13-27920190-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_000209.4(PDX1):ā€‹c.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

Scores

9
6
4

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4O:1

Conservation

PhyloP100: 4.51
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]

Genome browser will be placed here

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
PDX1NM_000209.4 linkuse as main transcriptc.52T>C p.Cys18Arg missense_variant 1/2 ENST00000381033.5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PDX1ENST00000381033.5 linkuse as main transcriptc.52T>C p.Cys18Arg missense_variant 1/21 NM_000209.4 P1

Frequencies

GnomAD3 genomes
AF:
0.000112
AC:
17
AN:
152174
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000483
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:
0.000221
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000109
AC:
16
AN:
146476
Hom.:
0
AF XY:
0.0000886
AC XY:
7
AN XY:
79006
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000408
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.000131
Gnomad NFE exome
AF:
0.000242
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000248
AC:
346
AN:
1397628
Hom.:
0
Cov.:
33
AF XY:
0.000239
AC XY:
165
AN XY:
689382
show subpopulations
Gnomad4 AFR exome
AF:
0.0000634
Gnomad4 AMR exome
AF:
0.0000280
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000835
Gnomad4 NFE exome
AF:
0.000293
Gnomad4 OTH exome
AF:
0.000397
GnomAD4 genome
AF:
0.000112
AC:
17
AN:
152292
Hom.:
0
Cov.:
33
AF XY:
0.000107
AC XY:
8
AN XY:
74484
show subpopulations
Gnomad4 AFR
AF:
0.0000481
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:
0.000221
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000138
Hom.:
0
Bravo
AF:
0.000147
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000266
AC:
2
ExAC
AF:
0.0000806
AC:
7

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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 07, 2023This 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 submitterclinical testingGeneDxJul 25, 2019Published 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 submittercurationBroad Center for Mendelian Genomics, Broad Institute of MIT and HarvardJan 22, 2020The 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 submitterclinical testingFulgent Genetics, Fulgent GeneticsFeb 09, 2022- -
Diabetes mellitus type 2, susceptibility to Other:1
risk factor, no assertion criteria providedliterature onlyOMIMNov 01, 1999- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.91
BayesDel_addAF
Pathogenic
0.19
D
BayesDel_noAF
Pathogenic
0.32
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.88
D
Eigen
Uncertain
0.63
Eigen_PC
Uncertain
0.57
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Benign
0.69
T
M_CAP
Pathogenic
0.64
D
MetaRNN
Pathogenic
0.95
D
MetaSVM
Uncertain
0.69
D
MutationAssessor
Benign
1.9
L
MutationTaster
Benign
1.0
D
PrimateAI
Pathogenic
0.89
D
PROVEAN
Pathogenic
-4.4
D
REVEL
Pathogenic
0.90
Sift
Uncertain
0.0050
D
Sift4G
Benign
0.13
T
Polyphen
1.0
D
Vest4
0.87
MVP
0.99
MPC
2.7
ClinPred
0.85
D
GERP RS
5.3
Varity_R
0.88
gMVP
0.75

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.

Other links and lift over

dbSNP: rs137852785; hg19: chr13-28494327; API