Submissions for variant NM_003119.4(SPG7):c.861+2dup

gnomAD frequency: 0.00004  dbSNP: rs771256761

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001060596	SCV001225296	pathogenic	Hereditary spastic paraplegia 7	2022-06-27	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 855345). This variant has been observed in individual(s) with clinical features of hereditary spastic paraplegia (PMID: 22964162; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs771256761, gnomAD 0.002%). This sequence change falls in intron 6 of the SPG7 gene. It does not directly change the encoded amino acid sequence of the SPG7 protein. It affects a nucleotide within the consensus splice site.
Paris Brain Institute, Inserm - ICM	RCV001060596	SCV001451038	pathogenic	Hereditary spastic paraplegia 7		criteria provided, single submitter	clinical testing
GeneDx	RCV001548055	SCV001767904	pathogenic	not provided	2023-10-18	criteria provided, single submitter	clinical testing	Intronic +5 splice site variant in a gene for which loss-of-function is a known mechanism of disease, and both in silico predictors and evolutionary conservation support a deleterious effect; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22964162, 34758253)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001060596	SCV002766217	likely pathogenic	Hereditary spastic paraplegia 7	2022-11-26	criteria provided, single submitter	clinical testing	Variant summary: SPG7 c.861+2dupT alters a 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: Three predict the variant abolishes a canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8e-06 in 249420 control chromosomes (gnomAD). c.861+2dupT has been reported in the literature as a biallelic genotype in individuals affected with Spastic Paraplegia and spinocerebellar ataxia (van Gassen_2012, Hewamadduma_2018, van den Ameele_2021). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters have assessed the variant since 2014: one classified the variant as likely pathogenic and one as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Institute of Human Genetics, University Hospital of Duesseldorf	RCV001060596	SCV004046797	pathogenic	Hereditary spastic paraplegia 7		criteria provided, single submitter	not provided
Genomics England Pilot Project, Genomics England	RCV001060596	SCV001760388	likely pathogenic	Hereditary spastic paraplegia 7		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV001548055	SCV001808040	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001548055	SCV001929737	pathogenic	not provided		no assertion criteria provided	clinical testing