Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000413571 | SCV000491392 | likely pathogenic | not provided | 2015-12-30 | criteria provided, single submitter | clinical testing | The E47K variant in the FA2H gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The E47K variant was not observed in approximately 4000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The E47K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. The E47K variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded. |
| Baylor Genetics | RCV001336096 | SCV001529392 | uncertain significance | Hereditary spastic paraplegia 35 | 2018-07-31 | criteria provided, single submitter | clinical testing | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. |
| Labcorp Genetics |
RCV001337611 | SCV001531218 | uncertain significance | Spastic paraplegia | 2021-07-26 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamic acid with lysine at codon 47 of the FA2H protein (p.Glu47Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This variant has not been reported in the literature in individuals with FA2H-related conditions. ClinVar contains an entry for this variant (Variation ID: 372860). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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. |