ClinVar Miner

Submissions for variant NM_175914.5(HNF4A):c.593T>G (p.Leu198Arg)

dbSNP: rs1568735272
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel RCV003883161 SCV004697853 uncertain significance Monogenic diabetes 2023-12-25 reviewed by expert panel curation The c.593T>G variant in the hepatic nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of leucine to arginine at codon 198 (p.(Leu198Arg)) of NM_175914.5. This variant is located within the ligand-binding domain (codons 180-220 and 300-350) of HNF4A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.98, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, c.593T>G 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 10/22/2023): PP3, PM1_Supporting, PM2_Supporting.
Athena Diagnostics RCV000711962 SCV000842373 uncertain significance not provided 2018-02-28 criteria provided, single submitter clinical testing
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic RCV003148852 SCV003804759 likely risk allele 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 rs1568735272 in MODY, yet.

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