NM_000209.4(PDX1):c.670G>A (p.Glu224Lys) AND not specified

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Oct 28, 2022
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001659687.8

Allele description [Variation Report for NM_000209.4(PDX1):c.670G>A (p.Glu224Lys)]

NM_000209.4(PDX1):c.670G>A (p.Glu224Lys)

Gene:

PDX1:pancreatic and duodenal homeobox 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

13q12.2

Genomic location:

Preferred name:

NM_000209.4(PDX1):c.670G>A (p.Glu224Lys)

HGVS:

NC_000013.11:g.27924519G>A
NG_008183.1:g.9489G>A
NM_000209.4:c.670G>AMANE SELECT
NP_000200.1:p.Glu224Lys
NC_000013.10:g.28498656G>A
NM_000209.3:c.670G>A

Protein change:

E224K; GLU224LYS

Links:

OMIM: 600733.0007; dbSNP: rs137852787

NCBI 1000 Genomes Browser:

rs137852787

Molecular consequence:

NM_000209.4:c.670G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001879349	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics criteria)	Likely benign (Mar 11, 2021)	unknown	clinical testing	PubMed (6) [See all records that cite these PMIDs] 27535533, 28095440, 14764823, 17126328, 25041077, 26467025
SCV002600763	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Oct 28, 2022)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 14764823, 17126328, 27535533, 28095440, 25041077, 29439679 Citation Link,
SCV003839825	Genetic Services Laboratory, University of Chicago	no assertion criteria provided	Likely benign (Jul 11, 2022)	germline	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001879349

Athena Diagnostics

criteria provided, single submitter

(Athena Diagnostics criteria)

Likely benign
(Mar 11, 2021)

unknown

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

SCV002600763

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Oct 28, 2022)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

Citation Link,

SCV003839825

Genetic Services Laboratory, University of Chicago

no assertion criteria provided

Likely benign
(Jul 11, 2022)

germline

clinical testing

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.

Karbassi I, Maston GA, Love A, DiVincenzo C, Braastad CD, Elzinga CD, Bright AR, Previte D, Zhang K, Rowland CM, McCarthy M, Lapierre JL, Dubois F, Medeiros KA, Batish SD, Jones J, Liaquat K, Hoffman CA, Jaremko M, Wang Z, Sun W, Buller-Burckle A, et al.

Hum Mutat. 2016 Jan;37(1):127-34. doi: 10.1002/humu.22918. Epub 2015 Oct 29.

PubMed [citation]

PMID:: 26467025
PMCID:: PMC4737317

Insulin promoter factor-1 mutations and diabetes in Trinidad: identification of a novel diabetes-associated mutation (E224K) in an Indo-Trinidadian family.

Cockburn BN, Bermano G, Boodram LL, Teelucksingh S, Tsuchiya T, Mahabir D, Allan AB, Stein R, Docherty K, Bell GI.

J Clin Endocrinol Metab. 2004 Feb;89(2):971-8.

PubMed [citation]

PMID:: 14764823

See all PubMed Citations (7)

Details of each submission

From Athena Diagnostics, SCV001879349.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002600763.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genetic Services Laboratory, University of Chicago, SCV003839825.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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