NM_000209.4:c.670G>A
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
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).
Frequency
Consequence
NM_000209.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -13 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000322 AC: 49AN: 152172Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00129 AC: 304AN: 236358Hom.: 3 AF XY: 0.00175 AC XY: 226AN XY: 129080
GnomAD4 exome AF: 0.000528 AC: 769AN: 1455564Hom.: 7 Cov.: 31 AF XY: 0.000752 AC XY: 544AN XY: 723848
GnomAD4 genome AF: 0.000315 AC: 48AN: 152284Hom.: 0 Cov.: 32 AF XY: 0.000470 AC XY: 35AN XY: 74464
ClinVar
Submissions by phenotype
not specified Uncertain:1Benign:2
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. -
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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. -
Type 2 diabetes mellitus Uncertain:2
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. -
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:1Benign:1
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) -
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Maturity-onset diabetes of the young type 4 Uncertain:1Benign:1
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Type 2 diabetes mellitus;C1833382:Maturity-onset diabetes of the young type 4 Uncertain:1
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Maturity onset diabetes mellitus in young Benign:1
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. -
Monogenic diabetes Benign:1
ACMG Criteria: PS3 (PMID:17126328,14764823), PP3, BS1 (1000G SAS), BS2 (type2diabetesgenetics.org), BP4 -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at