Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Athena Diagnostics | RCV000993261 | SCV001146094 | pathogenic | not provided | 2020-12-09 | criteria provided, single submitter | clinical testing | This variant is expected to result in the loss of a functional protein. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant segregates with disease in multiple families. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant abolishes the transcriptional activity of the protein (PMID: 10581189). |
| Invitae | RCV000993261 | SCV002238579 | pathogenic | not provided | 2021-08-23 | criteria provided, single submitter | clinical testing | This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 805627). This variant is also known as P379fsdelCT. This premature translational stop signal has been observed in individual(s) with maturity-onset diabetes of the young (PMID: 8945470, 31216263). This sequence change creates a premature translational stop signal (p.Pro379Argfs*39) in the HNF1A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HNF1A are known to be pathogenic (PMID: 15928245, 18003757). |
| Clinical Genomics, |
RCV002319610 | SCV002604907 | likely pathogenic | Maturity onset diabetes mellitus in young | criteria provided, single submitter | research | Mutations in HNF1A gene can predispose to MODY3. It is associated with both micro and macrovascular complications of diabetes, especially cardiovascular complications. Associated with glucosuria. May respond well to sulfonylureas. However, more evidence is required to confer the association of this particular variant rs1593060890 with MODY3. | |
| Ambry Genetics | RCV002319610 | SCV002612552 | pathogenic | Maturity onset diabetes mellitus in young | 2019-01-14 | criteria provided, single submitter | clinical testing | The c.1136_1137delCT pathogenic mutation, located in coding exon 6 of the HNF1A gene, results from a deletion of two nucleotides at nucleotide positions 1136 to 1137, causing a translational frameshift with a predicted alternate stop codon (p.P379Rfs*39). This mutation, designated as P379fsdelCT, was observed in one family to co-segregate with disease in 5 affected and 2 unaffected family members (Yamagata K et al. Nature, 1996 Dec;384:455-8). Functional studies demonstrated this mutation caused incorrect localization and accumulation of the protein in the cytoplasm and nucleus; DNA binding ability was also reduced to 30-40% of wild type protein (Bjørkhaug L et al. J. Clin. Endocrinol. Metab., 2003 Feb;88:920-31). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. |
| ARUP Laboratories, |
RCV000993261 | SCV003799472 | pathogenic | not provided | 2022-03-16 | criteria provided, single submitter | clinical testing | The HNF1A c.1136_1137delCT; p.Pro379ArgfsTer39 variant (rs1593060890) is reported in the literature in individuals with MODY (Brahm 2016, Pavic 2018, Yamagata 1996) and is also reported in ClinVar (Variation ID: 805627). Additionally, functional studies show an effect on transactivation activity and nuclear import of the variant protein (Yang 1999). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by deleting two nucleotides, resulting in a truncated protein. Based on available information, this variant is considered to be pathogenic. References: Brahm AJ et al. Genetic Confirmation Rate in Clinically Suspected Maturity-Onset Diabetes of the Young. Can J Diabetes. 2016 Dec;40(6):555-560. PMID: 27634015. Pavic T et al. Maturity onset diabetes of the young due to HNF1A variants in Croatia. Biochem Med (Zagreb). 2018 Jun 15;28(2):020703. PMID: 29666556. Yamagata K et al. Mutations in the hepatocyte nuclear factor-1alpha gene in maturity-onset diabetes of the young (MODY3). Nature. 1996 Dec 5;384(6608):455-8. PMID: 8945470. Yang Q et al. Structure/function studies of hepatocyte nuclear factor-1alpha, a diabetes-associated transcription factor. Biochem Biophys Res Commun. 1999 Dec 9;266(1):196-202. PMID: 10581189. |
| Baylor Genetics | RCV004559831 | SCV005049297 | pathogenic | Maturity-onset diabetes of the young type 3 | 2024-01-26 | criteria provided, single submitter | clinical testing |