Submissions for variant NM_014946.4(SPAST):c.1081C>T (p.Pro361Ser)

dbSNP: rs1553315350

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001911794	SCV002175563	pathogenic	Hereditary spastic paraplegia 4	2021-07-26	criteria provided, single submitter	clinical testing	This variant disrupts the p.Pro361 amino acid residue in SPAST. Other variant(s) that disrupt this residue have been observed in individuals with SPAST-related conditions (PMID: 16788734, 19494379), which suggests that this may be a clinically significant amino acid residue. 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. This variant has been observed in individual(s) with autosomal dominant hereditary spastic paraplegia (PMID: 18701882, 25341883, Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with serine at codon 361 of the SPAST protein (p.Pro361Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. For these reasons, this variant has been classified as Pathogenic.
Neuberg Centre For Genomic Medicine, NCGM	RCV001911794	SCV005061099	pathogenic	Hereditary spastic paraplegia 4		criteria provided, single submitter	clinical testing	The observed missense variant c.1081C>T(p.Pro361Ser) in SPAST gene has been reported previously in individuals with spastic paraplegia (Shoukier M, et al., 2009). This variant disrupts the p.Pro361 amino acid residue in SPAST. Other variants that disrupt this residue has been observed in individuals with SPAST-related conditions (Luo Y, et al., 2014).The c.1081C>T variant is absent in gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic. The amino acid Proline at position 361 is changed to a Serine changing protein sequence and it might alter its composition and physico-chemical properties. Multiple lines of computational evidence (Polyphen, SIFT and MutationTaster) predict a damaging effect on protein structure and function for this variant. The amino acid change p.Pro361Ser in SPAST is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.