Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV005831603 | SCV006526765 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2025-06-24 | criteria provided, single submitter | clinical testing | The p.H235D variant (also known as c.703C>G), located in coding exon 5 of the FH gene, results from a C to G substitution at nucleotide position 703. The histidine at codon 235 is replaced by aspartic acid, an amino acid with similar properties. This variant was reported in individual(s) with features consistent with hereditary leiomyomatosis and renal cell cancer (Ambry internal data). Other variant(s) at the same codon, p.H235R (c.704A>G), have been identified in individual(s) with features consistent with hereditary leiomyomatosis and renal cell cancer (Gardie B et al. J. Med. Genet. 2011 Apr;48(4):226-34; Muller M et al. Clin. Genet., 2017 Dec;92:606-615). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Labcorp Genetics |
RCV003574775 | SCV004364178 | likely pathogenic | not provided | 2025-10-23 | criteria provided, single submitter | clinical testing | This sequence change replaces histidine, which is basic and polar, with aspartic acid, which is acidic and polar, at codon 235 of the FH protein (p.His235Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with renal cell cancer (PMID: 33402335). ClinVar contains an entry for this variant (Variation ID: 393569). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt FH protein function with a positive predictive value of 95%. This variant disrupts the p.His235 amino acid residue in FH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21398687, 23203078; internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
| Genomic Diagnostic Laboratory, |
RCV000445621 | SCV000537241 | likely pathogenic | Hereditary leiomyomatosis and renal cell cancer | 2017-01-17 | criteria provided, single submitter | clinical testing |