Submissions for variant NM_025137.4(SPG11):c.7000-3_7000-2insAGG

dbSNP: rs312262787

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000034256	SCV001204731	pathogenic	Hereditary spastic paraplegia 11	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change falls in intron 38 of the SPG11 gene. It does not directly change the encoded amino acid sequence of the SPG11 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs312262787, gnomAD 0.0009%). This variant has been observed in individual(s) with clinical features of hereditary spastic paraplegia (PMID: 19196735; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 41355). Studies have shown that this variant results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 19196735). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003323368	SCV004029724	likely pathogenic	Hereditary spastic paraplegia	2023-07-03	criteria provided, single submitter	clinical testing	Variant summary: SPG11 c.7000-3_7000-2insGGA introduces 3 nucleotides 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: four predict the variant abolishes a 3' acceptor site, and four predict the variant creates a 3' acceptor site four nucleotides upstream, potentially leading to a frameshift. At least one publication reports experimental evidence supporting these predictions, finding that the variant affects mRNA splicing through the generation of a new 3' acceptor site that introduces four nucleotides and leads to a frameshift (p.Ala2334GlufsX6; Crimella_2009). The variant allele was found at a frequency of 8e-06 in 250878 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7000-3_7000-2insGGA has been reported in the literature in at least two compound heterozygous siblings affected with Hereditary Spastic Paraplegia (e.g., Crimella_2009). These data indicate that the variant may be associated with disease. The following publication was ascertained in the context of this evaluation (PMID: 19196735). One submitter has reported clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
GeneReviews	RCV000034256	SCV000058196	pathologic	Hereditary spastic paraplegia 11	2013-01-31	no assertion criteria provided	curation	Converted during submission to Pathogenic.