ClinVar Miner

Submissions for variant NM_014946.3(SPAST):c.1331A>G (p.Asp444Gly) (rs886041597)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000360918 SCV000330292 pathogenic not provided 2016-07-07 criteria provided, single submitter clinical testing The D444G variant has been reported previously in an individual with pure hereditary spastic paraplegia (Elert-Dobkowska et al., 2015). It was not observed in approximately 6,500 individuals of European and African Americanancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in thesepopulations. The D444G variant is a non-conservative amino acid substitution, which is likely to impact secondaryprotein structure as these residues differ in polarity, charge, size and/or other properties. This substitution alters aconserved position in the AAA domain of the SPAST protein, which has been demonstrated to be an importantfunctional domain for microtubule disassembly (Errico et al., 2002; Solowska et al., 2015). Missense variants at thesame codon (D444E, D444N) as well as missense variants in neighboring codons (E442K, E442A, S445N, S445R)have been reported in the Human Gene Mutation Database in association with spastic paraplegia (Stenson et al.,2014), Additionally, in silico analysis predicts this variant is probably damaging to the protein structure/function.

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