ClinVar Miner

Submissions for variant NM_014946.3(SPAST):c.289C>A (p.Pro97Thr) (rs372005558)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000611456 SCV000729343 likely benign not specified 2018-01-17 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Illumina Clinical Services Laboratory,Illumina RCV000263474 SCV000430099 likely benign Spastic paraplegia, autosomal dominant 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000205409 SCV000260246 uncertain significance Spastic paraplegia 4, autosomal dominant 2015-08-27 criteria provided, single submitter clinical testing This sequence change replaces proline with threonine at codon 97 of the SPAST protein (p.Pro97Thr). The proline residue is moderately conserved and there is a small physicochemical difference between proline and threonine. This variant is present in population databases (rs372005558, 0.09%) and has been reported in the literature in individuals affected with hereditary spastic paraplegia (PMID: 20718791). In this study, one individual was also reported to have a pathogenic, truncating variant in SPAST which suggests that the c.289 C>A variant is not the primary cause of disease in this individual. 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 tolerated, but these predictions have not been confirmed by published functional studies. In summary, this is a rare missense change that is not predicted to affect protein function or cause disease. However the evidence is insufficient at this time to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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