Total submissions: 9
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000198662 | SCV000251477 | likely pathogenic | not provided | 2024-07-29 | criteria provided, single submitter | clinical testing | Published functional studies suggest a reduction in enzyme activity for fumarate and malate conversion in vitro (PMID: 37255402); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34643235, 36211164, 37255402) |
| Labcorp Genetics |
RCV000198662 | SCV000825418 | pathogenic | not provided | 2024-12-26 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 350 of the FH protein (p.Arg350Trp). This variant is present in population databases (rs755436052, gnomAD 0.006%). This missense change has been observed in individual(s) with autosomal recessive fumarate hydratase deficiency (PMID: 34643235). ClinVar contains an entry for this variant (Variation ID: 214418). 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%. For these reasons, this variant has been classified as Pathogenic. |
| Department Of Genetics, |
RCV000696839 | SCV000891505 | likely pathogenic | Fumarase deficiency | 2024-06-12 | criteria provided, single submitter | curation | |
| Illumina Laboratory Services, |
RCV000696839 | SCV001257490 | uncertain significance | Fumarase deficiency | 2017-04-27 | criteria provided, single submitter | clinical testing | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. |
| Institute for Clinical Genetics, |
RCV000198662 | SCV002010138 | uncertain significance | not provided | 2021-11-03 | criteria provided, single submitter | clinical testing | |
| Center for Genomic Medicine, |
RCV002465557 | SCV002760534 | uncertain significance | not specified | 2023-08-15 | criteria provided, single submitter | clinical testing | |
| Institute of Human Genetics Munich, |
RCV000696839 | SCV002764700 | likely pathogenic | Fumarase deficiency | 2020-12-02 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV003165454 | SCV003855149 | uncertain significance | Hereditary cancer-predisposing syndrome | 2024-02-16 | criteria provided, single submitter | clinical testing | The p.R350W variant (also known as c.1048C>T), located in coding exon 7 of the FH gene, results from a C to T substitution at nucleotide position 1048. The arginine at codon 350 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration was found in a homozygous state in a proband meeting clinical criteria for FH deficiency (Jasinge E et al. Lab Med, 2022 May;53:e48-e50). 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 available evidence, the clinical significance of this alteration remains unclear. |
| Baylor Genetics | RCV000696839 | SCV005057764 | likely pathogenic | Fumarase deficiency | 2024-01-25 | criteria provided, single submitter | clinical testing |