ClinVar Miner

Submissions for variant NM_014946.3(SPAST):c.1276C>G (p.Leu426Val) (rs1060502227)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000482415 SCV000568708 pathogenic not provided 2017-02-13 criteria provided, single submitter clinical testing The L426V variant in the SPAST gene has been reported previously in multiple unrelated individuals with childhood and adult onset hereditary spastic paraplegia (Fonknechten et al., 2000; Meijer et al., 2002; Alvarez et al., 2010; McCorquodale et al., 2011; Nanetti et al., 2012). Functional studies demonstrate that overexpression of the L426V variant results in constitutive binding to microtubules, and may potentially alter their regulation (Errico et al., 2001). The L426V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position, within the AAA ATPase domain, that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret L426V as a pathogenic variant.
Invitae RCV000459046 SCV000548909 pathogenic Spastic paraplegia 4, autosomal dominant 2018-12-21 criteria provided, single submitter clinical testing This sequence change replaces leucine with valine at codon 426 of the SPAST protein (p.Leu426Val). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in multiple individuals affected with autosomal dominant hereditary spastic paraplegia (PMID: 10699187, 11843700, 15841487, 20718791, 22960362). In one affected individual, this variant has been shown to arise de novo (PMID: 20932283). Experimental studies have shown that this missense variant alters the cellular localization of the SPAST protein in a manner similar to other known pathogenic missense variants (PMID: 11809724). For these reasons, this variant has been classified as Pathogenic.

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