Submissions for variant NM_025137.4(SPG11):c.6739_6742del (p.Glu2247fs)

dbSNP: rs312262782

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000034249	SCV000545194	pathogenic	Hereditary spastic paraplegia 11	2024-01-26	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu2247Leufs*14) 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 (rs312262782, gnomAD 0.009%). This premature translational stop signal has been observed in individuals with hereditary spastic paraplegia (PMID: 18079167, 20301389, 20571989, 23443022, 26556829). ClinVar contains an entry for this variant (Variation ID: 41348). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000493252	SCV000583291	pathogenic	not provided	2022-11-19	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20571989, 18079167, 26556829, 20390432, 31980526, 27016404, 35572931)
Department of Biochemistry, Faculty of Medicine, University of Khartoum	RCV000034249	SCV002573705	pathogenic	Hereditary spastic paraplegia 11		criteria provided, single submitter	research	Found in trans with another loss-of-function variant
Ambry Genetics	RCV002362609	SCV002666952	pathogenic	Inborn genetic diseases	2022-04-15	criteria provided, single submitter	clinical testing	The c.6739_6742delGAGT pathogenic mutation, located in coding exon 36 of the SPG11 gene, results from a deletion of 4 nucleotides at nucleotide positions 6739 to 6742, causing a translational frameshift with a predicted alternate stop codon (p.E2247Lfs*14). This alteration has been detected as compound heterozygous or homozygous in multiple unrelated individuals with SPG11-related neurologic disorders (Stevanin G et al. Brain, 2008 Mar;131:772-84; de Bot ST et al. Eur J Hum Genet, 2013 Nov;21:1312-5; Denora PS et al. Brain, 2016 06;139:1723-34; Montecchiani C et al. Brain, 2016 Jan;139:73-85). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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	RCV000034249	SCV002763674	pathogenic	Hereditary spastic paraplegia 11		criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002490455	SCV002793437	pathogenic	Amyotrophic lateral sclerosis type 5; Hereditary spastic paraplegia 11; Charcot-Marie-Tooth disease axonal type 2X	2021-12-08	criteria provided, single submitter	clinical testing
GeneReviews	RCV000034249	SCV000058189	not provided	Hereditary spastic paraplegia 11		no assertion provided	literature only