Submissions for variant NM_014946.4(SPAST):c.1774del (p.Lys591_Ile592insTer)

dbSNP: rs1680185365

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV001288792	SCV001476151	pathogenic	not provided	2020-02-04	criteria provided, single submitter	clinical testing	The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and not found in general population data.
Mayo Clinic Laboratories, Mayo Clinic	RCV001288792	SCV001715443	pathogenic	not provided	2020-03-11	criteria provided, single submitter	clinical testing	PVS1_strong, PS4_moderate, PM1, PM2
Labcorp Genetics (formerly Invitae), Labcorp	RCV002542997	SCV003249977	pathogenic	Hereditary spastic paraplegia 4	2023-01-15	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the SPAST protein in which other variant(s) (p.Ile592Lys) have been determined to be pathogenic (PMID: 31157359; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 994982). This variant is also known as p.Ile592fs. This premature translational stop signal has been observed in individuals with hereditary spastic paraplegia (PMID: 26208798, 26671083). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ile592*) in the SPAST gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 25 amino acid(s) of the SPAST protein.
Molecular Genetics, Royal Melbourne Hospital	RCV002542997	SCV004812770	likely pathogenic	Hereditary spastic paraplegia 4	2023-03-30	criteria provided, single submitter	clinical testing	This sequence change in SPAST is a frameshift variant that may cause a premature stop codon, p.(Ile592*), that is predicted to escape nonsense mediated decay and remove <10% of the protein, however it is a truncation of a functionally important region (AAA domain, amino acids 342-599) in a gene where loss-of-function is an established disease mechanism (PMID: 32979422; ClinGen). This variant is absent from gnomAD v2.1 and v3.1. This variant has been reported in at least two probands with pure hereditary spastic paraplegia (PMID: 26208798, 26671083). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PVS1_Strong, PS4_Supporting, PM2_Supporting.