Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Paris Brain Institute, |
RCV001361865 | SCV001450979 | pathogenic | Hereditary spastic paraplegia 4 | criteria provided, single submitter | clinical testing | ||
Invitae | RCV001361865 | SCV001557855 | uncertain significance | Hereditary spastic paraplegia 4 | 2020-02-04 | criteria provided, single submitter | clinical testing | This variant has been observed in individual(s) with hereditary spastic paraplegia (Invitae). 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.Leu447 amino acid residue in SPAST. Other variant(s) that disrupt this residue have been observed in individuals with SPAST-related conditions (PMID: 18701882), which suggests that this may be a clinically significant amino acid residue. 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 is not present in population databases (ExAC no frequency). This sequence change replaces leucine with serine at codon 447 of the SPAST protein (p.Leu447Ser). The leucine residue is highly conserved and there is a large physicochemical difference between leucine and serine. |
3billion | RCV001361865 | SCV002058765 | uncertain significance | Hereditary spastic paraplegia 4 | 2022-01-03 | criteria provided, single submitter | clinical testing | Same nucleotide change resulting in same amino acid change has been previously reported to be associated with SPAST related disorder (ClinVar ID: VCV000989174, PS1_P). A different missense change at the same codon has been reported to be associated with SPAST related disorder (PMID:18701882, PM5_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.879, 3CNET: 0.978, PP3_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline. |