Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000078146 | SCV000251432 | likely pathogenic | not provided | 2024-09-13 | criteria provided, single submitter | clinical testing | Published functional studies suggest a damaging effect: increased intracellular fumarate levels compared to wild-type (PMID: 25004247); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26839173, 23757202, 25004247, 35821608, 33848143, 36777509, 36773955) |
| Labcorp Genetics |
RCV000078146 | SCV000283664 | pathogenic | not provided | 2023-12-31 | criteria provided, single submitter | clinical testing | This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 434 of the FH protein (p.Cys434Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hereditary leiomyomatosis and renal cell cancer (HLRCC) (PMID: 25004247; Invitae). ClinVar contains an entry for this variant (Variation ID: 92453). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects FH function (PMID: 25004247). For these reasons, this variant has been classified as Pathogenic. |
| Ambry Genetics | RCV000492797 | SCV000581667 | pathogenic | Hereditary cancer-predisposing syndrome | 2022-12-01 | criteria provided, single submitter | clinical testing | The p.C434Y pathogenic mutation (also known as c.1301G>A), located in coding exon 9 of the FH gene, results from a G to A substitution at nucleotide position 1301. The cysteine at codon 434 is replaced by tyrosine, an amino acid with highly dissimilar properties. This alteration was identified in a 6-year-old boy who presented with pheochromocytoma and further in vitro analyses showed that this alteration is catalytically inactive (Clark GR et al. J. Clin. Endocrinol. Metab. 2014 Oct; 99(10):E2046-50). This alteration has been identified in multiple individuals with FH-related features, including cutaneous and uterine leiomyomas (Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). 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. |
| Myriad Genetics, |
RCV003315601 | SCV004018710 | likely pathogenic | Hereditary leiomyomatosis and renal cell cancer | 2023-07-10 | criteria provided, single submitter | clinical testing | This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 25004247]. Functional studies indicate this variant impacts protein function [PMID: 25004247]. This variant is expected to disrupt protein structure [Myriad internal data]. |
| Eurofins Ntd Llc |
RCV000078146 | SCV000109984 | uncertain significance | not provided | 2013-03-06 | flagged submission | clinical testing |