Submissions for variant NM_175914.5(HNF4A):c.926G>A (p.Arg309His)

gnomAD frequency: 0.00001  dbSNP: rs369429452

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV004699124	SCV005201071	likely pathogenic	Monogenic diabetes	2024-08-01	reviewed by expert panel	curation	The c.926G>A variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of arginine to histidine at codon 309 (p.(Arg309His)) of NM_175914.5. This variant is located within the ligand-binding domain (codons 180-220 and 300-350) of HNF4A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.765, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant has an incomputable gnomAD v2.1.1 Grpmax filtering allele frequency due to 1 copy in the South Asian subpopulation and 0 copies in any other subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF Grpmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). This variant was identified in an individual with a clinical history suggestive of HNF4A-MODY (neonatal hyperinsulinemic hypoglycemia and negative genetic testing for ABCC8 and KCNJ11)(PP4; internal lab contributors). This variant segregated with diabetes and/or diazoxide-responsive hyperinsulinemic hypoglycemia, with 4 informative meioses in 1 family (PP1_Moderate; internal lab contributors). Another missense variant, c.925C>T p.Arg309Cys, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Arg309His (PM5_Supporting). In summary, c.926G>A meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PP1_Moderate, PP3, PP4, PM1_Supporting, PM2_Supporting, PM5_Supporting.
GeneDx	RCV000483537	SCV000574422	uncertain significance	not provided	2017-04-03	criteria provided, single submitter	clinical testing	The R309H variant in the HNF4A gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The R309H variant is observed in 1/62866 (0.002%) alleles from individuals of European background, in large population cohorts the ExAC dataset (Lek et al., 2016). The R309H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R309H as a variant of uncertain significance.
Geisinger Clinic, Geisinger Health System	RCV002285339	SCV002562116	likely pathogenic	Maturity-onset diabetes of the young type 1	2022-08-02	criteria provided, single submitter	research	PM1_Supporting, PM2, PP3, PM5_Supporting, PP4, PP1_Moderate
Clinical Genomics Laboratory, Washington University in St. Louis	RCV002285339	SCV004177138	likely pathogenic	Maturity-onset diabetes of the young type 1	2023-11-02	criteria provided, single submitter	clinical testing	A HNF4A c.926G>A (p.Arg309His) variant was identified in a heterozygous state. To our knowledge, this variant has not been reported in the medical literature and is only observed on 1/248,634 alleles in the general population (gnomAD v2.1.1). The variant has been reported in the ClinVar database as a variant of uncertain clinical significance by one submitter (ClinVar Variation ID: 424599). Computational predictors suggest that this variant is damaging, evidence that correlates with impact on HNF4A function. The HNF4A c.926G>A (p.Arg309His) variant is located within the ligand binding domain of HNF4A, which is defined as critical for protein function (Eeckhoute J et al., PMID: 14602925; Ng NHJ et al., PMID: 31195238; Lu P et al., PMID: 18829458). Another variant in the same codon, HNF4A c.926G>T (p.Arg309Leu) has been reported in two individuals with diabetes and is considered pathogenic (Mirshahi UL et al., PMID: 36257325, ClinVar Variation ID: 972810). Based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), the HNF4A c.926G>A (p.Arg309His) variant is classified as likely pathogenic.