rs193929377

Variant names:

• chr13-27920320-GC-G
• rs193929377
• NM_000209.4:c.188delC

Your query was ambiguous. Multiple possible variants found:

• chr13-27920320-GC-G
• chr13-27920320-GC-GCC

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1 PP5

The NM_000209.4(PDX1):​c.188delC​(p.Pro63ArgfsTer60) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000104 in 1,541,834 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000086 (0 hom.)
• Consequence: PDX1 NM_000209.4 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:10 U:1
• Conservation: PhyloP100: 0.540
• Publications: 16 publications found

Genes affected

PDX1 (HGNC:6107): (pancreatic and duodenal homeobox 1) The protein encoded by this gene is a transcriptional activator of several genes, including insulin, somatostatin, glucokinase, islet amyloid polypeptide, and glucose transporter type 2. The encoded nuclear protein is involved in the early development of the pancreas and plays a major role in glucose-dependent regulation of insulin gene expression. Defects in this gene are a cause of pancreatic agenesis, which can lead to early-onset insulin-dependent diabetes mellitus (IDDM), as well as maturity onset diabetes of the young type 4 (MODY4). [provided by RefSeq, Aug 2017]

PDX1 Gene-Disease associations (from GenCC):

• maturity-onset diabetes of the young type 4

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• pancreatic agenesis 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• permanent neonatal diabetes mellitus

  Inheritance: AR, AD Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
• monogenic diabetes

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• maturity-onset diabetes of the young

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• pancreatic agenesis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 13-27920320-GC-G is Pathogenic according to our data. Variant chr13-27920320-GC-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 21124.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDX1	NM_000209.4	c.188delC	p.Pro63ArgfsTer60	frameshift_variant	Exon 1 of 2	ENST00000381033.5	NP_000200.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDX1	ENST00000381033.5	c.188delC	p.Pro63ArgfsTer60	frameshift_variant	Exon 1 of 2	1	NM_000209.4	ENSP00000370421.4

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152126 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000145 AC: 2 AN: 138298 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000201

Gnomad OTH exome AF: 0.000248

GnomAD4 exome AF: 0.00000863 AC: 12 AN: 1389708 Hom.: 0 Cov.: 33 AF XY: 0.00000584 AC XY: 4 AN XY: 685020

African (AFR) AF: 0.00 AC: 0 AN: 31362

American (AMR) AF: 0.00 AC: 0 AN: 35432

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24756

East Asian (EAS) AF: 0.00 AC: 0 AN: 35606

South Asian (SAS) AF: 0.00 AC: 0 AN: 78490

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46976

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4784

European-Non Finnish (NFE) AF: 0.0000102 AC: 11 AN: 1074718

Other (OTH) AF: 0.0000174 AC: 1 AN: 57584

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152126 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74312

African (AFR) AF: 0.0000241 AC: 1 AN: 41430

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000302

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:10 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Maturity-onset diabetes of the young type 4 Pathogenic:3

Oct 22, 2024

Clinical Genomics Laboratory, Washington University in St. Louis

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PDX1 c.188del (p.Pro63Argfs*60) variant has been reported in numerous individuals affected with maturity-onset diabetes of the young type 4 (MODY4), and is reported to segregate with disease in at least 10 individuals (Fajans S et al., PMID: 20621032; Stoffers D et al., PMID: 8988180; Thomas I et al., PMID: 19496967). Homozygosity for this variant has been reported in individuals with neonatal diabetes mellitus with pancreatic agenesis, (Caetano L et al., PMID: 28436541; Fajans S et al., PMID: 20621032; Thomas I et al., PMID: 19496967; Wright N et al., PMID: 8506821). This variant has been reported in the ClinVar database as a pathogenic/likely pathogenic germline variant by multiple submitters and a variant of unknown significance by one submitter (ClinVar Variation ID: 21124). The PDX1 c.188del (p.Pro63Argfs*60) variant has been observed on 2/138298 alleles in the general population (gnomAD v.2.1.1). This variant causes a frameshift by deleting one nucleotide, leading to a premature codon; however, because this occurs in the penultimate exon, this is not predicted to lead to nonsense mediated decay. Functional studies show that this variant results in premature truncation of the PDX1 protein (Stoffers D et al., PMID: 9649577). Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic. -

Jan 22, 2020

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

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). -

Jul 01, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:2 Uncertain:1

Nov 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 gene product 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. -

Jan 25, 2017

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 16, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified as heterozygous in a patient with MODY and an affected child with impaired glucose tolerance in published literature, both with caudal pancreatic agenesis (PMID: 28436541); 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 (PMID: 8988180); 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 (PMID: 15001545); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26543388, 9326926, 20301620, 8506821, 8988180, 20621032, 19496967, 15001545, 28436541) -

Maturity-onset diabetes of the young type 4;C3891828:Pancreatic agenesis 1 Pathogenic:1

Jul 14, 2016

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Type 2 diabetes mellitus;C1833382:Maturity-onset diabetes of the young type 4;C3891828:Pancreatic agenesis 1 Pathogenic:1

Sep 27, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Maturity onset diabetes mellitus in young Pathogenic:1

Oct 15, 2019

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Permanent neonatal diabetes mellitus Pathogenic:1

Jul 05, 2011

GeneReviews

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

- -

Pancreatic agenesis 1 Pathogenic:1

Jul 01, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.54
Mutation Taster		=23/177	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs193929377; hg19: chr13-28494457;