Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV004776449 | SCV005387836 | uncertain significance | Monogenic diabetes | 2024-10-13 | reviewed by expert panel | curation | The c.703G>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of glutamate to glutamine at codon 235 (p.(Glu235Gln)) of NM_000545.8. This variant is 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, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.816, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant has an incomputable gnomAD v2.1.1 Grpmax filtering allele frequency due to its absence in the European non-Finnish subpopulation and only 1 copy in any other subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF GrpmaxPopmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). This variant was identified in a single individual 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: 19336507). This variant does not meet the MDEP criteria of reduced function in either transactivation or nuclear localization assays, as defined as < 40% of WT activity (PMID: 26853433). In summary, c.703G>C 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 2.1.1, approved 8/11/2023): PM1_Supporting, PM2_Supporting, PP3. |
| Clinical Genomics, |
RCV002051925 | SCV002604995 | uncertain risk allele | 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 rs1353807357 with MODY3. | |
| Molecular Genetics, |
RCV002051925 | SCV002318408 | likely benign | Maturity onset diabetes mellitus in young | criteria provided, single submitter | clinical testing | ||
| Broad Center for Mendelian Genomics, |
RCV001248894 | SCV001422575 | uncertain significance | Maturity-onset diabetes of the young type 3 | 2020-01-22 | criteria provided, single submitter | curation | The p.Glu235Gln variant in HNF1A has been reported in an Indian individual with maturity-onset diabetes of the young (PMID: 19336507), and has been identified in 0.003% (1/30604) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1353807357). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. In vitro functional studies provide some evidence that the p.Glu235Gln variant may slightly impact protein function (PMID: 26853433). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The p.Glu235Gln variant is located in a region of HNF1A that is essential to protein folding and stability, suggesting that this variant is in a functional domain and slightly supports pathogenicity (PMID: 26853433). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PP3, PS3_Supporting, PM1_Supporting (Richards 2015). |