Submissions for variant NM_000209.4(PDX1):c.725C>T (p.Pro242Leu)

gnomAD frequency: 0.00115  dbSNP: rs193922358

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000455258	SCV000052738	likely benign	not specified	2019-02-05	criteria provided, single submitter	clinical testing	Variant summary: The variant, PDX1 (legacy gene name IPF1) c.725C>T (p.Pro242Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four 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 134384 control chromosomes, predominantly at a frequency of 0.0022 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1760 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 Non-Finnish European origin. Mohan et al (Mohan_2018) state that the variant was found in similar frequencies in MODY cases and in general population in South India and suggests that the variant most likely have little to no effect on risk of developing MODY. The variant c.725C>T has been reported in the literature in individuals affected with MODY (Ang_2016, Chambers_2016). However, these reports do not provide unequivocal conclusions about association of the variant with the disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000455258	SCV000540009	uncertain significance	not specified	2016-03-28	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: LP by Labcorp (2011). Low reads. Could not find any publications.
GeneDx	RCV000840733	SCV000982671	likely benign	not provided	2019-11-15	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 29439679)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000840733	SCV001121499	likely benign	not provided	2024-01-22	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001249016	SCV001422872	benign	Maturity-onset diabetes of the young type 4	2020-01-22	criteria provided, single submitter	curation	The p.Pro242Leu variant in PDX1 has been reported in at least 1 Asian individual with maturity-onset diabetes of the young type 4 (PMID: 27420379), and has been identified in 0.2% (124/58140) of European (non-Finnish) chromosomes and multiple other populations at lower frequencies by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs193922358). This variant has been seen in the general population at a frequency high enough to rule out a pathogenic role. This variant has also been reported in ClinVar as having conflicting interpretations of pathogenicity (Variation ID: 36411). Computational prediction tools, including splice predictors, and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, this variant meets criteria to be classified as benign for MODY type 4 in an autosomal dominant manner based on computational tool predictions and the frequency of this variant in multiple populations. ACMG/AMP Criteria applied: BP4, BA1 (Richards 2015).
Athena Diagnostics	RCV000455258	SCV001476620	benign	not specified	2019-11-01	criteria provided, single submitter	clinical testing
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002464002	SCV002605233	uncertain significance	Pancreatic hypoplasia		criteria provided, single submitter	research	Potent homozygous mutations in the PDX1 gene can lead to pancreatic agenesis/pancreatic hypoplasia and neonatal diabetes mellitus. However no sufficient evidence is found to ascertain the role of this particular variant rs193922358, yet.
Revvity Omics, Revvity	RCV000840733	SCV003814822	uncertain significance	not provided	2022-04-20	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004549391	SCV004754938	likely benign	PDX1-related disorder	2020-10-14	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).