role of Pancreatic Duodenum Homeobox Protein-1 in the Development of Diabetes Mellitus. | Habener JF | Drug news & perspectives | 2002 | PMID: 12677187 |
Functional expression and analysis of the pancreatic transcription factor PDX-1 in yeast. | Ozcan S | Biochemical and biophysical research communications | 2002 | PMID: 12099699 |
Contribution of known and unknown susceptibility genes to early-onset diabetes in scandinavia: evidence for heterogeneity. | Lindgren CM | Diabetes | 2002 | PMID: 11978663 |
Screening for MODY mutations, GAD antibodies, and type 1 diabetes--associated HLA genotypes in women with gestational diabetes mellitus. | Weng J | Diabetes care | 2002 | PMID: 11772903 |
Functional consequences of mutations in the MODY4 gene (IPF1) and coexistence with MODY3 mutations. | Weng J | Diabetologia | 2001 | PMID: 11270685 |
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Text-mined citations for rs199644078 ...
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.