Total submissions: 7
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV002222009 | SCV002499512 | pathogenic | Monogenic diabetes | 2022-04-10 | reviewed by expert panel | curation | The c.598C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to tryptophan at codon 200 (p.(Arg200Trp)) of NM_000545.8. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.775, which is greater than the MDEP VCEP threshold of 0.70 (PP3) and is absent from gnomAD v2.1.1 (PM2_Supporting). Another missense variant, c.599G>A, p.(Arg200Gln), has been interpreted as pathogenic by the ClinGen MDEP, and p.Arg200Trp has a greater Grantham distance (PM5). This variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and negative autoantibodies) (PP4_Moderate; PMID: 32238361). This variant was identified in at least ten unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMIDs: 17440016, 9754819, 29927023, 32238361; internal lab contributors). Lastly, this variant segregated with diabetes, with five informative meioses in five families with MODY (PP1_Strong; internal lab contributors). In summary, c.598C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PP1_Strong, PM2_Supporting, PP3, PS4, PP4_Moderate, PM5. |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000030505 | SCV000053176 | pathogenic | Maturity onset diabetes mellitus in young | 2021-05-14 | criteria provided, single submitter | clinical testing | Variant summary: HNF1A c.598C>T (p.Arg200Trp) results in a non-conservative amino acid change located in the Homeobox domain (IPR001356) 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 251336 control chromosomes (gnomAD). c.598C>T has been reported in the literature in multiple individuals affected with Maturity Onset Diabetes Of The Young 3 and has been documented to co-segregate with disease in affected families (e.g. Chevre_1998, Frayling_2001, Barrio_2002, Sahu_2007, Yorifuji_2012, Flannick_2013, Docena_2014, Bonnefond_2020, Ma_2020). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant causes a defect in nuclear import which is expected to lead to altered gene activity. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. |
Gene |
RCV001570589 | SCV001794908 | likely pathogenic | not provided | 2023-08-23 | criteria provided, single submitter | clinical testing | Published functional studies show possible interference with protein localization; however, proper localization does not appear to be entirely eliminated (Bjrkhaug et al., 2005); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28012402, 29927023, 33046911, 16274290, 12453420, 9754819, 22060211, 17440016, 24014008, 34789499, 28410371, 33852230, 34440499, 36208030, 36504295, 35796342, 12050210) |
Athena Diagnostics | RCV001570589 | SCV001880084 | pathogenic | not provided | 2021-07-01 | criteria provided, single submitter | clinical testing | This variant was not reported in large, multi-ethnic, general populations (http://gnomad.broadinstitute.org). This variant associates with disease in multiple families. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic. Assessment of experimental evidence suggests this variant results in abnormal protein function. Experiments show this variant results in significant loss of nuclear localization of the HNF-1alpha protein (PMID: 16274290). The variant is located in a region that is considered important for protein function and/or structure. |
Geisinger Clinic, |
RCV002285260 | SCV002562140 | pathogenic | Maturity-onset diabetes of the young type 3 | 2022-08-02 | criteria provided, single submitter | research | PS4, PP1_strong, PM2, PM5, PP3, PP4 |
Invitae | RCV001570589 | SCV003485966 | pathogenic | not provided | 2022-07-30 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 200 of the HNF1A protein (p.Arg200Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with maturity-onset diabetes of the young (PMID: 9754819, 22060211, 33046911). ClinVar contains an entry for this variant (Variation ID: 36824). 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) performed at Invitae indicates that this missense variant is expected to disrupt HNF1A protein function. This variant disrupts the p.Arg200 amino acid residue in HNF1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15522234, 15841481, 16274290, 30663027; 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. |
Seattle Children's Hospital Molecular Genetics Laboratory, |
RCV002285260 | SCV004174093 | pathogenic | Maturity-onset diabetes of the young type 3 | no assertion criteria provided | clinical testing |