ClinVar Miner

Submissions for variant NM_014946.4(SPAST):c.1550T>C (p.Leu517Ser)

dbSNP: rs2148759388
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Paris Brain Institute, Inserm - ICM RCV001391343 SCV001451002 pathogenic Hereditary spastic paraplegia 4 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001391343 SCV004252354 uncertain significance Hereditary spastic paraplegia 4 2024-07-31 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 517 of the SPAST protein (p.Leu517Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of hereditary spastic paraplegia (PMID: 34983064; Invitae). ClinVar contains an entry for this variant (Variation ID: 988971). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SPAST protein function with a positive predictive value of 80%. This variant disrupts the p.Leu517 amino acid residue in SPAST. Other variant(s) that disrupt this residue have been observed in individuals with SPAST-related conditions (PMID: 27077743; Invitae), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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