ClinVar Genomic variation as it relates to human health

ACMG criteria: PP3 (REVEL 0.928 + 10 predictors) + BA1 (0.7% in gnomAD SA, 0.2% in gnomAD Latino and ENF) + PS3 (PMID 16092045, in vitro studies of P33T showed a reduction in DNA-binding and transcriptional activation functions as compared to the wild-type IPF1 protein), BS2 (Five cases and six well-phenotyped controls in PMID: 21569088)= benign Variant found in seven healthy people at risk for T2DM based on fam hx or BMI or lab results in PMID: 27879211, of these people, at least one was glucose tolerant and thin. Variant found in MODY cohort in PMID: 29439679 but authors say unlikely to be cause given frequency of variant in general population

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported in multiple individuals with type 2 diabetes mellitus and/or maturity-onset diabetes of the young (MODY) [PMID: 16092045, 19228875, 21569088]

Identified in patients with MODY, type 2 diabetes, gestational diabetes, and ketosis-prone diabetes in published literature (PMID: 16092045, 21569088, 19228875), however, also reported in multiple unaffected family members and unaffected controls in these studies; Published functional studies demonstrate a damaging effect due to impaired DNA-binding activity of the protein and misregulation of transcriptional targets (PMID: 16092045, 30930126); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 10720084, 12618559, 26543388, 21569088, 30709774, 19228875, 27879211, 29439679, 30930126, 27884173, 34426522, 33565752, Harris2021[CaseReport], 33795639, 34278679, 34741762, 36208030, 34938542, 34988346, 36100423, 35333605, 36178555, 36208343, 16092045)

Variant summary: The variant, PDX1 (legacy gene name IPF1) c.97C>A (p.Pro33Thr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0023 in 169614 control chromosomes in the gnomAD database, including 2 homozygotes (gnomAD). The observed variant frequency is approximately 1844 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 benign. However, the phenotype of MODY4 and/or other forms of monogenic/polygenic diabetes in the control individuals within the gnomAD database cannot be excluded. The variant c.97C>A has been reported in the literature in individuals within a single family affected with MODY4 (Gragnoli_2005). However, this study predated the emergence of large control databases such as gnomAD and ExAC. In another report of its presence in an individual(s) with ketone-prone diabetes, the authors conclude that this phenotype is not predominantly a Monogenic Diabetic Syndrome. Lastly, it has been reported in individuals with type 2 diabetes where it was identified at a similar frequency in cases as well as normoglycemic controls (Haaland_2009, Edghill_2011). Therefore, these reports do not provide unequivocal conclusions about association of the variant with MODY4 and favor a benign outcome consistent with its high frequency in controls. At least one publication reports a moderate (30-50%) reduction in DNA binding and transcriptional activation functions of this variant in vitro (Gragnoli_2005) however, the implications of this finding to the mechanism and pathophysiology of MOD4 are not clear. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified this variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely benign.

The p.Pro33Thr variant in PDX1 has been reported in 1 individual with maturity-onset diabetes of the young type 4 (PMID: 16092045), but has been identified in 0.7% (164/22330) of South Asian chromosomes as well as other populations at lesser frequencies by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs192902098). This variant has also been reported in ClinVar as having conflicting interpretations of pathogenicity (Variation ID: 36414). In vitro functional studies provide some evidence that the p.Pro33Thr variant may impact protein function (PMID: 16092045, 30930126). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Pro33Thr variant is uncertain. ACMG/AMP Criteria applied: BA1, PS3_moderate, PP3 (Richards 2015).

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.