ClinVar Genomic variation as it relates to human health

The c.83C>T variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of alanine to valine at codon 28 (p.(Ala28Val)) of NM_175914.5. This variant was identified in a normoglycemic individual >70 years old, and the expected penetrance for HNF4A-MODY is 95% by age 70 (internal lab contributor) (BS2). The Grpmax filtering allele frequency of the c.83C>T variant in gnomAD v2.1.1 is 0.0007020%, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied. This variant has a REVEL score of 0.186, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF4A function. This variant was identified in an individual with diabetes; however, the calculated MODY probability is <50% (internal lab contributor). In summary, c.83C>T 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 8/11/2023): BS2.

Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. Computational tools disagree on the variant's effect on normal protein function.

Potent mutations in HNF4A are associated with poor insulin secretion in response to hyperglycemia. Associated with MODY1. Patients initially respond well to sulfonylureas but eventually become insulin dependent. However, more evidence is required to ascertain the role of this particular variant rs140143857 in MODY, yet.

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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on HNF4A protein function. This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 28 of the HNF4A protein (p.Ala28Val). This variant is present in population databases (rs140143857, gnomAD 0.005%). This missense change has been observed in individual(s) with maturity onset diabetes of the young (PMID: 30447144). This variant is also known as c.149C>T (p.A50V). ClinVar contains an entry for this variant (Variation ID: 994900). 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.