Submissions for variant NM_000209.4(PDX1):c.188del (p.Pro63fs)

dbSNP: rs193929377

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000503973	SCV000596387	pathogenic	Maturity-onset diabetes of the young type 4; Pancreatic agenesis 1	2016-07-14	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000516632	SCV000614426	pathogenic	not provided	2017-01-25	criteria provided, single submitter	clinical testing
GeneDx	RCV000516632	SCV001167854	pathogenic	not provided	2022-09-20	criteria provided, single submitter	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 (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)
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001249085	SCV001423046	pathogenic	Maturity-onset diabetes of the young type 4	2020-01-22	criteria provided, single submitter	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).
Ambry Genetics	RCV002408471	SCV002719153	likely pathogenic	Maturity onset diabetes mellitus in young	2019-10-15	criteria provided, single submitter	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.
Fulgent Genetics, Fulgent Genetics	RCV002476994	SCV002804127	pathogenic	Maturity-onset diabetes of the young type 4; Pancreatic agenesis 1; Type 2 diabetes mellitus	2021-09-27	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000516632	SCV003442028	uncertain significance	not provided	2023-08-31	criteria provided, single submitter	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 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.
OMIM	RCV001847609	SCV000029624	pathogenic	Pancreatic agenesis 1	2010-07-01	no assertion criteria provided	literature only
OMIM	RCV001249085	SCV000029625	pathogenic	Maturity-onset diabetes of the young type 4	2010-07-01	no assertion criteria provided	literature only
GeneReviews	RCV000020214	SCV000040551	pathologic	Permanent neonatal diabetes mellitus	2011-07-05	no assertion criteria provided	curation	Converted during submission to Pathogenic.