Submissions for variant NM_175914.5(HNF4A):c.224G>A (p.Arg75Lys)

Minimum review status:		Collection method:
Minimum conflict level: Report conflict between different conditions
		ClinVar version:

Total submissions: 3

Download table as spreadsheet

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV003993663	SCV004812224	uncertain significance	Monogenic diabetes	2024-04-05	reviewed by expert panel	curation	The c.224G>A variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of arginine to lysine at codon 75 (p.Arg75Lys)) of NM_175914.5. This variant resides in an amino acid within the HNF4alpha DNA binding domain that are necessary for homodimer formation, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.777, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). It was identified in an individual with gestational diabetes; however, the MODY probability is unable to be calculated due to lack of clinical information (ClinVar ID:430844). In summary, c.224G>A meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PM1, PP3, PM2_Supporting.
Institute of Endocrinology, Diabetes & Metabolism, Max Healthcare Institute Ltd.	RCV000495952	SCV000583613	uncertain significance	Maturity-onset diabetes of the young type 1	2017-06-28	criteria provided, single submitter	research	The patient, whose clinical indication suggests gestational diabetes, harbors one copy of this novel heterozygous variant in the HNF4A gene. This variant was present in the conserved region of the gene and predicted to be damaging by in silico analysis. This variant was present in the exon-intron boundary (exon-2) and showed mild effect on the splicing machinery. Variations in HNF4A gene have been shown to play a causative role in Maturity Onset Diabetes of the Young (MODY), late onset diabetes and beta cell dysfunction albeit at different amino acid positions when compared to the observed variant in the patient. This variant is not reported in public databases ExAC or 1000G, therefore it is considered novel. Role of HNF4A in the context of gestational diabetes is less clear and thus the observed novel variant was labelled as a VARIANT OF UNKNOWN SIGNIFICANCE (VUS).
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV003148755	SCV003804606	likely pathogenic	Maturity onset diabetes mellitus in young		criteria provided, single submitter	research	Potent mutations in HNF4A are associated with poor insulin secretion in response to hyperglycemia. Associated with MODY1. Patients initially respond well to sulfonylureas but eventually become insulin dependent. However, more evidence is required to ascertain the role of this particular variant rs1131692187 in MODY, yet.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.