ClinVar Miner

Submissions for variant NM_014946.3(SPAST):c.1216A>G (p.Ile406Val) (rs587777757)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000497406 SCV000589637 likely pathogenic not provided 2018-11-14 criteria provided, single submitter clinical testing A variant that is likely pathogenic has been identified in the SPAST gene. The c.1216 A>G has been previously reported in multiple individuals with HSP; however, functional characterization of the variant was not completed (Svenstrup et al., 2009; McDermott et al., 2006; de Bot et al., 2010). The c.1216 A>G variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Several in-silico splice prediction models predict that c.1216 A>G creates a cryptic donor site upstream of the natural donor site in intron 9 and may lead to abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. If c.1216 A>G does not alter splicing, it will result in the I406V missense change. This substitution alters a conserved position in the AAA domain of the SPAST protein, which has been demonstrated to be an important functional domain for microtubule disassembly (Errico et al., 2002; Blackstone et al., 2011; Solowska et al., 2015). Furthermore, missense variants at the same residue (I406R) and in nearby residues (F403L, S407R/I, A408V, A409T, S410R) have been reported in the Human Gene Mutation Database in association with SPAST-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. However, the I406V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
OMIM RCV000006029 SCV000026211 pathogenic Spastic paraplegia 4, autosomal dominant 2006-02-14 no assertion criteria provided literature only

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