Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV001011782 | SCV001172144 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-12-27 | criteria provided, single submitter | clinical testing | The p.E499K variant (also known as c.1495G>A), located in coding exon 10 of the FH gene, results from a G to A substitution at nucleotide position 1495. The glutamic acid at codon 499 is replaced by lysine, an amino acid with similar properties. This variant has been reported in 1/1120 pediatric cancer patients who underwent whole genome sequencing and/or whole exome sequencing; this patient was diagnosed with adrenocortical carcinoma (Zhang J et al. N Engl J Med, 2015 Dec;373:2336-2346). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001585920 | SCV001821248 | uncertain significance | not specified | 2021-08-13 | criteria provided, single submitter | clinical testing | Variant summary: FH c.1495G>A (p.Glu499Lys) results in a conservative amino acid change located in the Fumarase C, C-terminal domain (IPR018951) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250106 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1495G>A has been reported in the literature as a "probably benign" variant in at-least one individual affected with Adenocortical carcinoma within a cohort of patients younger than 20 years of age (example, Zhang_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Leiomyomatosis And Renal Cell Cancer. At-least one co-occurrence with another pathogenic variant has been reported in the same case from the study ascertained above (TP53 c.1010G>A , p.R337H, Zhang_2015), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. |
| Invitae | RCV002549347 | SCV003246431 | uncertain significance | not provided | 2022-11-04 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 499 of the FH protein (p.Glu499Lys). This variant is present in population databases (rs750838853, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of FH-related conditions (PMID: 26580448). ClinVar contains an entry for this variant (Variation ID: 819323). 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 not expected to disrupt FH protein function. 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. |
| Natera, |
RCV001326411 | SCV002094174 | uncertain significance | Fumarase deficiency | 2020-09-15 | no assertion criteria provided | clinical testing |