ClinVar

Description

Variant summary: HNF1A c.955G>A (p.Gly319Ser) results in a non-conservative amino acid change located in the Hepatocyte nuclear factor 1, beta isoform, C-terminal domain (IPR006897) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. This variant, located in the exonic-splice region alters the conserved last nucleotide of exon 4 adjacent to the canonical intronic splice donor site. Several computational tools predict a significant impact on normal splicing: Four predict the variant weakens the canonical 5' splice donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Triggs-Raine_2002). Two abnormal transcripts present only in the G319S cell line included premature termination codons as a result of the inclusion of seven nucleotides from intron 4 or the deletion of exon 8. The variant allele was found at a frequency of 0.00028 in 206130 control chromosomes, predominantly at a frequency of 0.087 among the Ontario Oji-Cree nondiabetic control chromosomes (Hegele_1999). The observed variant frequency is approximately 11 fold of the estimated maximal expected allele frequency for a pathogenic variant in HNF1A causing Maturity Onset Diabetes Of The Young 3 phenotype (2.5e-05), strongly suggesting that the variant is benign. c.955G>A has been reported in the literature as a risk factor associated with a risk for Type 2 diabetes characterized by onset at an earlier age, higher postprandial plasma glucose, and lower body mass index (BMI) (Hegele_1999). These report(s) do not provide unequivocal conclusions about association of the variant with Maturity Onset Diabetes Of The Young 3. At least one publication reports experimental evidence evaluating an impact on protein function (Triggs-Raine_2002). The most pronounced variant effect results in an approximately 50% reduction in transcription ability while not affecting DNA binding or protein stability in-vitro. The combination of the reduced activity of the G319S protein and abnormal splicing transcripts has been thought to increase the susceptibility to diabetes (Li_2022). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the conflicting evidence outlined above, the variant was classified as uncertain significance in association to Maturity Onset Diabetes Of The Young 3.