Submissions for variant NM_014946.4(SPAST):c.1537-11A>G

dbSNP: rs549538513

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000685954	SCV000813455	uncertain significance	Hereditary spastic paraplegia 4	2018-01-24	criteria provided, single submitter	clinical testing	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. Experimental studies using RT-PCR shows that this intronic change results in a leaky splicing defect with expression of normal transcripts as well as transcripts lacking exon 13 or exons 13-14 (PMID: 26208798). This variant has been reported in an individual with hereditary spastic paraplegia (PMID: 26208798). This variant is not present in population databases (ExAC no frequency). This sequence change falls in intron 13 of the SPAST gene. It does not directly change the encoded amino acid sequence of the SPAST protein.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000685954	SCV002548510	likely pathogenic	Hereditary spastic paraplegia 4	2022-05-18	criteria provided, single submitter	clinical testing	Variant summary: SPAST c.1537-11A>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 3' acceptor site, while two predict the variant weakens a 3' acceptor site and two predict the variant creates a cryptic 3' acceptor site. One publication reporting RT-PCR analysis showed a patient with the variant had leaky splicing, having bands for the normal splicing product, a product with exon 14 deleted and a product with exons 13-14 deleted (Park_2015). The patient from this report had HSP symptoms beginning at the age of 26 years, his mother had similar symptoms but was not genetically tested, while his younger brother carried the variant but did not have any symptoms of the disease. The authors state the brothers young age may be the reason he did not have symptoms, or reduced penetrance due to the leaky splice effect of the variant. Additionally, the variant was reported in another pair of brothers, with only one brother having his HSP phenotype described in the report (Bae_2021). These data indicate that the variant may be associated with disease. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.