ClinVar Miner

Submissions for variant NM_014946.3(SPAST):c.1676G>A (p.Gly559Asp) (rs864622179)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000432874 SCV000615390 pathogenic not provided 2018-08-20 criteria provided, single submitter clinical testing
GeneDx RCV000432874 SCV000521176 likely pathogenic not provided 2016-12-23 criteria provided, single submitter clinical testing The G559D has been reported multiple times in individuals with spastic paraplegia (including Hentati et al., 2000;Meijer et al., 2002, McCorquodale et al., 2011). It was not observed in approximately 6,500 individuals of Europeanand African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benignvariant in these populations. The G559D 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 other properties. Thissubstitution alters a conserved position in the AAA domain of the SPAST protein, which has been demonstrated tobe an important functional domain for microtubule disassembly (Errico et al., 2002; Solowska et al., 2015). In silicoanalysis is inconsistent in its predictions as to whether or not the variant is damaging to the proteinstructure/function. Therefore, the G559D variant is likely pathogenic; however, the possibility that it is benigncannot be completely excluded.
Invitae RCV000205236 SCV000259582 likely pathogenic Spastic paraplegia 4, autosomal dominant 2017-12-13 criteria provided, single submitter clinical testing This sequence change replaces glycine with aspartic acid at codon 559 of the SPAST protein (p.Gly559Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has been reported in many (>10) families affected with hereditary spastic paraplegia, the majority of whom were of French Canadian descent (PMID: 11087788, 11843700, 15248095, 17598600, 22960362, 20718791). This variant is also known as Gly527Asp, 1583G>A and c.G1801A in the literature. ClinVar contains an entry for this variant (Variation ID: 219608). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
SIB Swiss Institute of Bioinformatics RCV000205236 SCV000883277 uncertain significance Spastic paraplegia 4, autosomal dominant 2018-10-15 criteria provided, single submitter curation This variant is interpreted as Uncertain Significance - Insufficient Evidence, for Spastic paraplegia 4, autosomal dominant. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP1 => Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (https://www.ncbi.nlm.nih.gov/pubmed/11843700).

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