Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Athena Diagnostics | RCV000993263 | SCV001146096 | uncertain significance | not provided | 2019-08-07 | criteria provided, single submitter | clinical testing | |
| Fulgent Genetics, |
RCV002489482 | SCV002799624 | 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 | 2024-01-17 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003489997 | SCV004242007 | uncertain significance | not specified | 2023-12-08 | criteria provided, single submitter | clinical testing | Variant summary: HNF1A c.1322C>A (p.Thr441Lys) results in a non-conservative amino acid change located in the hepatocyte nuclear factor 1, beta isoform, C-terminal domain (IPR006897) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.3e-05 in 1608490 control chromosomes, exclusively within the Non-Finnish European subpopulation in the gnomAD database at a frequency of 3.1e-05. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately equal to the estimated maximal expected allele frequency for a pathogenic variant in HNF1A causing Maturity Onset Diabetes Of The Young 3 phenotype (2.5e-05), suggesting that the variant may be a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.1322C>A in individuals affected with Maturity Onset Diabetes Of The Young 3 has been reported. At least one publication reports experimental evidence evaluating an impact on protein function (Althari_2020). These results showed that the variant had reduced nuclear localization, approximately 40% compared to WT, but demonstrated no damaging impact on DNA binding activity. The following publication has been ascertained in the context of this evaluation (PMID: 32910913). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Both submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. |
| Labcorp Genetics |
RCV000993263 | SCV005834720 | uncertain significance | not provided | 2024-10-23 | criteria provided, single submitter | clinical testing | This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 441 of the HNF1A protein (p.Thr441Lys). This variant is present in population databases (rs371544082, gnomAD 0.006%). This missense change has been observed in individual(s) with type 2 diabetes (PMID: 32910913). ClinVar contains an entry for this variant (Variation ID: 805629). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt HNF1A protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects HNF1A function (PMID: 32910913). 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. |