Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV003326016 | SCV004032119 | likely pathogenic | Monogenic diabetes | 2023-08-14 | reviewed by expert panel | curation | The c.695T>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of leucine to proline at codon 232 (p.(Leu232Pro)) of NM_000545.8. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.936, which is greater than the MDEP VCEP threshold of 0.70 (PP3). It is also 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). Additionally, functional studies demonstrated the p.Leu232Pro protein has DNA binding and transactivation below 40% of wild type, indicating that this variant impacts protein function (PS3_Supporting, internal lab contributor). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in three unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 29875428, internal lab contributors). 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, treated with low-dose sulfonylureas, and persistent C-peptide) (PP4_Moderate; internal lab contributor). This variant also segregated with diabetes/hepatic adenomas, with three informative meioses in two families (PP1_Moderate; PMID: 29875428, internal lab contributors). In summary, the c.695T>C variant meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PP1_Moderate, PP3, PP4_Moderate, PM1_Supporting, PM2_Supporting, PS3_Supporting. |
| Ambry Genetics | RCV002362483 | SCV002663908 | likely pathogenic | Maturity onset diabetes mellitus in young | 2016-05-23 | criteria provided, single submitter | clinical testing | The p.L232P variant (also known as c.695T>C), located in coding exon 3 of the HNF1A gene, results from a T to C substitution at nucleotide position 695. The leucine at codon 232 is replaced by proline, an amino acid with similar properties. This variant has been detected by our laboratory in three individuals, from one family, each with a clinical diagnosis of MODY; two of these individuals also have hepatic adenomas. Based on internal structural analysis, this variant is buried in the DNA binding domain and is anticipated to result in a significant decrease in structural stability (Chi YI et al., Mol. Cell 2002 Nov; 10(5):1129-37). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |