Submissions for variant NM_175914.5(HNF4A):c.863G>A (p.Arg288Gln)

gnomAD frequency: 0.00004  dbSNP: rs371124358

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000779347	SCV000915941	uncertain significance	Maturity-onset diabetes of the young type 1	2018-11-29	criteria provided, single submitter	clinical testing	The HNF4A c.929G>A (p.Arg310Gln) missense variant has been reported in two studies and found in a total of three individuals with maturity onset diabetes of the young (MODY) in a heterozygous state (Johansen et al. 2005; Bansal et al. 2017). The variant is absent from 100 control individuals and is reported at a frequency of 0.000105 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the limited evidence, the p.Arg310Gln variant is classified as a variant of unknown significance but suspicious for pathogenicity for maturity onset diabetes of the young. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Illumina Laboratory Services, Illumina	RCV001139379	SCV001299524	uncertain significance	Familial hyperinsulinism	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000779347	SCV001422830	uncertain significance	Maturity-onset diabetes of the young type 1	2020-01-22	criteria provided, single submitter	curation	The p.Arg310Gln variant in HNF4A has not been previously reported in individuals with MODY, and has been identified in 0.009% (12/126714) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs371124358). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, while the clinical significance of the p.Arg310Gln variant is uncertain, these data suggest that it is more likely to be benign. ACMG/AMP Criteria applied: BS1 (Richards 2015).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001526903	SCV001737649	uncertain significance	not specified	2023-07-02	criteria provided, single submitter	clinical testing	Variant summary: HNF4A c.863G>A (p.Arg288Gln) results in a conservative amino acid change located in the Nuclear hormone receptor, ligand-binding domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 247962 control chromosomes. The observed variant frequency is approximately 18.0 fold of the estimated maximal expected allele frequency for a pathogenic variant in HNF4A causing monogenic diabetes (3.1e-06), suggesting that the variant may be benign. However, this data must be taken with caution due to the potential inclusion of mild-phenotype patients within the large population-based cohort. c.863G>A has been reported in the literature in a family with monogenic diabetes (segregation is specified, however the number of family members with disease is not mentioned; Johansen_2005) and in two individuals from a type 2 diabetes cohort (Bansal_2017). These data do not allow any conclusion about variant significance. 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: 29207974, 24097065, 24476040, 23227446, 15928245). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Revvity Omics, Revvity	RCV003133587	SCV003808687	uncertain significance	not provided	2021-09-16	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV003133587	SCV004298081	uncertain significance	not provided	2024-01-10	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 288 of the HNF4A protein (p.Arg288Gln). This variant is present in population databases (rs371124358, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of maturity onset diabetes of the young (PMID: 15928245, 29207974). This variant is also known as c.929G>A, p.Arg301Gln or p.Arg310Gln. ClinVar contains an entry for this variant (Variation ID: 632373). 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.