Variant rs193929377 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_000209.4(PDX1):c.188delC(p.Pro63fs) 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

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:9U:1

Conservation

PhyloP100: 0.540

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

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 id is 21124.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=5, Likely_pathogenic=1}. Variant chr13-27920320-GC-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDX1	NM_000209.4 linkuse as main transcript	c.188delC	p.Pro63fs	frameshift_variant	1/2	ENST00000381033.5	NP_000200.1	P52945

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDX1	ENST00000381033.5 linkuse as main transcript	c.188delC	p.Pro63fs	frameshift_variant	1/2	1	NM_000209.4	ENSP00000370421.4		P52945

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152126

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.0000145

AC:

AN:

138298

Hom.:

AF XY:

0.00

AC XY:

AN XY:

74906

show subpopulations

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 SAS 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:

AN:

1389708

Hom.:

Cov.:

AF XY:

0.00000584

AC XY:

AN XY:

685020

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000102

Gnomad4 OTH exome

AF:

0.0000174

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152126

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74312

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000302

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:9Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:2Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 31, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 25, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 20, 2022	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) -

Maturity-onset diabetes of the young type 4

Pathogenic:2

Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	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). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2010	- -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 14, 2016

- -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 27, 2021

- -

Maturity onset diabetes mellitus in young

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 15, 2019

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

Pathogenic, no assertion criteria provided

curation

GeneReviews

Jul 05, 2011

- -

Pancreatic agenesis 1

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 2010

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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