ClinVar Miner

Submissions for variant NM_014946.4(SPAST):c.1775T>A (p.Ile592Lys)

dbSNP: rs1553321237
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000644898 SCV000766616 pathogenic Hereditary spastic paraplegia 4 2021-04-15 criteria provided, single submitter clinical testing 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 and their clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individual(s) with hereditary spastic paraplegia (PMID: 31157359, Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 536446). This sequence change replaces isoleucine with lysine at codon 592 of the SPAST protein (p.Ile592Lys). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and lysine. This variant is not present in population databases (ExAC no frequency).
Mayo Clinic Laboratories, Mayo Clinic RCV001508983 SCV001715444 likely pathogenic not provided 2020-02-07 criteria provided, single submitter clinical testing PM1, PM2, PM6, PP3
GeneDx RCV001508983 SCV001819742 pathogenic not provided 2019-06-20 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 31157359)
Developmental and Behavioral Pediatrics, First Affiliated Hospital of Jilin University RCV000644898 SCV002576304 likely pathogenic Hereditary spastic paraplegia 4 no assertion criteria provided provider interpretation

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