ClinVar Miner

Submissions for variant NM_175914.5(HNF4A):c.587C>A (p.Ala196Asp)

gnomAD frequency: 0.00001  dbSNP: rs1032164393
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001526952 SCV001737722 uncertain significance not specified 2024-07-09 criteria provided, single submitter clinical testing Variant summary: HNF4A c.587C>A (p.Ala196Asp) results in a non-conservative amino acid change located in the Nuclear hormone receptor, ligand-binding domain (IPR000536) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251184 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.587C>A in individuals affected with Maturity Onset Diabetes Of The Young 1/Neonatal Diabetes Mellitus and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 1172869). Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx RCV001773765 SCV001994291 uncertain significance not provided 2024-06-12 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Located in the critical Ligand binding domain (PMID: 23348805); This variant is associated with the following publications: (PMID: 23348805)
Fulgent Genetics, Fulgent Genetics RCV002501856 SCV002814194 uncertain significance Maturity-onset diabetes of the young type 1; Type 2 diabetes mellitus; Fanconi renotubular syndrome 4 with maturity-onset diabetes of the young 2022-05-27 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001773765 SCV004655287 uncertain significance not provided 2023-02-28 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 196 of the HNF4A protein (p.Ala196Asp). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with HNF4A-related conditions. ClinVar contains an entry for this variant (Variation ID: 1172869). 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.

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