Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001784418 | SCV000937743 | pathogenic | not provided | 2023-02-08 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Arg43*) in the FH gene. FH has two initiator codons, p.Met1 and p.Met44, which result in two different functional isoforms that localize to the mitochondria and cytosol, respectively (PMID: 21929734, 27037871). Loss-of-function variants in FH are known to be pathogenic (PMID: 11865300, 21398687). Variants affecting the mitochondrial isoform confer risk for fumarate hydratase deficiency, while variants that affect the cytosolic isoform confer risk for hereditary leiomyomatosis and renal cell cancer. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with FH-related conditions. ClinVar contains an entry for this variant (Variation ID: 644260). This variant disrupts the mitochondria-targeting sequence (MTS) of the FH protein, which is important for protein import into the mitochondria (PMID: 27037871). This suggests that disruption of this region is causative of fumarate hydratase deficiency. For these reasons, this variant has been classified as Pathogenic for autosomal recessive fumarate hydratase deficiency. However, this variant is not likely to confer risk for autosomal dominant hereditary leiomyomatosis and renal cell cancer. |
| Baylor Genetics | RCV003467368 | SCV004197375 | likely pathogenic | Fumarase deficiency | 2023-02-27 | criteria provided, single submitter | clinical testing | |
| Clinical Genetics Laboratory, |
RCV001784418 | SCV005197936 | pathogenic | not provided | 2022-05-27 | criteria provided, single submitter | clinical testing | |
| Gene |
RCV001784418 | SCV005376382 | uncertain significance | not provided | 2023-10-26 | criteria provided, single submitter | clinical testing | Nonsense variant in a gene for which loss-of-function is a known mechanism of disease; however, a downstream in-frame ATG could serve as an alternate initiator codon (Dik et al., 2016); Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 27037871, 21929734, 21398687, 11865300) |
| Fulgent Genetics, |
RCV005021203 | SCV005644255 | likely pathogenic | Fumarase deficiency; Hereditary leiomyomatosis and renal cell cancer | 2024-02-01 | criteria provided, single submitter | clinical testing |