rs137852785
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_000209.4(PDX1):āc.52T>Cā(p.Cys18Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000234 in 1,549,920 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Genomes: š 0.00011 ( 0 hom., cov: 33)
Exomes š: 0.00025 ( 0 hom. )
Consequence
PDX1
NM_000209.4 missense
NM_000209.4 missense
Scores
9
6
4
Clinical Significance
Conservation
PhyloP100: 4.51
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.952
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PDX1 | NM_000209.4 | c.52T>C | p.Cys18Arg | missense_variant | 1/2 | ENST00000381033.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PDX1 | ENST00000381033.5 | c.52T>C | p.Cys18Arg | missense_variant | 1/2 | 1 | NM_000209.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000112 AC: 17AN: 152174Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000109 AC: 16AN: 146476Hom.: 0 AF XY: 0.0000886 AC XY: 7AN XY: 79006
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GnomAD4 exome AF: 0.000248 AC: 346AN: 1397628Hom.: 0 Cov.: 33 AF XY: 0.000239 AC XY: 165AN XY: 689382
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GnomAD4 genome ? AF: 0.000112 AC: 17AN: 152292Hom.: 0 Cov.: 33 AF XY: 0.000107 AC XY: 8AN XY: 74484
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 07, 2023 | This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 18 of the PDX1 protein (p.Cys18Arg). This variant is present in population databases (rs137852785, gnomAD 0.02%). This missense change has been observed in individual(s) with type 1 diabetes, type 2 diabetes, or maturity onset diabetes of the young (PMID: 10545530, 11022198, 30191644). ClinVar contains an entry for this variant (Variation ID: 8862). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PDX1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PDX1 function (PMID: 10545530, 30930126). 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 25, 2019 | Published functional studies demonstrate a damaging effect with moderate reduction in insulin gene activation by the PDX1 protein, reduced glucose response function, and impaired function on beta-like cell differentiation (Macfarlane et al., 1999; Wang et al., 2019); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Identified in individuals with diabetes in published literature (Macfarlane et al., 1999; Flannick et al., 2013). However, this variant did not segregate with disease in one family and was observed in a control subject in another study (Macfarlane et al., 1999; Edghill et al., 2011); This variant is associated with the following publications: (PMID: 28609558, 24097065, 21569088, 11914043, 10545530, 29034891, 27879214, 30930126, 30191644, 31589614) - |
Type 2 diabetes mellitus Uncertain:1
Uncertain significance, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Jan 22, 2020 | The p.Cys18Arg variant in PDX1 has been reported in at least 3 individuals with type 2 diabetes mellitus (PMID: 10545530, 27879214; DOI: 10.7324/JABB.2013.1205), and has been identified in 0.02173% (15/69030) of European (non-Finnish) chromosomes, 0.01066% (2/18762) of European (Finnish) chromosomes, and 0.003943% (1/25360) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs137852785). In vitro functional studies provide some evidence that the p.Cys18Arg variant may slightly impact protein function, resulting in moderately decreased binding activity to the insulin promoter and decreased transcription of insulin in response to hyperglycemia (PMID: 30930126, 10545530). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The p.Cys18Arg variant did not segregate with type 2 diabetes mellitus in 3 affected relatives of individuals with the variant, suggesting that this variant is not pathogenic for type 2 diabetes mellitus (PMID: 10545530). The variant is located in a region of PDX1 that is important for protein binding, suggesting that this variant is in a functional domain and slighly supports pathogenicity (PMID: 27879214). In summary, the clinical significance of the p.Cys18Arg variant is uncertain. ACMG/AMP Criteria applied: BS4, PP3, PS4_supporting, PS3_supporting, PM1_supporting (Richards 2015). - |
Type 2 diabetes mellitus;C1833382:Maturity-onset diabetes of the young type 4;C3891828:Pancreatic agenesis 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Feb 09, 2022 | - - |
Diabetes mellitus type 2, susceptibility to Other:1
risk factor, no assertion criteria provided | literature only | OMIM | Nov 01, 1999 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
D
MutationAssessor
Benign
L
MutationTaster
Benign
D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Uncertain
D
Sift4G
Benign
T
Polyphen
D
Vest4
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at