ClinVar

Description

The c.872dupC variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 292 (NM_000545.8), adding 25 novel amino acids before encountering a stop codon (p.(Gly292ArgfsTer25)). This variant, located in biologically-relevant exon 4 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). Additionally, this variant segregated with diabetes, with at least 100 informative meioses in multiple families with MODY (PP1_Strong; internal lab contributors). This variant was identified as a de novo occurrence with confirmed parental relationships in one individual and unconfirmed parental relationships in another individual with diabetes, but whose clinical picture is suggestive but not highly specific for HNF1A-MODY (MODY probability calculator result >50% but HNF4A not tested) (PS2_Moderate; PMID:9166684, internal lab contributors). The variant is located in a poly-C tract and failed QC in gnomAD v2.1.1 in a manner typical of single base deletions in poly-C tracts in NGS; therefore, PM2_Supporting could not be applied. This variant was identified in at least 200 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because PM2_Supporting cannot be applied (internal lab contributors). In summary, c.872dupC meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/21): PVS1, PS2_Moderate, PP1_Strong.