ClinVar Miner

Submissions for variant NM_014946.3(SPAST):c.1477G>C (p.Asp493His) (rs1060499939)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000476656 SCV000645348 uncertain significance Spastic paraplegia 4, autosomal dominant 2017-04-10 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with histidine at codon 493 of the SPAST protein (p.Asp493His). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and histidine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a SPAST-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. A different missense substitution at this codon (p.Asp493Gly) has been reported to segregate with hereditary spastic paraplegia (HSP) in a single family (PMID: 16682546), but the clinical significance of this variant is uncertain. In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.
TIDEX, University of British Columbia RCV000476656 SCV000540926 likely pathogenic Spastic paraplegia 4, autosomal dominant 2017-04-12 criteria provided, single submitter research There is a second alternative allele (T) as this same base pair location in this patient.

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