Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000445241 | SCV000533039 | uncertain significance | not provided | 2016-10-20 | criteria provided, single submitter | clinical testing | A variant of uncertain significance has been identified in the FH gene. The L303V variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The L303V variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The L303V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Another non-conservative missense variant at this position, L303S, has previously been reported in a single individual with mild fumarase deficiency who was also heterozygous for another missense variant in the FH gene, although the phase of these variants was not reported (Kimonis et al., 2012). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. |
| Labcorp Genetics |
RCV000445241 | SCV002308800 | uncertain significance | not provided | 2023-12-26 | criteria provided, single submitter | clinical testing | This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 303 of the FH protein (p.Leu303Val). 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: 390255). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. This variant disrupts the p.Leu303 amino acid residue in FH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22595425; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. |
| Fulgent Genetics, |
RCV002481331 | SCV002783795 | uncertain significance | Fumarase deficiency; Hereditary leiomyomatosis and renal cell cancer | 2022-02-08 | criteria provided, single submitter | clinical testing |