Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV001025446 | SCV001187634 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-09-23 | criteria provided, single submitter | clinical testing | The p.L22* variant (also known as c.65T>G), located in coding exon 1 of the FH gene, results from a T to G substitution at nucleotide position 65. This changes the amino acid from a leucine to a stop codon within coding exon 1. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. However, there is a second in-frame methionine at p.M44. Proteins initiated from the first methionine are targeted to the mitochondrion while proteins initiated from the second methionine are targeted to the cytoplasm due to the lack of the mitochondrial targeting sequence encoded between them (Dik E et al. Traffic, 2016 Jul;17:720-32; Magrane M et al., Database (Oxford) 2011). Data suggest that it is the cytoplasmic protein that conveys the tumor suppressor function of FH (Yogev O et al. PLoS Biol., 2010 Mar;8:e1000328). This alteration and others that are expected to adversely affect the protein before the second methionine, have been observed in numerous individuals who do not have a personal or family history that is consistent with or suggestive of HLRCC (Ambry internal data). The clinical impact of this variant in terms of autosomal recessive Fumarase Deficiency is also unclear due to the lack of this variant being associated with this autosomal recessive disease in the literature and internally. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Invitae | RCV002508277 | SCV001417238 | pathogenic | not provided | 2023-10-18 | criteria provided, single submitter | clinical testing | 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 FH tumor predisposition syndrome. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FH are known to be pathogenic (PMID: 11865300, 21398687). 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: 826506). 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 FH tumor predisposition syndrome. |
| Gene |
RCV002508277 | SCV002817826 | uncertain significance | not provided | 2022-12-27 | criteria provided, single submitter | clinical testing | Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); 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); This variant is associated with the following publications: (PMID: 27037871) |
| Baylor Genetics | RCV003461407 | SCV004197327 | uncertain significance | Fumarase deficiency | 2023-08-30 | criteria provided, single submitter | clinical testing |