Submissions for variant NM_175914.5(HNF4A):c.932G>T (p.Arg311Leu)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV004598221	SCV005092013	likely pathogenic	Monogenic diabetes	2024-07-31	reviewed by expert panel	curation	The c.932G>T variant in the HNF4 homeobox A gene, HNF4A, causes an amino acid change of arginine to leucine at codon 311 (p.(Arg311Leu)) of NM_175914.4. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.986, which is greater than the MDEP threshold of 0.70 (PP3). Two other missense variants, c.932G>A p.Arg311His and c.931C>T p.Arg311Cys, have been interpreted as pathogenic by the ClinGen MDEP and p.Arg311Leu has a greater Grantham distance than p.Arg311His (PM5_Strong). This variant was identified in an individual with a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50% and negative genetic testing for HNF1A) (PP4; internal lab contributors). In summary, c.932G>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 2.0.0, approved 10/11/2023): PM5_Strong, PP3, PP4, PM1_Supporting, PM2_Supporting.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002870902	SCV003223406	uncertain significance	not provided	2023-03-03	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 2018786). This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 311 of the HNF4A protein (p.Arg311Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with HNF4A-related conditions. 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. This variant disrupts the p.Arg311 amino acid residue in HNF4A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25414397, 36257325). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Genetic Services Laboratory, University of Chicago	RCV003151421	SCV003839591	uncertain significance	not specified	2022-07-23	no assertion criteria provided	clinical testing	DNA sequence analysis of the HNF4A gene demonstrated a sequence change, c.932G>T, in exon 8 that results in an amino acid change, p.Arg311Leu. This sequence change does not appear to have been previously described in individuals with HNF4A-related disorders and has also not been described in population databases such as ExAC and gnomAD. The p.Arg311Leu change affects a highly conserved amino acid residue located in a domain of the HNF4A protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg311Leu substitution. Other amino acid substitutions at this position (p.Arg311His, p.Arg311Cys) have been reported in individuals with maturity-onset diabetes of the young (PMID: 24947580, 22060211, 26059258). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Arg311Leu change remains unknown at this time. Heterozygous pathogenic variants in HNF4A are associated with Fanconi renotubular syndrome4, with maturity-onset diabetes of the young [OMIM# 616026]