rs137852785

Positions:

chr13-27920190-T-C

Variant summary

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

The NM_000209.4(PDX1):c.52T>C(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 (★★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00025 ( 0 hom. )

Consequence

PDX1
NM_000209.4 missense

Scores

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]

PDX1 links:

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
PDX1	NM_000209.4 linkuse as main transcript	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 linkuse as main transcript	c.52T>C	p.Cys18Arg	missense_variant	1/2	1	NM_000209.4	P1

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152174

Hom.:

Cov.:

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:

AN:

146476

Hom.:

AF XY:

0.0000886

AC XY:

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.:

Cov.:

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:

AN:

152292

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

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.:

Bravo

AF:

0.000147

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000266

AC:

ExAC

AF:

0.0000806

AC:

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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Pathogenic

0.32

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.88

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.69

M_CAP

Pathogenic

0.64

MetaRNN

Pathogenic

0.95

MetaSVM

Uncertain

0.69

MutationAssessor

Benign

1.9

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-4.4

REVEL

Pathogenic

0.90

Sift

Uncertain

0.0050

Sift4G

Benign

0.13

Polyphen

1.0

Vest4

0.87

MVP

0.99

MPC

2.7

ClinPred

0.85

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over