Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000644893 | SCV000766611 | pathogenic | Hereditary spastic paraplegia 4 | 2022-06-09 | criteria provided, single submitter | clinical testing | This missense change has been observed in individuals with clinical features of spastic paraplegia (Invitae). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg450 amino acid residue in SPAST. Other variant(s) that disrupt this residue have been observed in individuals with SPAST-related conditions (PMID: 21546041; Invitae), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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 expected to disrupt SPAST protein function. ClinVar contains an entry for this variant (Variation ID: 536442). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 450 of the SPAST protein (p.Arg450Gly). |
| Greenwood Genetic Center Diagnostic Laboratories, |
RCV000644893 | SCV002061744 | likely pathogenic | Hereditary spastic paraplegia 4 | 2021-12-01 | criteria provided, single submitter | clinical testing | PM5, PM2, PM1, PP3 |
| Concord Molecular Medicine Laboratory, |
RCV000644893 | SCV004012071 | pathogenic | Hereditary spastic paraplegia 4 | 2024-02-20 | criteria provided, single submitter | clinical testing | This variant has been detected in an affected individual and segregation study on both parents confirmed the variant to be de novo. In silico analysis by REVEL suggests this variant to be damaging (REVEL: 0.898). It is located in the critical core ATPase AAA-type domain (IPR003959) and in a mutational hot spot. The variation is absent in control population (GnomAD). Another amino acid changes in the same residue location has been observed in individuals with HSP (PMID: 21546041). |