Submissions for variant NM_000209.4(PDX1):c.716C>A (p.Pro239Gln)

gnomAD frequency: 0.00993  dbSNP: rs199644078

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000515153	SCV000152173	likely benign	not specified	2016-03-29	criteria provided, single submitter	clinical testing
Personalized Diabetes Medicine Program, University of Maryland School of Medicine	RCV000445403	SCV000537094	benign	Monogenic diabetes	2018-08-14	criteria provided, single submitter	research	ACMG criteria: BA1 (2.8% in gnomAD African)= benign (REVEL score 0.221 + PP3 (3 predictors) + BP4 (8 predictors)= conflicting evidence, not using)
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000117899	SCV000610490	likely benign	not provided	2017-02-27	criteria provided, single submitter	clinical testing
Mendelics	RCV000988972	SCV001138927	likely benign	Maturity-onset diabetes of the young type 4	2019-05-28	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000515153	SCV001476619	benign	not specified	2019-10-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000117899	SCV001847059	benign	not provided	2019-01-10	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 11270685, 27884173, 24097065)
Invitae	RCV000117899	SCV002410122	benign	not provided	2024-01-25	criteria provided, single submitter	clinical testing
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002250564	SCV002520727	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, the role of this particular variant (rs199644078) of PDX1 in pancreatic agenesis/hypoplasia and neonatal diabetes mellitus remains uncertain.
Ambry Genetics	RCV002371951	SCV002665601	benign	Maturity onset diabetes mellitus in young	2016-05-05	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000515153	SCV004038279	likely benign	not specified	2023-08-07	criteria provided, single submitter	clinical testing	Variant summary: PDX1 c.716C>A (p.Pro239Gln) 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 0.006 in 109586 control chromosomes in the gnomAD database, including 6 homozygotes. The observed variant frequency significantly exceeds 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 benign. c.716C>A has been reported in the literature in individuals affected with Familial Monogenic Diabetes (Maturity Onset Diabetes Of The Young 4)/Neonatal Diabetes Mellitus (example, Weng_2001, Weng_2002, Lindgren_2002, Haaland_2009, Huang_2002, Zhang_2004). In our ascertainment of families with this variant, 10 transmissions of the variant allele and 6 transmissions of the reference allele to affected individuals was reported supporting lack of segregation with a disease phenotype. In our ascertainment, the penetrance of Familial Monogenic Diabetes (Maturity Onset Diabetes Of The Young 4)/Neonatal Diabetes Mellitus (0.53) due to this variant appears to be lower than expected (0.8), therefore, no conclusions can be drawn from these data. At least one publication reports experimental evidence evaluating an impact on protein function (example, Weng_2001). The most pronounced variant effect results in normal expression and binding activity to the insulin gene promoter but reduced activation of the insulin-gene transcription in response to increased glucose concentrations compared with the wild-type IPF1 protein. The following publications have been ascertained in the context of this evaluation (PMID: 11270685, 11772903, 11978663, 15111508, 19228875, 12099699, 15028942, 12677187). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
CeGaT Center for Human Genetics Tuebingen	RCV000117899	SCV004132940	benign	not provided	2023-04-01	criteria provided, single submitter	clinical testing	PDX1: BS1, BS2
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000117899	SCV004564115	benign	not provided	2023-10-14	criteria provided, single submitter	clinical testing