Submissions for variant NM_025137.4(SPG11):c.3291+3A>G

gnomAD frequency: 0.00001  dbSNP: rs773192977

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001229274	SCV001401716	uncertain significance	Hereditary spastic paraplegia 11	2022-08-19	criteria provided, single submitter	clinical testing	This sequence change falls in intron 18 of the SPG11 gene. It does not directly change the encoded amino acid sequence of the SPG11 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs773192977, gnomAD 0.003%). This variant has been observed in individual(s) with hereditary spastic paraplegia (PMID: 33669240). ClinVar contains an entry for this variant (Variation ID: 956464). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
Ambry Genetics	RCV002322106	SCV002606048	uncertain significance	Inborn genetic diseases	2021-12-22	criteria provided, single submitter	clinical testing	The c.3291+3A>G intronic variant results from an A to G substitution 3 nucleotides after coding exon 18 in the SPG11 gene. This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003323823	SCV004029723	uncertain significance	not specified	2023-07-05	criteria provided, single submitter	clinical testing	Variant summary: SPG11 c.3291+3A>G alters a 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 weakens a 5' donor site and one predicts the variant has no significant impact on splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.2e-05 in 251400 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3291+3A>G has been reported in the literature as a compound heterozygous genotype in an individual affected with Hereditary Spastic Paraplegia (Risi_2021). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 33669240). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.