Submissions for variant NM_175914.5(HNF4A):c.734G>A (p.Arg245His)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV003330376	SCV004037478	pathogenic	Monogenic diabetes	2023-09-15	reviewed by expert panel	curation	The c.734G>A variant in the HNF4A gene causes an amino acid change of arginine to histidine at codon 245 (p.Arg254His) of NM_175914.4. Functional studies demonstrated the p.Arg254His protein has transactivation below 60% of wildtype, indicating that this variant impacts protein function (PS3_Supporting; PMID: 30325586). This variant was identified in 7 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; internal lab collaborators, PMIDs: 30325586, 21922456). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Another missense variant, c.733C>T p.Arg245Cys, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Arg345His (PM5_Supporting). This variant segregated with diabetes, with at least 4 informative meioses in 3 families (PP1_Strong; internal lab collaborators). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.92, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in an individual with a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A, and personal history of being large for gestational age) (PP4_Moderate; internal lab collaborators). In summary, c.734G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1.0, approved 8/11/2023): PS3_Supporting, PS4, PM2_Supporting, PM5_Supporting, PP1_Strong, PP3, PP4_Moderate.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004690403	SCV005185457	pathogenic	Maturity onset diabetes mellitus in young	2024-05-06	criteria provided, single submitter	clinical testing	Variant summary: HNF4A c.734G>A (p.Arg245His) results in a non-conservative amino acid change located in the Nuclear hormone receptor, ligand-binding domain (IPR000536) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251468 control chromosomes. c.734G>A has been reported in the literature in individuals affected with Maturity Onset Diabetes Of The Young 1/Neonatal Diabetes Mellitus (Motzkau_2012, Sugawara_2019). Additionally another missense variant (c.733C>T, R245C) has been classified as pathogenic by ClinGen Monogenic Variant Curation Expert panel. These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <50% of normal transactivation activity (Sugawara_2019). The following publications have been ascertained in the context of this evaluation (PMID: 21922456, 30325586). ClinVar contains an entry for this variant (Variation ID: 2581134). Based on the evidence outlined above, the variant was classified as pathogenic.