Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000479836 | SCV000570817 | likely pathogenic | not provided | 2016-07-21 | criteria provided, single submitter | clinical testing | The G409C variant has notbeen published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge.It was not observed in approximately 6,500 individuals of European and African American ancestry inthe NHLBI Exome Sequencing Project, indicating it is not a common benign variant in thesepopulations. The G409C variant is a non-conservative amino acid substitution, which is likely toimpact secondary protein structure as these residues differ in polarity, charge, size and/or otherproperties. This substitution occurs at a position that is conserved across species. Missense variants innearby residues and at the same codon (G409D) have been reported in the Human Gene MutationDatabase in association with spastic paraplegia (Stenson et al., 2014), supporting the functionalimportance of this region of the protein. In silico analysis predicts this variant is probably damagingto the protein structure/function. Therefore, this variant is likely pathogenic; however, the possibilitythat it is benign cannot be excluded. |
| Labcorp Genetics |
RCV002526601 | SCV003234612 | pathogenic | Hereditary spastic paraplegia 3A | 2022-10-01 | criteria provided, single submitter | clinical testing | 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 ATL1 protein function. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly409 amino acid residue in ATL1. Other variant(s) that disrupt this residue have been observed in individuals with ATL1-related conditions (PMID: 25193411; Invitae), which suggests that this may be a clinically significant amino acid residue. ClinVar contains an entry for this variant (Variation ID: 421566). This missense change has been observed in individual(s) with hereditary spastic paraplegia (Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 409 of the ATL1 protein (p.Gly409Cys). |