Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Athena Diagnostics | RCV001288637 | SCV001475908 | uncertain significance | not provided | 2020-02-12 | criteria provided, single submitter | clinical testing | |
| Molecular Genetics, |
RCV002221271 | SCV002498621 | uncertain significance | Maturity-onset diabetes of the young type 1 | 2023-03-30 | criteria provided, single submitter | clinical testing | This sequence change in HNF4A is predicted to replace valine with methionine at codon 88 (p.(Val88Met), also known as NM_175914.4:c.196G>A p.(Val66Met)). The valine residue is highly conserved (100 vertebrates, UCSC), and is located in the nuclear receptor domain. The variant is in a region of high missense constraint (amino acids 59-135) and a mutational hotspot (amino acids 85-89, ClinVar). There is a small physicochemical difference between valine and methionine. The highest population minor allele frequency in gnomAD v2.1 is 0.009% (3/34,570 alleles, 0 homozygotes) in the Latino/admixed American population. This variant has been reported in at least one proband with maturity-onset diabetes of the young (LOVD). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (6/6 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.4.0, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PM1, PP3. |
| Clinical Genomics, |
RCV003148968 | SCV003804604 | likely risk allele | Maturity onset diabetes mellitus in young | criteria provided, single submitter | research | Potent mutations in HNF4A are associated with poor insulin secretion in response to hyperglycemia. Associated with MODY1. Patients initially respond well to sulfonylureas but eventually become insulin dependent. However, more evidence is required to ascertain the role of this particular variant rs369182343 in MODY, yet. | |
| Revvity Omics, |
RCV001288637 | SCV003808685 | uncertain significance | not provided | 2022-01-21 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV001288637 | SCV004535481 | uncertain significance | not provided | 2024-04-29 | criteria provided, single submitter | clinical testing | This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 66 of the HNF4A protein (p.Val66Met). This variant is present in population databases (rs369182343, gnomAD 0.009%). This missense change has been observed in individual(s) with type I diabetes (PMID: 31264968). ClinVar contains an entry for this variant (Variation ID: 994901). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on HNF4A protein function. 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. |