Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV001213823 | SCV001385473 | uncertain significance | Hereditary spastic paraplegia 4 | 2019-08-27 | criteria provided, single submitter | clinical testing | 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 disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with SPAST-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with lysine at codon 464 of the SPAST protein (p.Glu464Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. 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. This variant disrupts the p.Glu464 amino acid residue in SPAST. Other variant(s) that disrupt this residue (p.Glu464Asp, p.Glu464Ala) have been observed in individuals with SPAST-related conditions (PMID: 23252998, 20718791), which suggests that this may be a clinically significant amino acid residue. |
Genome Diagnostics Laboratory, |
RCV001847192 | SCV002105607 | likely pathogenic | Hereditary spastic paraplegia | 2020-03-01 | criteria provided, single submitter | clinical testing |