ClinVar Miner

Submissions for variant NM_175914.5(HNF4A):c.589C>A (p.Leu197Met)

dbSNP: rs1775879070
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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 RCV003481037 SCV004223884 uncertain significance Monogenic diabetes 2023-12-25 reviewed by expert panel curation The c.589C>A variant in the hepatic nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of leucine to methionine at codon 197 (p.(Leu197Met)) 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 0.9029, 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.589C>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.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV001248997 SCV001422841 uncertain significance Maturity-onset diabetes of the young type 1 2020-01-22 criteria provided, single submitter curation The p.Leu219Met variant in HNF4A has not been previously reported in individuals with MODY and was absent from large population studies. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. p.Leu219Met is located in a region of HNF4A that is essential to protein folding and stability, suggesting that this variant is in a functional domain and supports pathogenicity (PMID: 15123688, 15826954). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PM1, PP3 (Richards 2015).
Genetics and Molecular Pathology, SA Pathology RCV002272431 SCV002556830 likely pathogenic Fanconi renotubular syndrome 4 with maturity-onset diabetes of the young 2021-05-14 criteria provided, single submitter clinical testing

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