ClinVar Genomic variation as it relates to human health

The c.871C>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of proline to threonine at codon 291 (p.(Pro291Thr)) of NM_000545.8. This variant segregated with diabetes, with three informative meioses in one families with MODY (PP1; PMID: 22432108). Additionally, this variant was identified in a normoglycemic individual >70 years old, and the expected penetrance for HNF1A-MODY is 95% by age 70 (BS2; internal lab contributor). Lastly, the c.871C>A variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A) (PP4; PMID: 18003757. In summary, c.871C>A meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 6/4/2021): BS2, PP4, PP1

The p.Pro291Thr variant in HNF1A has been reported in at least 2 European individuals with maturity-onset diabetes of the young (PMID: 18003757, 30455330), and has been identified in 0.006% (2/33380) of Latino chromosomes and 0.0009% (1/108298) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs151256267). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. In vitro functional studies provide some evidence that the p.Pro291Thr variant may slightly impact protein function (PMID: 30455330). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS4_Supporting, PS3_Supporting (Richards 2015).

This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 291 of the HNF1A protein (p.Pro291Thr). This variant is present in population databases (rs151256267, gnomAD 0.003%). This missense change has been observed in individual(s) with maturity-onset diabetes of the young (PMID: 18003757, 30455330). ClinVar contains an entry for this variant (Variation ID: 972814). 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 not expected to disrupt HNF1A protein function. 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.