ClinVar Miner

Submissions for variant NM_014946.3(SPAST):c.1494G>C (p.Arg498Ser) (rs1553319075)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000644884 SCV000766602 pathogenic Spastic paraplegia 4, autosomal dominant 2018-11-22 criteria provided, single submitter clinical testing This sequence change replaces arginine with serine at codon 498 of the SPAST protein (p.Arg498Ser). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with spastic paraplegia, including at least one individual in whom this variant was found to be de novo (PMID: 26671083, Invitae). ClinVar contains an entry for this variant (Variation ID: 536434). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant disrupts the p.Arg498 amino acid residue in SPAST. Other variants that disrupt this residue have been observed in individuals with SPAST-related disease (PMID: 16832076, 20932283, 28572275), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.

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