Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV004568659 | SCV005050179 | pathogenic | Monogenic diabetes | 2024-05-10 | reviewed by expert panel | curation | The c.692G>A variant in the hepatocyte nuclear factor 4 alpha gene, HNF4A, causes an amino acid change of arginine to glutamine at codon 231 (p.(Arg231Gln)) of NM_175914.5. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.896, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in 10 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID:12413008, PMID:12627330, internal lab contributors). This variant segregated with diabetes, with at least four informative meioses in two families (PP1_Strong; PMID:12413008, internal lab contributor). One individual has a clinical history highly specific for HNF4A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A, negative autoantibodies, and response to low-dose sulfonylureas) (PP4_Moderate; internal lab contributor). In summary, c.692G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PP1_Strong, PS4, PP4_Moderate, PP3, PM2_Supporting. |
| Athena Diagnostics | RCV000516891 | SCV000613659 | likely pathogenic | not provided | 2016-10-20 | criteria provided, single submitter | clinical testing | |
| Gene |
RCV000516891 | SCV002586934 | likely pathogenic | not provided | 2024-12-13 | 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; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Also known as p.(Arg244Gln); This variant is associated with the following publications: (PMID: 12627330, 23227446, 12413008, 32971154, 36257325, 33242514) |
| Labcorp Genetics |
RCV000516891 | SCV004298079 | pathogenic | not provided | 2023-12-01 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 231 of the HNF4A protein (p.Arg231Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of maturity-onset diabetes of the young (PMID: 12413008, 12627330; Invitae). This variant is also known as p.Arg244Gln. ClinVar contains an entry for this variant (Variation ID: 447520). 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. Experimental studies have shown that this missense change affects HNF4A function (PMID: 12413008). This variant disrupts the p.Arg231 amino acid residue in HNF4A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 32418360, 36257325; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |