Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV004566710 | SCV005050166 | pathogenic | Monogenic diabetes | 2024-05-09 | reviewed by expert panel | curation | The c.421C>T variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, results in a premature termination at codon 141 (p.(Arg141Ter)) of NM_175914.5. This variant, located in biologically-relevant exon 4 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). This variant is absent from gnomAD v2.1.1 (PM2_Supporting), and was identified in at least 10 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID: 9294105, internal lab contributors). Three individuals had a clinical history highly specific for HNF4A-MODY monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A, and response to low-dose sulfonylureas) (PP4_Moderate; internal lab contributors). This variant also segregated with diabetes, with at least seven informative meioses in two families (PP1_Strong; PMID: 9294105, internal lab contributor). In summary, c.421C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PVS1, PP1_Strong, PS4, PP4_Moderate, PM2_Supporting). |
| Athena Diagnostics | RCV000516683 | SCV000613653 | pathogenic | not provided | 2021-08-17 | 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 has been identified in at least one individual with clinical features associated with this gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. Experiments indicate this variant impairs transcriptional activity (PMID: 10606640, 11435618). |
| Labcorp Genetics |
RCV000516683 | SCV004298076 | pathogenic | not provided | 2024-02-24 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Arg141*) in the HNF4A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HNF4A are known to be pathogenic (PMID: 20164212, 23275527, 23348805, 24097065). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with maturity onset diabetes of the young (PMID: 9294105). This variant is also known as R154X. ClinVar contains an entry for this variant (Variation ID: 9211). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects HNF4A function (PMID: 10606640). For these reasons, this variant has been classified as Pathogenic. |
| OMIM | RCV000009791 | SCV000030012 | pathogenic | Maturity-onset diabetes of the young type 1 | 2001-07-01 | no assertion criteria provided | literature only |