ClinVar Miner

Submissions for variant NM_175914.5(HNF4A):c.640T>A (p.Ser214Thr)

dbSNP: rs1060499693
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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 RCV004567930 SCV005050173 uncertain significance Monogenic diabetes 2024-05-09 reviewed by expert panel curation The c.640T>A variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of serine to threonine at codon 214 (p.Ser214Thr)) of NM_175914.5. This variant is located within the ligand-binding domain (codons 180-220) of HNF4A, which is defined as critical for the protein's function by the ClinGen MDEP (PM1_Supporting). It is also predicted to be deleterious by computational evidence, with a REVEL score of 0.966, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). A number of other missense variants at this codon (c.640T>G, p.Ser214Ala; c.641C>T, p.Ser214Phe; c.641C>A, p.Ser214Tyr) have been classified as VUS by the ClinGen MDEP; therefore, PM5 will not be applied. In summary, c.640T>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): PP3, PM1_Supporting, PM2_Supporting.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic RCV003148740 SCV003804760 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 rs1060499693 in MODY, yet.
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare RCV000449632 SCV000537783 likely pathogenic Maturity-onset diabetes of the young type 1 no assertion criteria provided clinical testing

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