The p.Pro63Argfs variant in PDX1 has been reported in 9 individuals with maturity-onset diabetes of the young type 4 (MODY type 4), segregated with disease in those 9 affected relatives from 1 family (PMID: 20621032), and this variant has been identified in 0.002% (1/49632) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; rs193929377). This variant has also been reported in ClinVar as pathogenic (Variation ID: 21124). In vitro functional studies provide some evidence that the p.Pro63Argfs variant may slightly impact protein function (PMID:15001545). However, these types of assays may not accurately represent biological function. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 63 and leads to a premature termination codon 60 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the PDX1 gene is an established disease mechanism in MODY type 4. In summary, this variant meets criteria to be classified as pathogenic for MODY type 4 in an autosomal dominant manner based on the predicted impact of this loss of function variant and the strong segregation seen with this variant and MODY type 4. ACMG/AMP Criteria applied: PVS1, PP1_strong, PM2, PS3_supporting (Richards 2015).
ClinVar Genomic variation as it relates to human health
NM_000209.4(PDX1):c.188del (p.Pro63fs)
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.
(10)
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.
Conflicting classifications of pathogenicity
Pathogenic(5); Likely pathogenic(1); Uncertain significance(1)
Pathogenic(5); Likely pathogenic(1); Uncertain significance(1)
10
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000209.4(PDX1):c.188del (p.Pro63fs)
Variation ID: 21124 Accession: VCV000021124.21
- Type and length
-
Deletion, 1 bp
- Location
-
Cytogenetic: 13q12.2 13: 27920321 (GRCh38) [ NCBI UCSC ] 13: 28494458 (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 May 3, 2013 May 1, 2024 Aug 31, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000209.4:c.188del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000200.1:p.Pro63fs frameshift NM_000209.3(PDX1):c.188delC NM_000209.3:c.188delC NC_000013.11:g.27920326del NC_000013.10:g.28494463del NG_008183.1:g.5296del - Protein change
- P63fs
- Other names
- -
- Canonical SPDI
- NC_000013.11:27920320:CCCCCC:CCCCC
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- 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. |
|||
| PDX1 | - | - |
GRCh38 GRCh37 |
167 | 203 | |
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. |
|---|---|---|---|---|
| Pathogenic (1) |
no assertion criteria provided
|
Jul 5, 2011 | RCV000020214.11 | |
| Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
|
Aug 31, 2023 | RCV000516632.18 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jul 14, 2016 | RCV000503973.13 | |
| Pathogenic (2) |
criteria provided, single submitter
|
Jan 22, 2020 | RCV001249085.13 | |
| Pathogenic (1) |
no assertion criteria provided
|
Jul 1, 2010 | RCV001847609.10 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Sep 27, 2021 | RCV002476994.8 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Oct 15, 2019 | RCV002408471.9 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Jul 14, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
MODY, type IV
Pancreatic agenesis 1
Affected status: yes
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV000596387.1
First in ClinVar: Aug 28, 2017 Last updated: Aug 28, 2017 |
|
|
|
Pathogenic
(Jan 25, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Athena Diagnostics
Accession: SCV000614426.1
First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017 |
|
|
|
Pathogenic
(Jan 22, 2020)
|
criteria provided, single submitter
Method: curation
|
Maturity-onset diabetes of the young type 4
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001423046.2
First in ClinVar: Jul 19, 2020 Last updated: Feb 05, 2022 |
Comment:
The p.Pro63Argfs variant in PDX1 has been reported in 9 individuals with maturity-onset diabetes of the young type 4 (MODY type 4), segregated with disease … (more)
The p.Pro63Argfs variant in PDX1 has been reported in 9 individuals with maturity-onset diabetes of the young type 4 (MODY type 4), segregated with disease in those 9 affected relatives from 1 family (PMID: 20621032), and this variant has been identified in 0.002% (1/49632) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; rs193929377). This variant has also been reported in ClinVar as pathogenic (Variation ID: 21124). In vitro functional studies provide some evidence that the p.Pro63Argfs variant may slightly impact protein function (PMID:15001545). However, these types of assays may not accurately represent biological function. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 63 and leads to a premature termination codon 60 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the PDX1 gene is an established disease mechanism in MODY type 4. In summary, this variant meets criteria to be classified as pathogenic for MODY type 4 in an autosomal dominant manner based on the predicted impact of this loss of function variant and the strong segregation seen with this variant and MODY type 4. ACMG/AMP Criteria applied: PVS1, PP1_strong, PM2, PS3_supporting (Richards 2015). (less)
|
|
|
Pathogenic
(Sep 27, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Type 2 diabetes mellitus
Pancreatic agenesis 1 Maturity-onset diabetes of the young type 4
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002804127.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Pathogenic
(Sep 20, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001167854.4
First in ClinVar: Mar 16, 2020 Last updated: Mar 04, 2023 |
Comment:
Identified as heterozygous in a patient with MODY and an affected child with impaired glucose tolerance in published literature, both with caudal pancreatic agenesis (Caetano … (more)
Identified as heterozygous in a patient with MODY and an affected child with impaired glucose tolerance in published literature, both with caudal pancreatic agenesis (Caetano et al., 2018); Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 221 amino acids are lost and replaced with 59 incorrect amino acids (Stoffers et al., 1997a); Published functional studies demonstrate that the variant results in increased binding of coactivator p300 compared to wild-type, suggesting a dominant negative effect due to depletion of available p300 for target gene activation (Stanojevic et al., 2004); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26543388, 9326926, 20301620, 8506821, 8988180, 20621032, 19496967, 28436541, 15001545) (less)
|
|
|
Uncertain significance
(Aug 31, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003442028.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Pro63Argfs*60) in the PDX1 gene. While this is not anticipated to result in nonsense mediated decay, … (more)
This sequence change creates a premature translational stop signal (p.Pro63Argfs*60) in the PDX1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 221 amino acid(s) of the PDX1 protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with maturity onset diabetes of the young and/or permanent neonatal diabetes (PMID: 8988180, 20621032, 28436541). This variant is also known as a single nucleotide deletion within codon 63 or P63fsdelC. ClinVar contains an entry for this variant (Variation ID: 21124). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal 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)
|
|
|
Likely pathogenic
(Oct 15, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Maturity onset diabetes mellitus in young
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002719153.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The c.188delC variant, located in coding exon 1 of the PDX1 gene, results from a deletion of one nucleotide at nucleotide position 188, causing a … (more)
The c.188delC variant, located in coding exon 1 of the PDX1 gene, results from a deletion of one nucleotide at nucleotide position 188, causing a translational frameshift with a predicted alternate stop codon (p.P63Rfs*60). This variant has been reported in two individual with neonatal diabetes and pancreatic agenesis; the parents of both infants were confirmed heterozygous and were diagnosed with maturity-onset diabetes of the young (MODY) (Stoffers DA et al. Nat. Genet., 1997 Jan;15:106-10; Stoffers DA et al. Nat. Genet., 1997 Oct;17:138-9; Thomas IH et al. Pediatr Diabetes, 2009 Nov;10:492-6; Fajans SS et al. Transl Res, 2010 Jul;156:7-14). In one multigenerational family, this variant was shown to segregate with disease with a LOD score of 3.43; of note, multiple individuals in the pedigree had type 2 diabetes and were negative for this variant (Stoffers DA et al. Nat. Genet., 1997 Oct;17:138-9). In another family, this variant was identified in a proband with MODY and a child with impaired glucose tolerance; both individuals had dorsal pancreatic agenesis (Caetano LA et al. Clin. Genet., 2018 02;93:382-386). Protein analysis demonstrated 2 mutant PDX1 proteins produced by this variant: a smaller mutant protein which encodes a truncated amino-terminal protein lacking a DNA binding domain and a nuclear localization signal but including an unique carboxy-terminal sequence arising from the frame shift that is expected to be transcriptionally inactive and a larger mutant protein using an alternate, out-of-frame initiation codon that is returned to in-frame by the cytosine deletion and lacks the amino-terminal transactivation domain but includes the DNA-binding homeodomain and the carboxy-terminal domain, suggesting a dominant-negative mechanism (Stoffers DA et al. J. Clin. Invest., 1998 Jul;102:232-41). (Stoffers DA et al. Nat. Genet., 1997 Oct;17:138-9). Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
|
|
|
Pathogenic
(Jul 01, 2010)
|
no assertion criteria provided
Method: literature only
|
MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 4
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000029625.3
First in ClinVar: Apr 04, 2013 Last updated: Jan 26, 2024 |
Comment on evidence:
Stoffers et al. (1997) found a frameshift resulting from a 1-bp deletion in the IPF1 gene in a female Caucasian infant in whom the diagnosis … (more)
Stoffers et al. (1997) found a frameshift resulting from a 1-bp deletion in the IPF1 gene in a female Caucasian infant in whom the diagnosis of pancreatic agenesis (PAGEN1; 260370) was made shortly after birth (Wright et al., 1993). The infant was underweight for gestational age and presented with neonatal diabetes mellitus at birth and, at age 18 days, with pancreatic exocrine insufficiency. Ultrasound examination revealed that the pancreas was absent. After replacement of insulin and pancreatic enzymes, she developed normally and at 5 years of age continued to do well. There was a strong family history of noninsulin-dependent diabetes mellitus. Stoffers et al. (1997) found the child to be homozygous for deletion of a single cytosine in codon 63 of the IPF1 gene, resulting in termination after 59 additional codons (Pro63fsdelC). In a later paper, Stoffers et al. (1997) demonstrated that whereas homozygosity of the Pro63fsdelC mutation led to pancreatic agenesis, heterozygosity was associated with a new type of early-onset type 2 diabetes mellitus (MODY4; 606392). In the course of expressing the mutant IPF1 protein in eukaryotic cells, Stoffers et al. (1998) detected a second IPF1 isoform, recognized by COOH- but not NH2-terminal-specific antisera. This isoform localized to the nucleus and retained DNA-binding functions. Internal translation initiating at an out-of-frame AUG accounted for the appearance of the protein. The reading frame crossed over to the wildtype IPF1 reading frame at the site of the point deletion just carboxy-proximal to the transactivation domain. Thus, the single mutated allele results in the translation of 2 IPF1 isoforms; the first consists of the NH2-terminal transactivation domain and is sequestered in the cytoplasm, and the second contains the COOH-terminal DNA-binding domain but lacks the transactivation domain. The COOH-terminal domain IPF1 isoform does not activate transcription and inhibits the transactivation functions of wildtype IPF1. This circumstance suggested that the mechanism of diabetes in individuals with this mutation may be not only reduced gene dosage but also a dominant-negative inhibition of transcription of the insulin gene and other beta cell-specific genes regulated by the mutant IPF1. Thomas et al. (2009) reported a family in which a male infant with pancreatic agenesis, whose parents were later determined to have MODY, was homozygous for the same 1-bp deletion in the PDX1 gene (188delC; Pro63fsTer60) identified by Stoffers et al. (1997) in a similar family. Thomas et al. (2009) suggested that the 2 families might be related. Fajans et al. (2010) restudied the family reported by Thomas et al. (2009), ultimately identifying 110 members of the 5-generation Michigan-Kentucky pedigree; 34 family members were being treated for diabetes, and 10 of those diabetics carried the 1-bp deletion in PDX1 (188delC) and were considered to have MODY4. Fajans et al. (2010) identified a single 2.5-Mb region on chromosome 13 shared by the Michigan-Kentucky pedigree and the Virginia pedigree, originally reported by Wright et al. (1993), that also carried the 1-bp deletion in PDX1. The size of the shared region suggested that the PDX1 frameshift mutation emerged in a recent ancestor common to both probands and that a complex pedigree structure connected the 2 probands. (less)
|
|
|
Pathogenic
(Jul 01, 2010)
|
no assertion criteria provided
Method: literature only
|
PANCREATIC AGENESIS 1
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000029624.3
First in ClinVar: Apr 04, 2013 Last updated: Jan 26, 2024 |
Comment on evidence:
Stoffers et al. (1997) found a frameshift resulting from a 1-bp deletion in the IPF1 gene in a female Caucasian infant in whom the diagnosis … (more)
Stoffers et al. (1997) found a frameshift resulting from a 1-bp deletion in the IPF1 gene in a female Caucasian infant in whom the diagnosis of pancreatic agenesis (PAGEN1; 260370) was made shortly after birth (Wright et al., 1993). The infant was underweight for gestational age and presented with neonatal diabetes mellitus at birth and, at age 18 days, with pancreatic exocrine insufficiency. Ultrasound examination revealed that the pancreas was absent. After replacement of insulin and pancreatic enzymes, she developed normally and at 5 years of age continued to do well. There was a strong family history of noninsulin-dependent diabetes mellitus. Stoffers et al. (1997) found the child to be homozygous for deletion of a single cytosine in codon 63 of the IPF1 gene, resulting in termination after 59 additional codons (Pro63fsdelC). In a later paper, Stoffers et al. (1997) demonstrated that whereas homozygosity of the Pro63fsdelC mutation led to pancreatic agenesis, heterozygosity was associated with a new type of early-onset type 2 diabetes mellitus (MODY4; 606392). In the course of expressing the mutant IPF1 protein in eukaryotic cells, Stoffers et al. (1998) detected a second IPF1 isoform, recognized by COOH- but not NH2-terminal-specific antisera. This isoform localized to the nucleus and retained DNA-binding functions. Internal translation initiating at an out-of-frame AUG accounted for the appearance of the protein. The reading frame crossed over to the wildtype IPF1 reading frame at the site of the point deletion just carboxy-proximal to the transactivation domain. Thus, the single mutated allele results in the translation of 2 IPF1 isoforms; the first consists of the NH2-terminal transactivation domain and is sequestered in the cytoplasm, and the second contains the COOH-terminal DNA-binding domain but lacks the transactivation domain. The COOH-terminal domain IPF1 isoform does not activate transcription and inhibits the transactivation functions of wildtype IPF1. This circumstance suggested that the mechanism of diabetes in individuals with this mutation may be not only reduced gene dosage but also a dominant-negative inhibition of transcription of the insulin gene and other beta cell-specific genes regulated by the mutant IPF1. Thomas et al. (2009) reported a family in which a male infant with pancreatic agenesis, whose parents were later determined to have MODY, was homozygous for the same 1-bp deletion in the PDX1 gene (188delC; Pro63fsTer60) identified by Stoffers et al. (1997) in a similar family. Thomas et al. (2009) suggested that the 2 families might be related. Fajans et al. (2010) restudied the family reported by Thomas et al. (2009), ultimately identifying 110 members of the 5-generation Michigan-Kentucky pedigree; 34 family members were being treated for diabetes, and 10 of those diabetics carried the 1-bp deletion in PDX1 (188delC) and were considered to have MODY4. Fajans et al. (2010) identified a single 2.5-Mb region on chromosome 13 shared by the Michigan-Kentucky pedigree and the Virginia pedigree, originally reported by Wright et al. (1993), that also carried the 1-bp deletion in PDX1. The size of the shared region suggested that the PDX1 frameshift mutation emerged in a recent ancestor common to both probands and that a complex pedigree structure connected the 2 probands. (less)
|
|
|
pathologic
(Jul 05, 2011)
|
no assertion criteria provided
Method: curation
|
Permanent Neonatal Diabetes Mellitus
Affected status: not provided
Allele origin:
not provided
|
GeneReviews
Accession: SCV000040551.2
First in ClinVar: Apr 04, 2013 Last updated: May 03, 2013 |
Comment:
Converted during submission to Pathogenic.
|
Comment:
Comment:
Identified as heterozygous in a patient with MODY and an affected child with impaired glucose tolerance in published literature, both with caudal pancreatic agenesis (Caetano et al., 2018); Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 221 amino acids are lost and replaced with 59 incorrect amino acids (Stoffers et al., 1997a); Published functional studies demonstrate that the variant results in increased binding of coactivator p300 compared to wild-type, suggesting a dominant negative effect due to depletion of available p300 for target gene activation (Stanojevic et al., 2004); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26543388, 9326926, 20301620, 8506821, 8988180, 20621032, 19496967, 28436541, 15001545)
Comment:
This sequence change creates a premature translational stop signal (p.Pro63Argfs*60) in the PDX1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 221 amino acid(s) of the PDX1 protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with maturity onset diabetes of the young and/or permanent neonatal diabetes (PMID: 8988180, 20621032, 28436541). This variant is also known as a single nucleotide deletion within codon 63 or P63fsdelC. ClinVar contains an entry for this variant (Variation ID: 21124). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal 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.
Comment:
The c.188delC variant, located in coding exon 1 of the PDX1 gene, results from a deletion of one nucleotide at nucleotide position 188, causing a translational frameshift with a predicted alternate stop codon (p.P63Rfs*60). This variant has been reported in two individual with neonatal diabetes and pancreatic agenesis; the parents of both infants were confirmed heterozygous and were diagnosed with maturity-onset diabetes of the young (MODY) (Stoffers DA et al. Nat. Genet., 1997 Jan;15:106-10; Stoffers DA et al. Nat. Genet., 1997 Oct;17:138-9; Thomas IH et al. Pediatr Diabetes, 2009 Nov;10:492-6; Fajans SS et al. Transl Res, 2010 Jul;156:7-14). In one multigenerational family, this variant was shown to segregate with disease with a LOD score of 3.43; of note, multiple individuals in the pedigree had type 2 diabetes and were negative for this variant (Stoffers DA et al. Nat. Genet., 1997 Oct;17:138-9). In another family, this variant was identified in a proband with MODY and a child with impaired glucose tolerance; both individuals had dorsal pancreatic agenesis (Caetano LA et al. Clin. Genet., 2018 02;93:382-386). Protein analysis demonstrated 2 mutant PDX1 proteins produced by this variant: a smaller mutant protein which encodes a truncated amino-terminal protein lacking a DNA binding domain and a nuclear localization signal but including an unique carboxy-terminal sequence arising from the frame shift that is expected to be transcriptionally inactive and a larger mutant protein using an alternate, out-of-frame initiation codon that is returned to in-frame by the cytosine deletion and lacks the amino-terminal transactivation domain but includes the DNA-binding homeodomain and the carboxy-terminal domain, suggesting a dominant-negative mechanism (Stoffers DA et al. J. Clin. Invest., 1998 Jul;102:232-41). (Stoffers DA et al. Nat. Genet., 1997 Oct;17:138-9). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Comment:
Converted during submission to Pathogenic.
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:
The p.Pro63Argfs variant in PDX1 has been reported in 9 individuals with maturity-onset diabetes of the young type 4 (MODY type 4), segregated with disease in those 9 affected relatives from 1 family (PMID: 20621032), and this variant has been identified in 0.002% (1/49632) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; rs193929377). This variant has also been reported in ClinVar as pathogenic (Variation ID: 21124). In vitro functional studies provide some evidence that the p.Pro63Argfs variant may slightly impact protein function (PMID:15001545). However, these types of assays may not accurately represent biological function. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 63 and leads to a premature termination codon 60 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the PDX1 gene is an established disease mechanism in MODY type 4. In summary, this variant meets criteria to be classified as pathogenic for MODY type 4 in an autosomal dominant manner based on the predicted impact of this loss of function variant and the strong segregation seen with this variant and MODY type 4. ACMG/AMP Criteria applied: PVS1, PP1_strong, PM2, PS3_supporting (Richards 2015).
Comment:
Identified as heterozygous in a patient with MODY and an affected child with impaired glucose tolerance in published literature, both with caudal pancreatic agenesis (Caetano et al., 2018); Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 221 amino acids are lost and replaced with 59 incorrect amino acids (Stoffers et al., 1997a); Published functional studies demonstrate that the variant results in increased binding of coactivator p300 compared to wild-type, suggesting a dominant negative effect due to depletion of available p300 for target gene activation (Stanojevic et al., 2004); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26543388, 9326926, 20301620, 8506821, 8988180, 20621032, 19496967, 28436541, 15001545)
Comment:
This sequence change creates a premature translational stop signal (p.Pro63Argfs*60) in the PDX1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 221 amino acid(s) of the PDX1 protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with maturity onset diabetes of the young and/or permanent neonatal diabetes (PMID: 8988180, 20621032, 28436541). This variant is also known as a single nucleotide deletion within codon 63 or P63fsdelC. ClinVar contains an entry for this variant (Variation ID: 21124). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal 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.
Comment:
The c.188delC variant, located in coding exon 1 of the PDX1 gene, results from a deletion of one nucleotide at nucleotide position 188, causing a translational frameshift with a predicted alternate stop codon (p.P63Rfs*60). This variant has been reported in two individual with neonatal diabetes and pancreatic agenesis; the parents of both infants were confirmed heterozygous and were diagnosed with maturity-onset diabetes of the young (MODY) (Stoffers DA et al. Nat. Genet., 1997 Jan;15:106-10; Stoffers DA et al. Nat. Genet., 1997 Oct;17:138-9; Thomas IH et al. Pediatr Diabetes, 2009 Nov;10:492-6; Fajans SS et al. Transl Res, 2010 Jul;156:7-14). In one multigenerational family, this variant was shown to segregate with disease with a LOD score of 3.43; of note, multiple individuals in the pedigree had type 2 diabetes and were negative for this variant (Stoffers DA et al. Nat. Genet., 1997 Oct;17:138-9). In another family, this variant was identified in a proband with MODY and a child with impaired glucose tolerance; both individuals had dorsal pancreatic agenesis (Caetano LA et al. Clin. Genet., 2018 02;93:382-386). Protein analysis demonstrated 2 mutant PDX1 proteins produced by this variant: a smaller mutant protein which encodes a truncated amino-terminal protein lacking a DNA binding domain and a nuclear localization signal but including an unique carboxy-terminal sequence arising from the frame shift that is expected to be transcriptionally inactive and a larger mutant protein using an alternate, out-of-frame initiation codon that is returned to in-frame by the cytosine deletion and lacks the amino-terminal transactivation domain but includes the DNA-binding homeodomain and the carboxy-terminal domain, suggesting a dominant-negative mechanism (Stoffers DA et al. J. Clin. Invest., 1998 Jul;102:232-41). (Stoffers DA et al. Nat. Genet., 1997 Oct;17:138-9). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Comment:
Converted during submission to Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| PDX1 -MODY and dorsal pancreatic agenesis: New phenotype of a rare disease. | Caetano LA | Clinical genetics | 2018 | PMID: 28436541 |
| Permanent Neonatal Diabetes Mellitus. | Adam MP | - | 2016 | PMID: 20301620 |
| Obesity and hyperinsulinemia in a family with pancreatic agenesis and MODY caused by the IPF1 mutation Pro63fsX60. | Fajans SS | Translational research : the journal of laboratory and clinical medicine | 2010 | PMID: 20621032 |
| Neonatal diabetes mellitus with pancreatic agenesis in an infant with homozygous IPF-1 Pro63fsX60 mutation. | Thomas IH | Pediatric diabetes | 2009 | PMID: 19496967 |
| Pancreas duodenum homeobox-1 transcriptional activation requires interactions with p300. | Stanojevic V | Endocrinology | 2004 | PMID: 15001545 |
| Insulin promoter factor-1 gene mutation linked to early-onset type 2 diabetes mellitus directs expression of a dominant negative isoprotein. | Stoffers DA | The Journal of clinical investigation | 1998 | PMID: 9649577 |
| Early-onset type-II diabetes mellitus (MODY4) linked to IPF1. | Stoffers DA | Nature genetics | 1997 | PMID: 9326926 |
| Pancreatic agenesis attributable to a single nucleotide deletion in the human IPF1 gene coding sequence. | Stoffers DA | Nature genetics | 1997 | PMID: 8988180 |
| Permanent neonatal diabetes mellitus and pancreatic exocrine insufficiency resulting from congenital pancreatic agenesis. | Wright NM | American journal of diseases of children (1960) | 1993 | PMID: 8506821 |
| https://erepo.clinicalgenome.org/evrepo/ui/interpretation/806a526f-6ccf-43a7-b76d-c04f4df9231e | - | - | - | - |
Text-mined citations for rs193929377 ...
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Record last updated Oct 27, 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.