rs137852787

Variant names:

• chr13-27924519-G-A
• rs137852787
• NM_000209.4:c.670G>A

Your query was ambiguous. Multiple possible variants found:

• chr13-27924519-G-A
• chr13-27924519-G-C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_000209.4(PDX1):​c.670G>A​(p.Glu224Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000508 in 1,607,848 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. E224E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00053 (7 hom.)
• Consequence: PDX1 NM_000209.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:6
• Conservation: PhyloP100: 6.23
• Publications: 19 publications found

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 Gene-Disease associations (from GenCC):

• maturity-onset diabetes of the young type 4

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• pancreatic agenesis 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• permanent neonatal diabetes mellitus

  Inheritance: AR, AD Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
• monogenic diabetes

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• maturity-onset diabetes of the young

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• pancreatic agenesis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 7 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: -0.26592 (below the threshold of 3.09). Trascript score misZ: -1.1553 (below the threshold of 3.09). GenCC associations: The gene is linked to pancreatic agenesis 1, monogenic diabetes, pancreatic agenesis, maturity-onset diabetes of the young, permanent neonatal diabetes mellitus, maturity-onset diabetes of the young type 4.
• BP4: Computational evidence support a benign effect (MetaRNN=0.008775234).
• BP6: Variant 13-27924519-G-A is Benign according to our data. Variant chr13-27924519-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 8863.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000315 (48/152284) while in subpopulation SAS AF = 0.00972 (47/4834). AF 95% confidence interval is 0.00751. There are 0 homozygotes in GnomAd4. There are 35 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 7 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDX1	NM_000209.4	c.670G>A	p.Glu224Lys	missense_variant	Exon 2 of 2	ENST00000381033.5	NP_000200.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDX1	ENST00000381033.5	c.670G>A	p.Glu224Lys	missense_variant	Exon 2 of 2	1	NM_000209.4	ENSP00000370421.4

Frequencies

GnomAD3 genomes AF: 0.000322 AC: 49 AN: 152172 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00992

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00129 AC: 304 AN: 236358 AF XY: 0.00175

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000688

GnomAD4 exome AF: 0.000528 AC: 769 AN: 1455564 Hom.: 7 Cov.: 31 AF XY: 0.000752 AC XY: 544 AN XY: 723848

African (AFR) AF: 0.0000300 AC: 1 AN: 33326

American (AMR) AF: 0.00 AC: 0 AN: 44084

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26038

East Asian (EAS) AF: 0.00 AC: 0 AN: 39548

South Asian (SAS) AF: 0.00851 AC: 731 AN: 85908

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52206

Middle Eastern (MID) AF: 0.000226 AC: 1 AN: 4432

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110022

Other (OTH) AF: 0.000600 AC: 36 AN: 60000

GnomAD4 genome AF: 0.000315 AC: 48 AN: 152284 Hom.: 0 Cov.: 32 AF XY: 0.000470 AC XY: 35 AN XY: 74464

African (AFR) AF: 0.00 AC: 0 AN: 41576

American (AMR) AF: 0.00 AC: 0 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00972 AC: 47 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67992

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000257 Hom.: 0

Bravo AF: 0.0000680

ExAC AF: 0.00151 AC: 182

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:2

Jul 11, 2022

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

DNA sequence analysis of the PDX1 gene demonstrated a sequence change, c.670G>A, in exon 2 that results in an amino acid change, p.Glu224Lys. This sequence change has been previously identified in the heterozygous state in individuals with diabetes (PMID: 14764823, 28095440). In vitro functional studies have indicated that this variant may reduce transactivation potential of IPF-1 (PMID: 17126328). This sequence change has been described in the gnomAD database with a frequency of 0.996% in the South Asian subpopulation (dbSNP rs137852787). The p.Glu224Lys change affects a highly conserved amino acid residue located in a domain of the PDX1 protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Glu224Lys substitution. Due to the high population frequency, insufficient evidences, and the lack of functional studies, the clinical significance of the p.Glu224Lys change remains unknown at this time. -

Oct 28, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PDX1 c.670G>A (p.Glu224Lys) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0013 in 236358 control chromosomes, predominantly at a frequency of 0.01 within the South Asian subpopulation in the gnomAD database, including 3 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 8000-fold of the estimated maximal expected allele frequency for a pathogenic variant in PDX1 causing Familial Monogenic Diabetes (Maturity Onset Diabetes Of The Young 4)/Neonatal Diabetes Mellitus phenotype (1.3e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. Nevertheless, c.670G>A has been reported in the literature in multiple individuals of Indian origin affected with Familial Monogenic Diabetes (Maturity Onset Diabetes Of The Young 4)/Neonatal Diabetes Mellitus (Cockburn_2004, Chapla_2015, Doddabelavangala_2017). However, these reports do not provide unequivocal conclusions about association of the variant with disease due to limited genotyping analysis or due to limited/inconclusive segregation data. One study carried out a comprehensive genomic analysis of 289 individuals from India, and concluded the variant to occur at a similar frequency in MODY cases and in the general population (Mohan_2018). Experimental evidence evaluating an impact on protein function demonstrated the variant affects PDX1 transactivation (Cockburn_2004, Liu_2006). Three ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign and one ClinVar submitter (evaluation after 2014) cites it as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Jan 15, 2024

Athena Diagnostics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Type 2 diabetes mellitus Uncertain:2

-

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

The heterozygous p.Glu224Lys variant in PDX1 has been identified in at least 2 individuals with type 2 diabetes mellitus (PMID: 14764823), but has also been identified in >1% of South Asian chromosomes and 4 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In vitro functional studies provide some evidence that the p.Glu224Lys variant may slightly impact protein function (PMID: 14764823). However, these types of assays may not accurately represent biological function. In summary, the clinical significance of this variant is uncertain. -

Jun 22, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The observed missense c.670G>A(p.Glu224Lys) variant in PDX1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is present with an allele frequency of 0.1% in gnomAD Exomes database. This variant has been reported to the ClinVar database as Benign/ Likely Benign/ Uncertain Significance. This variant is found as benign polymorphism primarily in populations of South Asian origin. However, these reports do not provide unequivocal conclusions about association of the variant with disease due to limited genotyping analysis or due to limited/inconclusive segregation data (Doddabelavangala Mruthyunjaya M, et. al., 2017;Chapla A, et. al., 2015). Computational evidence (Polyphen - Possibly damaging, SIFT - Tolerated and MutationTaster -Disease causing) predicts conflicting evidence on protein structure and function for this variant. The reference amino acid in PDX1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Glu at position 224 is changed to a Lys changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Uncertain Significance (VUS). -

not provided Uncertain:1 Benign:1

Dec 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 28, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a reduction in PDX1 transactivation, suggesting normal glucose homeostasis may be affected (Liu et al., 2006; Cockburn et al., 2004); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28095440, 16092045, 28862987, 27535533, 25581748, 28436541, 18360684, 31127050, 17126328, 25041077, 14764823, 22581228, 31366392, 29439679, 29473506, 34426522, 34741762, 32763092) -

Maturity-onset diabetes of the young type 4 Uncertain:1 Benign:1

Feb 01, 2004

OMIM

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Dec 20, 2021

New York Genome Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Monogenic diabetes Benign:1

Jul 19, 2016

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

ACMG Criteria: PS3 (PMID:17126328,14764823), PP3, BS1 (1000G SAS), BS2 (type2diabetesgenetics.org), BP4 -

Maturity onset diabetes mellitus in young Benign:1

Aug 10, 2018

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Benign	-0.090	T
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T
Eigen	Benign	0.031
Eigen_PC	Benign	0.10
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.0088	T
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Benign	1.6	L
PhyloP100		6.2
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.61
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.049	D
Polyphen		0.69	P
Vest4		0.24
MutPred		0.65		Gain of catalytic residue at V220 (P = 0.001);
MVP		0.97
MPC		1.3
ClinPred		0.12	T
GERP RS		4.0
Varity_R		0.48
gMVP		0.65
Mutation Taster		=89/11	polymorphism

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

Other links and lift over

dbSNP: rs137852787; hg19: chr13-28498656; COSMIC: COSV107491587;