The c.340C>T variant in the hepatic nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of arginine to tryptophan at codon 114 (p.(Arg114Trp)) of NM_175914.5. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.919, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.000074, which is greater than the MDEP threshold for BS1 (0.000033) (BS1). This variant was identified in over 80 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4 cannot be applied because the variant MAF in gnomAD is above the ClinGen MDEP PM2_Supporting cutoff (PMID: 27486234, internal lab contributors). This variant was identified in an individual with a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50% and negative genetic testing for HNF1A) (PP4; internal lab contributors). This variant segregated with diabetes, with 31 informative meioses (PP1_Strong; internal lab contributors). This variant was identified in at least 3 nondiabetic individuals >70 years old, and the expected penetrance for HNF4A-monogenic diabetes is 95% by age 70 (BS2; PMID: 9313765. internal lab contributors) (BS2). This variant was identified in five individuals with an alternate molecular basis for disease, including two siblings with the HNF1A variant NM_000545.8:c872dup (p.Gly292fs*25) (BP5; PMID: 2351881, internal lab contributors). This variant has previously been considered to be pathogenic for a low penetrance form of MODY, and reporting has been of clinical utility for considering treatment with sulfonylureas, which have ~48% effectiveness in individuals with this variant (PMID: 27486234). In summary, c.340C>T meets phenotype, segregation, and computational criteria to be classified as likely pathogenic. While adding its population frequency, penetrance, and co-occurrence (which may have synergistic impact) criteria would lead to a likely benign classification, the MDEP consensus is that this should be considered a reportable likely pathogenic variant with reduced penetrance that may respond to sulfonylurea treatment. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): BS1, BS2, PP1_Strong, BP5, PP3, PP4.