Submissions for variant NM_175914.5(HNF4A):c.925C>T (p.Arg309Cys)

gnomAD frequency: 0.00001  dbSNP: rs193922479

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV004527307	SCV005040701	pathogenic	Monogenic diabetes	2024-04-06	reviewed by expert panel	curation	The c.925C>T variant in the Hepatocyte Nuclear Factor 4 Alpha gene, HNF4A, causes an amino acid change of Arginine to Cysteine at codon 309 (p.(Arg309Cys)) of NM_175914.5. This variant was identified in at least 10 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; Internal lab contributors). This variant is located within the ligand-binding domain of HNF4A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant has a gnomAD v2.1.1 Grpmax filtering allele frequency of 0.000002970 (below the MDEP threshold of 0.000003) and ≤ 2 copies observed in the European non-Finnish population and ≤ 1 copy in any other subpopulation, thereby meeting the ClinGen MDEP criteria for PM2_Supporting (PM2_Supporting). This variant segregated with diabetes, with 1 informative meiosis in each of 3 families with MODY (PP1_moderate; Internal lab contributors). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.787, which is greater than to the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in several individuals with a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A, responsiveness to sulfonylureas, and 1 family member with persistent neonatal hypoglycemia) (PP4_Moderate; Internal lab contributors). In summary, c.925C>T 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): PS4, PM1_Supporting, PM2_Supporting, PP1_Moderate, PP3, PP4_Moderate.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000030034	SCV000052689	likely pathogenic	Maturity-onset diabetes of the young type 1	2011-08-18	criteria provided, single submitter	curation	Converted during submission to Likely pathogenic.
Genetic Services Laboratory, University of Chicago	RCV000193933	SCV000247565	likely pathogenic	Hyperinsulinemia	2015-06-01	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000517103	SCV000613665	uncertain significance	not provided	2018-08-30	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001249093	SCV001423108	uncertain significance	Maturity onset diabetes mellitus in young	2020-01-22	criteria provided, single submitter	curation	The p.Arg331Cys (sometimes called p.Arg322Cys) variant in HNF4A has been reported in 1 individual with Maturity-Onset Diabetes of the Young and 1 individual with prediabetes at age 43 (PMID: 16917892, 29998026), and has been identified in 0.001788% (2/111864) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs193922479). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a carrier frequency. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported as a VUS and a likely pathogenic variant in ClinVar (Variation ID: 36364). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, PP3, PS4_Supporting (Richards 2015).
GeneDx	RCV000517103	SCV001780437	likely pathogenic	not provided	2024-05-17	criteria provided, single submitter	clinical testing	Reported in multiple unrelated individuals with diabetes or a clinical suspicion for MODY in published literature (PMID: 18356407, 16917892, 29998026, 34789499); however, detailed clinical information was not provided; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(R322C), p.(R331C); This variant is associated with the following publications: (PMID: 16917892, 23348805, 34789499, 29998026, 36208030, 36257325, 36504295, 18356407)
Geisinger Clinic, Geisinger Health System	RCV000030034	SCV002562115	pathogenic	Maturity-onset diabetes of the young type 1	2022-08-02	criteria provided, single submitter	research	PS4, PM1_supporting, PP1_moderate, PP4_moderate, PP3
Genetics and Molecular Pathology, SA Pathology	RCV000030034	SCV002761716	likely pathogenic	Maturity-onset diabetes of the young type 1	2021-12-13	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000517103	SCV003443776	uncertain significance	not provided	2023-11-29	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 309 of the HNF4A protein (p.Arg309Cys). This variant is present in population databases (rs193922479, gnomAD 0.002%). This missense change has been observed in individual(s) with clinical features of maturity onset diabetes of the young (PMID: 23348805, 29998026, 36208030, 36257325). This variant is also known as c.964C>T (p.Arg322Cys) or c.991C>T (p.Arg331Cys). ClinVar contains an entry for this variant (Variation ID: 36364). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on HNF4A protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV001249093	SCV005122028	likely pathogenic	Maturity onset diabetes mellitus in young	2024-05-29	criteria provided, single submitter	clinical testing	The c.925C>T (p.R309C) alteration is located in exon 8 (coding exon 8) of the HNF4A gene. This alteration results from a C to T substitution at nucleotide position 925, causing the arginine (R) at amino acid position 309 to be replaced by a cysteine (C). Based on data from gnomAD, the T allele has an overall frequency of 0.001% (2/248468) total alleles studied. The highest observed frequency was 0.002% (2/111864) of European (non-Finnish) alleles. This variant was reported in multiple individuals with a diagnosis or suspected diagnosis of MODY (Colclough, 2013; Raicevic, 2021; Mirshahi, 2022; Yorifuji, 2023). Two other alterations at the same codon, c.926G>T (p.R309L) and c.926G>A (p.R309H), have also been detected in individuals with a diagnosis or suspected diagnosis of MODY (Mirshahi, 2022). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001249093	SCV005202980	likely pathogenic	Maturity onset diabetes mellitus in young	2024-07-22	criteria provided, single submitter	clinical testing	Variant summary: HNF4A c.925C>T (p.Arg309Cys) results in a non-conservative amino acid change located in the Nuclear hormone receptor, ligand-binding domain (IPR000536) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 248468 control chromosomes. c.925C>T has been reported in the literature in individuals affected with Maturity Onset Diabetes Of The Young 1/Neonatal Diabetes Mellitus (e.g. Ellard_2006, Colclough_2013, Colclough_2022, Mirshahi_2022, Yorifuji_2023, Raicevic_2021, Spiro_2018). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 36208030, 34789499, 23348805, 16917892, 36257325, 33770274, 29998026, 36504295). ClinVar contains an entry for this variant (Variation ID: 36364). Based on the evidence outlined above, the variant was classified as likely pathogenic.
PreventionGenetics, part of Exact Sciences	RCV004752724	SCV005347378	uncertain significance	HNF4A-related disorder	2024-03-24	no assertion criteria provided	clinical testing	The HNF4A c.925C>T variant is predicted to result in the amino acid substitution p.Arg309Cys. This variant was reported in multiple individuals with maturity-onset diabetes of the young (MODY) (reported as p.Arg322Cys in Ellard et al. 2006. PubMed ID: 16917892; Colclough. 2013. PubMed ID: 23348805; Mirshahi et al. 2022. PubMed ID: 36257325, supplementary data) and found in an individual with late-onset diabetes and an elevated triglyceride level (documented as c.991C>T, p.Arg331Cy in Spiro et al. 2018. PubMed ID: 29998026). This variant was reported as uncertain in a large population-based cohort study (Table E1, Billings et al. 2022. PubMed ID: 36208030). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.