Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV001024493 | SCV001186516 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2019-10-24 | criteria provided, single submitter | clinical testing | The p.P192L variant (also known as c.575C>T), located in coding exon 5 of the FH gene, results from a C to T substitution at nucleotide position 575. The proline at codon 192 is replaced by leucine, an amino acid with similar properties. This alteration was previously identified to co-segregate with disease in one Spanish family with multiple cutaneous and uterine leiomyomata syndrome (MCL) (Chuang GS et al. J. Am. Acad. Dermatol., 2005 Mar;52:410-6). This variant is located near the substrate-binding motif of fumarate hydratase, in a region with many other reported pathogenic alterations. Based on structural analysis, several of these nearby alterations are predicted to be less destabilizing than p.P192L (Ambry internal data; Toro JR et al. Am. J. Hum. Genet., 2003 Jul;73:95-106; Chuang GS et al. J. Am. Acad. Dermatol., 2005 Mar;52:410-6; Ajalla Aleixo MA et al. FEBS J., 2019 May;286:1925-1940). 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 the majority of available evidence to date, this variant is likely to be pathogenic. |
| Invitae | RCV002551894 | SCV001234116 | pathogenic | not provided | 2023-08-03 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 825947). This variant is also known as p.Pro149Leu. This missense change has been observed in individuals with uterine leiomyomas, cutaneous leiomyomas and/or renal cell carcinoma (PMID: 15761418, 31831373; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 192 of the FH protein (p.Pro192Leu). |