ClinVar Miner

Submissions for variant NM_000545.8(HNF1A):c.526+1G>T

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 2
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel RCV003445171 SCV004174143 pathogenic Monogenic diabetes 2023-12-02 reviewed by expert panel curation 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.
Ambry Genetics RCV002341022 SCV002643842 pathogenic Maturity onset diabetes mellitus in young 2018-06-18 criteria provided, single submitter clinical testing 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.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.