Submissions for variant NM_175914.5(HNF4A):c.869G>A (p.Arg290His)

dbSNP: rs1191912908

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV004527405	SCV005040711	pathogenic	Monogenic diabetes	2024-04-06	reviewed by expert panel	curation	The c.869G>A variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of arginine to histidine at codon 290 (p.(Arg290His)) 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 an incomputable gnomAD v2.1.1 Grpmax filtering allele frequency due to 1 copy in the European non-Finnish 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 14 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; internal lab contributors). Two of these individuals had a clinical history highly specific for HNF4A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A, and sufonylurea-sensitive) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes, with 14 informative meioses in 6 families (PP1_Strong, internal lab contributors). In summary, c.869G>A meets the criteria to be classified as Pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PP1_Strong, PS4, PP4_Moderate, PP3, PM2_Supporting.
Athena Diagnostics	RCV000992167	SCV001144214	uncertain significance	not provided	2019-02-12	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001248988	SCV001422831	likely pathogenic	Maturity-onset diabetes of the young type 1	2020-01-22	criteria provided, single submitter	curation	The p.Arg312His variant in HNF4A has been reported in at least 12 individuals with MODY, segregated with disease in 4 affected relatives from 2 families (PMID: 26971647, 17407387, 23348805, 18811724, 16917892), and was absent from large population studies. In vitro functional studies provide some evidence that the XXXX variant may slightly impact protein function (PMID: 19478207). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The p.Arg312His variant is located in a region of HNF4A that is essential to protein folding and stability, suggesting that this variant is in a functional domain and supports pathogenicity (PMID: 21683639, 18811724). One additional likely pathogenic variant, resulting in a different amino acid change at the same position, (p.Arg312Cys), has been reported in association with disease in (the literature and ClinVar), slightly supporting that a change at this position may not be tolerated (PMID: 21683639, 18811724, 23348805/Variation ID: 447524). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PS4_moderate, PM1, PP3, PM5_supporting, PS3_supporting, PP1 (Richards 2015).
Genetic Services Laboratory, University of Chicago	RCV000992167	SCV002067525	likely pathogenic	not provided	2020-08-18	criteria provided, single submitter	clinical testing	DNA sequence analysis of the HNF4A gene demonstrated a sequence change, c.869G>A, in exon 8 that results in an amino acid change, p.Arg290His. This sequence change has been identified in a patient with gestational diabetes mellitus (GDM) (PMID: 30663027). A different sequence change affecting the same amino acid residue (p.Arg290Cys) has been described in an individual with diabetes at the age of 28 years and several of his family members who were either diagnosed with early onset diabetes or impaired glucose tolerance. This sequence change has been described in the gnomAD database in one individual which corresponds to a population frequency of 0.00040% (dbSNP rs1191912908). The p.Arg290His change affects a highly conserved amino acid residue located in a dimerization domain of the HNF4A protein that is known to be functional. The p.Arg290His substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). These collective evidences indicate that this sequence change is likely pathogenic; however functional studies have not been performed to prove this conclusively.
Geisinger Clinic, Geisinger Health System	RCV001248988	SCV002562114	pathogenic	Maturity-onset diabetes of the young type 1	2022-08-02	criteria provided, single submitter	research	PP3, PM2, PP1_Strong, PP4_Moderate, PS4
Labcorp Genetics (formerly Invitae), Labcorp	RCV000992167	SCV003443812	pathogenic	not provided	2022-07-10	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg290 amino acid residue in HNF4A. Other variant(s) that disrupt this residue have been observed in individuals with HNF4A-related conditions (PMID: 30447144), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 804918). This missense change has been observed in individuals with autosomal dominant familial hyperinsulinism and/or autosomal dominant maturity-onset diabetes of the young (PMID: 17407387, 26971647; Invitae). It has also been observed to segregate with disease in related individuals. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 290 of the HNF4A protein (p.Arg290His).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003317408	SCV004020407	pathogenic	Maturity onset diabetes mellitus in young	2023-06-21	criteria provided, single submitter	clinical testing	Variant summary: HNF4A c.869G>A (p.Arg290His) 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 allele was found at a frequency of 4e-06 (i.e., 1 heterozygote) in 248094 control chromosomes (gnomAD v2.1, Exomes dataset). c.869G>A has been reported in the literature in multiple families affected with Maturity Onset Diabetes Of The Young and hyperinsulinism (e.g., Ellard_2006, Pearson_2007, Plengvidhya_2008, Colclough_2013, Zubkova_2019, Gaal_2021), and the variant has been shown to segregate with disease in related individuals (e.g., Pearson_2007). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 23348805, 16917892, 34440499, 17407387, 18811724, 30663027). Five submitters have reported clinical-significance assessments for this variant to ClinVar after 2014, citing the variant as pathogenic (n = 2), likely pathogenic (n = 2), and VUS (n = 1). Based on the evidence outlined above, the variant was classified as pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003413778	SCV004108085	likely pathogenic	HNF4A-related disorder	2022-12-19	criteria provided, single submitter	clinical testing	The HNF4A c.869G>A variant is predicted to result in the amino acid substitution p.Arg290His. This variant has been reported in multiple individuals with Maturity Onset Diabetes of the Young (MODY), and segregated with disease in at least two families (described as p.Arg321His, Ellard et al 2006. PubMed ID: 16917892; described as p.R303H, Pearson ER et al 2007. PubMed ID: 17407387; described as R312H, Plengvidhya N et al 2008. PubMed ID: 18811724; Supp. Table S2, Colclough K et al 2013. PubMed ID: 23348805; Zubkova N et al 2019. PubMed ID: 30663027; Supplementary Data 5, Goodrich JK et al 2021. PubMed ID: 34108472). This variant is reported in 0.00090% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/20-43052700-G-A). This variant is interpreted as likely pathogenic.