Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV002222002 | SCV002499539 | pathogenic | Monogenic diabetes | 2022-04-02 | reviewed by expert panel | curation | The c.130delC variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 44 (NM_000545.8), adding 111 novel amino acids before encountering a stop codon (p.(Leu44TrpfsTer111)). This variant, located in biologically-relevant exon 1 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805) and is absent from gnomAD v2.1.1 (PM2_Supporting). Additionally, 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) (PP4; PMID: 15305805). This variant segregated with diabetes, with at least five informative meioses in two families with MODY (PP1_Strong; PMIDs: 15305805 and 12453976). This variant was Identified in two 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 (PMIDs: 15305805 and 12453976). In summary, c.130delC meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/21): PVS1, PM2_Supporting, PP1_Strong, PP4. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000030478 | SCV000053148 | pathogenic | Maturity-onset diabetes of the young type 3 | 2011-08-18 | criteria provided, single submitter | curation | Converted during submission to Pathogenic. |
| Clinical Genomics, |
RCV002326697 | SCV002601655 | 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 rs193922578 with MODY3. | |
| Ambry Genetics | RCV002326697 | SCV002693601 | pathogenic | Maturity onset diabetes mellitus in young | 2019-02-23 | criteria provided, single submitter | clinical testing | The c.130delC pathogenic mutation, located in coding exon 1 of the HNF1A gene, results from a deletion of one nucleotide at nucleotide position 130, causing a translational frameshift with a predicted alternate stop codon (p.L44Wfs*111). This mutation was identified in multiple individuals from two maturity-onset diabetes of the young families (Klupa T et al. Diabetes Care, 2002 Dec;25:2292-301; McKinney JL et al. Clin Invest Med, 2004 Jun;27:135-41). 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. |