Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV002561926 | SCV001389494 | uncertain significance | not provided | 2019-07-10 | criteria provided, single submitter | clinical testing | 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). This variant has not been reported in the literature in individuals with FH-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with glutamic acid at codon 339 of the FH protein (p.Ala339Glu). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and glutamic acid. |
| Ambry Genetics | RCV002339570 | SCV002643532 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2017-03-10 | criteria provided, single submitter | clinical testing | The p.A339E variant (also known as c.1016C>A), located in coding exon 7 of the FH gene, results from a C to A substitution at nucleotide position 1016. The alanine at codon 339 is replaced by glutamic acid, an amino acid with dissimilar properties. This variant has been observed in at least one individual who meets clinical diagnostic criteria for Hereditary Leiomyomatosis and Renal Cell Cancer Syndrome (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Internal structural analysis indicates that substitution is predicted to be more destabilizing than other nearby, known pathogenic variants (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic. |