ClinVar Miner

Submissions for variant NM_000457.5(HNF4A):c.998G>A (p.Arg333His) (rs1375557127)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000711966 SCV000842377 uncertain significance not provided 2017-11-22 criteria provided, single submitter clinical testing
Translational Genomics Laboratory,University of Maryland School of Medicine RCV000754815 SCV000882465 pathogenic Maturity-onset diabetes of the young, type 1 2017-10-19 criteria provided, single submitter clinical testing The c.923G>A variant in codon 308 (exon 10) of the Hepatocyte Nuclear Factor 4-Alpha gene, HNF4A, results in the substitution of Arginine to Histidine. Missense mutations in the HNF4A gene, including ones in exon 10, have been reported previously in patients with a clinical picture consistent with Maturity-Onset Diabetes of the Young, Type 1 (MODY1) (23348805). The c.923G>A variant was not observed in the NHLBI Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium databases; however, the c.923G>A variant has been previously identified in multiple individuals with a diagnosis of MODY1 (10768098, 24947580, 26059258), with evidence of co-segregation in three families (24947580, K. Colclough, personal communication, January 3rd, 2017). Different amino acid substitutions at Arg308 (Arg308Cys and Arg308Ser) have been identified in patients with a strong MODY1 phenotype and have shown co-segregation in one family (K. Colclough, personal communication, January 3rd, 2017). Additionally, multiple lines of computational evidence (SIFT, Polyphen, MutationTaster, FATHMM, MetaSVM, MetalR, Provean, GERP, CADD) predict this variant is probably damaging to the protein structure, function, or protein-protein interaction. The c.923G>A variant is located in the ligand-binding domain of the protein, a region of the protein that has minimal benign variation among individuals in population databases and in the literature (23485969, 16917892). ACMG criteria = PP1-strong, PM1, PM2, PM5, PP3
Broad Institute Rare Disease Group, Broad Institute RCV000754815 SCV001422859 uncertain significance Maturity-onset diabetes of the young, type 1 2020-01-22 no assertion criteria provided curation The p.Arg333His variant in HNF4A has been reported in at least 3 individuals with maturity-onset diabetes of the young type 1 (MODY1) (PMID: 24947580, 25414397, 26059258) and has been Identified in 0.005451% (1/18346) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1375557127). In vitro functional studies demonstrating reduced relative activity in cells transfected with the variant provide some evidence that the p.Arg333His variant may slightly impact protein function (PMID: 23485969). 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.Arg333His variant is located in a region of HNF1A that is essential to ligand binding and stability, suggesting that this variant is in a functional domain and slightly supports pathogenicity (PMID: 23485969). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: BS1, PM2, PP3, PS4_supporting, PS3_supporting, PM1_supporting (Richards 2015).

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