Submissions for variant NM_014946.4(SPAST):c.1724_1725insGCCGGGCGCGGTGGCTCACGCCTGTAATCCCAGCACTTTGGGAGGCCGAGGCGGGCGGATCACGAGGTCANNNNNNNNNNNNAAAAAAAAAAAAAAAAAAGAATATGTCTGCCAG (p.Ser575fs)

dbSNP: rs2148762802

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001376855	SCV001574041	pathogenic	Hereditary spastic paraplegia 4	2024-10-01	criteria provided, single submitter	clinical testing	This sequence change inserts a large fragment of DNA, likely a transposable element, in exon 16 of the SPAST gene (c.1724_1725insAlu), causing a frameshift at codon 575 (p.Ser575fs). The exact size and sequence of the insertion cannot be determined by the current assay. However, the insertion is expected to result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). A similar variant has been observed in individual(s) with hereditary spastic paraplegia (internal data). ClinVar contains an entry for this variant (Variation ID: 1065986). This variant disrupts a region of the SPAST protein in which other variant(s) (p.Thr615Ile) have been determined to be pathogenic (PMID: 12124993; internal data). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Retrotransposon insertions including LINE1 (L1), Alu, and SVA (SINE-VNTR-Alu) have been reported to disrupt protein function (PMID: 19763152, 20307669, 22406018). However the effect of this particular variant is unknown. For these reasons, this variant has been classified as Pathogenic.