Submissions for variant NM_014946.4(SPAST):c.1170G>A (p.Met390Ile)

dbSNP: rs1131691971

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000494283	SCV000583250	likely pathogenic	not provided	2016-08-11	criteria provided, single submitter	clinical testing	The M390I variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The M390I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a conserved position in the AAA domain of the SPAST protein, which has been demonstrated to be an important functional domain for microtubule disassembly (Errico et al., 2002; Blackstone et al., 2011; Solowska et al., 2015). Additionally, a missense variant at the same residue (M390V) and many variants in nearby residues have been reported in the Human Gene Mutation Database in association with spastic paraplegia. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the above information, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001364718	SCV001560881	pathogenic	Hereditary spastic paraplegia 4	2021-04-02	criteria provided, single submitter	clinical testing	This variant disrupts the p.Met390 amino acid residue in SPAST. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14732620, 20932283). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 clinical features of hereditary spastic paraplegia (PMID: Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 430448). This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with isoleucine at codon 390 of the SPAST protein (p.Met390Ile). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and isoleucine. For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV004730958	SCV005335754	likely pathogenic	SPAST-related disorder	2024-06-26	no assertion criteria provided	clinical testing	The SPAST c.1170G>A variant is predicted to result in the amino acid substitution p.Met390Ile. To our knowledge, this variant has not been reported in the literature. Several alternate substitutions of this amino acid residue (p.Met390Val, p.Met390Thr, p.Met390Arg, and p.Met390Lys) have been reported (often as de novo) in individuals with spastic paraplegia (Table S2, Dong et al. 2020. PubMed ID: 32005694; Chelban et al. 2017. PubMed ID: 28572275; Schieving et al. 2019. PubMed ID: 31157359; Table S2, Zech et al. 2020. PubMed ID: 33098801). This p.Met390Ile substitution is predicted damaging. This variant has not been reported in a large population database, indicating this variant is rare. This variant has been listed as pathogenic and likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/430448/). Given the evidence, we interpret this variant as likely pathogenic.