Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV002250357 | SCV002520653 | uncertain significance | Monogenic diabetes | 2022-05-02 | reviewed by expert panel | curation | The c.734G>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of glycine to valine at codon 245 (p.Gly245Val) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is also absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.956, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Lastly, this variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative antibodies, and low hsCRP; HNF4A not tested, but low hsCRP is specific to HNF1A vs. HNF4A) (PP4_Moderate; PMID: 30181854). Another missense variant, c.733G>A (p.Gly245Arg) has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied. In summary, c.734G>T 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 1.1, approved 9/30/2021): PM1_Supporting, PM2_Supporting, PP3, PP4_Moderate. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000030510 | SCV000053181 | likely pathogenic | Maturity-onset diabetes of the young type 3 | 2011-08-18 | criteria provided, single submitter | curation | Converted during submission to Likely pathogenic. |
| Athena Diagnostics | RCV000993273 | SCV001146110 | uncertain significance | not provided | 2019-03-22 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV000993273 | SCV005724875 | uncertain significance | not provided | 2024-06-23 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 245 of the HNF1A protein (p.Gly245Val). 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: 30181854, 36257325; Invitae). ClinVar contains an entry for this variant (Variation ID: 36829). 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 not expected to disrupt HNF1A protein function with a negative predictive value of 80%. This variant disrupts the p.Gly245 amino acid residue in HNF1A. Other variant(s) that disrupt this residue have been observed in individuals with HNF1A-related conditions (PMID: 19336507), which suggests that this may be a clinically significant amino acid residue. 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. |