Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV001843406 | SCV002102540 | uncertain significance | Monogenic diabetes | 2022-02-08 | reviewed by expert panel | curation | The c.1544C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of threonine to methionine at codon 515 (p.(Thr515Met)) of NM_000545.8. This variant has a REVEL score of 0.673, which is between the ClinGen MDEP thresholds, predicting neither a damaging nor benign impact on HNF1A function. While c.1544C>T has an allele frequency of .0000264 in the European non-Finnish population in gnomAD v2.1.1, it has 2 alleles in the Latino subpopulation; therefore, this variant does not meet the ClinGen MDEP-established cutoff for PM2_Supporting. This variant was identified in three unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4 cannot be applied because the variant MAF in gnomAD is above the ClinGen MDEP PM2_Supporting cutoff (PMID:29666556, PMID:29207974, internal lab contributor). One of these individuals has a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, antibody negative, and negative genetic testing for HNF4A) (PP4_Moderate; internal lab contributor). In summary, the c.1544C>T variant 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): PP4_Moderate. |
| Fulgent Genetics, |
RCV005006084 | SCV005634510 | uncertain significance | Diabetes mellitus type 1; Type 1 diabetes mellitus 20; Maturity-onset diabetes of the young type 3; Type 2 diabetes mellitus; Hepatic adenomas, familial; Nonpapillary renal cell carcinoma | 2024-02-28 | criteria provided, single submitter | clinical testing |