Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV001022288 | SCV001184003 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2019-07-30 | criteria provided, single submitter | clinical testing | The p.G144E variant (also known as c.431G>A), located in coding exon 4 of the FH gene, results from a G to A substitution at nucleotide position 431. The glycine at codon 144 is replaced by glutamic acid, an amino acid with similar properties. This alteration has been observed in at least one individual who has a personal or family history that is consistent with FH-associated disease (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on internal structural assessment, this alteration results in destabilization of the FH complex, near the substrate binding site (Ajalla Aleixo MA et al. FEBS J., 2019 May;286:1925-1940; Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Invitae | RCV002549552 | SCV003312312 | pathogenic | not provided | 2023-10-13 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 144 of the FH protein (p.Gly144Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of FH tumor predisposition syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 824791). 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) performed at Invitae indicates that this missense variant is expected to disrupt FH protein function. This variant disrupts the p.Gly144 amino acid residue in FH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 31831373; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
| Baylor Genetics | RCV003461391 | SCV004197349 | uncertain significance | Fumarase deficiency | 2023-07-05 | criteria provided, single submitter | clinical testing |