Submissions for variant NM_025137.4(SPG11):c.1203del (p.Asp402fs)

dbSNP: rs312262722

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000034169	SCV000942294	pathogenic	Hereditary spastic paraplegia 11	2023-05-20	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asp402Ilefs*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 (rs312262722, gnomAD 0.003%). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 41268). This premature translational stop signal has been observed in individual(s) with autosomal recessive hereditary spastic paraplegia (PMID: 17322883, 19105190, 19196735, 24833714). 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.
Paris Brain Institute, Inserm - ICM	RCV000034169	SCV001451242	pathogenic	Hereditary spastic paraplegia 11		criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002345266	SCV002651665	pathogenic	Inborn genetic diseases	2022-05-07	criteria provided, single submitter	clinical testing	The c.1203delA pathogenic mutation, located in coding exon 6 of the SPG11 gene, results from a deletion of one nucleotide at nucleotide position 1203, causing a translational frameshift with a predicted alternate stop codon (p.D402Ifs*14). This alteration has been detected as homozygous or compound heterozygous with another SPG11 alteration in multiple individuals with hereditary spastic paraplegia type 11 (SPG11) (Vural A et al. Mov Disord, 2021 07;36:1676-1688). (Chen X et al. BMC Neurol, 2020 Jan;20:2; D'Amore A et al. Front Neurol, 2018 Dec;9:981; Pensato V et al. Brain, 2014 Jul;137:1907-20; de Bot ST et al. Eur J Hum Genet, 2013 Nov;21:1312-5; Crimella C et al. J Med Genet, 2009 May;46:345-51; Denora PS et al. Hum Mutat, 2009 Mar;30:E500-19; Stevanin G et al. Nat Genet, 2007 Mar;39:366-72). 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	RCV000034169	SCV002764164	pathogenic	Hereditary spastic paraplegia 11		criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003398591	SCV004104622	pathogenic	SPG11-related condition	2023-08-30	criteria provided, single submitter	clinical testing	The SPG11 c.1203delA variant is predicted to result in a frameshift and premature protein termination (p.Asp402Ilefs*14). This variant was reported in the homozygous and compound heterozygous state in multiple patients with autosomal recessive spastic paraplegia (Stevanin et al. 2007. PubMed ID: 17322883; D'Amore A et al. 2018. PubMed ID: 30564185; Table S1, Vural et al. 2021. PubMed ID: 33624863). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/15-44943941-CT-C). Frameshift variants in SPG11 are expected to be pathogenic. This variant is interpreted as pathogenic.
GeneReviews	RCV000034169	SCV000058107	not provided	Hereditary spastic paraplegia 11		no assertion provided	literature only