Submissions for variant NM_025137.3(SPG11):c.5456_5457del (p.Glu1819Alafs)

dbSNP: rs312262764

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000034269	SCV000827609	pathogenic	Hereditary spastic paraplegia 11	2023-12-14	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu1819Alafs*10) in the SPG11 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SPG11 are known to be pathogenic (PMID: 19105190, 20110243, 22154821, 26556829). This variant is present in population databases (rs749819954, gnomAD 0.007%). This premature translational stop signal has been observed in individuals with autosomal recessive hereditary spastic paraplegia (PMID: 18337587; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 41368). For these reasons, this variant has been classified as Pathogenic.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001847641	SCV002105734	pathogenic	Hereditary spastic paraplegia	2020-03-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002345267	SCV002649117	pathogenic	Inborn genetic diseases	2021-02-03	criteria provided, single submitter	clinical testing	The c.5456_5457delAG pathogenic mutation, located in coding exon 30 of the SPG11 gene, results from a deletion of two nucleotides at nucleotide positions 5456 to 5457, causing a translational frameshift with a predicted alternate stop codon (p.E1819Afs*10). This mutation was detected in a compound heterozygous state with other truncating alterations in SPG11 in two siblings and one additional unrelated individual, all of whom had phenotypes consistent with hereditary spastic paraplegia (Paisan-Ruiz C et al. Neurology, 2008 Apr;70:1384-9; Kara E et al. Brain, 2016 07;139:1904-18). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Genome-Nilou Lab	RCV000034269	SCV002763832	pathogenic	Hereditary spastic paraplegia 11		criteria provided, single submitter	clinical testing
GeneReviews	RCV000034269	SCV000058209	pathologic	Hereditary spastic paraplegia 11	2013-01-31	no assertion criteria provided	curation	Converted during submission to Pathogenic.