ClinVar Genomic variation as it relates to human health

The c.526+1G>T variant in the HNF1 homeobox A gene, HNF1A, is predicted to remove a canonical splice donor site in intron 2 of NM_000545.8. This variant is predicted to cause loss of part of exon 2, leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1, PMID: 23348805). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The HNF1A(NM_000545.8):c.526+1G>A and c.526+1G>C variants at the same canonical nucleotide have been classified as pathogenic for monogenic diabetes by the ClinGen MDEP, and c.526+1G>T has a similar predicted impact by Splice AI (donor loss 100% and donor gain at -33bp 65%) (PS1_Supporting). This variant was identified in an individual with diabetes; however, the MODY probability is unable to be calculated due to lack of clinical information. This variant segregated with diabetes with one informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP. In summary, c.526+1G>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.1, approved 8/11/2023): PVS1, PS1_Supporting, PM2_Supporting.

The c.526+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 2 of the HNF1A gene. While this specific mutation has not been reported in the literature to date, two other mutations at the same location, c.526+1G>A and c.526+1G>C, have been reported in maturity-onset diabetes of the young (MODY)-3 patients (Frayling et al. Diabetes. 2001 Feb;50 Suppl1:S94-100; Bellanne-Chantelot et al. Diabetes. 2008 Feb;57(2):503-8; Habeb et al.Ann Saudi Med. 2011 Mar-Apr;31(2):190-3). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as pathogenic.