Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000439286 | SCV000521051 | uncertain significance | not provided | 2019-07-25 | criteria provided, single submitter | clinical testing | Published functional studies demonstrate a damaging effect with moderate reduction in insulin gene activation by the PDX1 protein, reduced glucose response function, and impaired function on beta-like cell differentiation (Macfarlane et al., 1999; Wang et al., 2019); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Identified in individuals with diabetes in published literature (Macfarlane et al., 1999; Flannick et al., 2013). However, this variant did not segregate with disease in one family and was observed in a control subject in another study (Macfarlane et al., 1999; Edghill et al., 2011); This variant is associated with the following publications: (PMID: 28609558, 24097065, 21569088, 11914043, 10545530, 29034891, 27879214, 30930126, 30191644, 31589614) |
| Broad Center for Mendelian Genomics, |
RCV000009412 | SCV001422588 | uncertain significance | Type 2 diabetes mellitus | 2020-01-22 | criteria provided, single submitter | curation | The p.Cys18Arg variant in PDX1 has been reported in at least 3 individuals with type 2 diabetes mellitus (PMID: 10545530, 27879214; DOI: 10.7324/JABB.2013.1205), and has been identified in 0.02173% (15/69030) of European (non-Finnish) chromosomes, 0.01066% (2/18762) of European (Finnish) chromosomes, and 0.003943% (1/25360) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs137852785). In vitro functional studies provide some evidence that the p.Cys18Arg variant may slightly impact protein function, resulting in moderately decreased binding activity to the insulin promoter and decreased transcription of insulin in response to hyperglycemia (PMID: 30930126, 10545530). 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. The p.Cys18Arg variant did not segregate with type 2 diabetes mellitus in 3 affected relatives of individuals with the variant, suggesting that this variant is not pathogenic for type 2 diabetes mellitus (PMID: 10545530). The variant is located in a region of PDX1 that is important for protein binding, suggesting that this variant is in a functional domain and slighly supports pathogenicity (PMID: 27879214). In summary, the clinical significance of the p.Cys18Arg variant is uncertain. ACMG/AMP Criteria applied: BS4, PP3, PS4_supporting, PS3_supporting, PM1_supporting (Richards 2015). |
| Fulgent Genetics, |
RCV002482844 | SCV002801330 | uncertain significance | Maturity-onset diabetes of the young type 4; Pancreatic agenesis 1; Type 2 diabetes mellitus | 2022-02-09 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV000439286 | SCV004267310 | uncertain significance | not provided | 2023-11-07 | criteria provided, single submitter | clinical testing | This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 18 of the PDX1 protein (p.Cys18Arg). This variant is present in population databases (rs137852785, gnomAD 0.02%). This missense change has been observed in individual(s) with type 1 diabetes, type 2 diabetes, or maturity onset diabetes of the young (PMID: 10545530, 11022198, 30191644). ClinVar contains an entry for this variant (Variation ID: 8862). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PDX1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PDX1 function (PMID: 10545530, 30930126). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
| OMIM | RCV001799504 | SCV000029630 | risk factor | Diabetes mellitus type 2, susceptibility to | 1999-11-01 | no assertion criteria provided | literature only |