Submissions for variant NM_025137.4(SPG11):c.5989_5992del (p.Leu1997fs)

dbSNP: rs312262776

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001095781	SCV001251629	pathogenic	SPG11-related spastic paraplegia	2020-02-27	criteria provided, single submitter	clinical testing	The SPG11 c.5989_5992delCTGT (p.Leu1997MetfsTer60) variant results in a frameshift and is predicted to result in a premature truncation of the protein. This variant has been reported in six individuals from four unrelated families diagnosed with spastic paraplegia, including in a homozygous state in four individuals from two consanguineous families and in a compound heterozygous state with a second predicted null variant in two individuals (Stevanin et al. 2008; Paisan-Ruiz et al. 2008; Stromillo et al. 2011; Conceicao Pereira et al. 2012). Control data are unavailable for this variant, which is reported at a frequency of 0.000026 in the European (non-Finnish) population of the Genome Aggregation Consortium. Based on the predicted truncating nature of the variant, the reported cases in the literature, and the variant's rarity, the p.Leu1997MetfsTer60 variant is classified as pathogenic for SPG11-related spastic paraplegia.
Invitae	RCV000034236	SCV001394007	pathogenic	Hereditary spastic paraplegia 11	2024-01-06	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu1997Metfs*60) 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 (rs312262776, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with hereditary spastic paraplegia (PMID: 18079167, 18337587, 22237444). 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. This variant is also known as c.5985delCTGT and p.L1997MfsX2056. ClinVar contains an entry for this variant (Variation ID: 41335). For these reasons, this variant has been classified as Pathogenic.
Paris Brain Institute, Inserm - ICM	RCV000034236	SCV001451265	pathogenic	Hereditary spastic paraplegia 11		criteria provided, single submitter	clinical testing
GeneDx	RCV002254905	SCV002526189	likely pathogenic	not provided	2022-06-07	criteria provided, single submitter	clinical testing	Identified in individuals with features of spastic paraplegia type 11, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (Stevanin et al., 2008; Stromillo et al., 2011); 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 a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21625935, 31589614, 18079167)
Genome-Nilou Lab	RCV000034236	SCV002763776	likely pathogenic	Hereditary spastic paraplegia 11		criteria provided, single submitter	clinical testing
Neurogenomics Lab, Neuroscience Institute, University Of Cape Town	RCV000034236	SCV003930339	pathogenic	Hereditary spastic paraplegia 11	2024-05-22	criteria provided, single submitter	research	PM2_supporting: the highest population allele frequency in gnomAD v4.0 is 0.00008001 (0.008%; 5/62492 alleles in Remaining population) and in gnomAD v3.1.2 is 0.00002413 (0.002%; 1/ 41440 alleles in African/African American population) and the variant is absent from an internal database of 1074 control alleles. PVS1 met: null variant (nonsense or frameshift variant, predicted to undergo NMD, exon is present in biologically-relevant transcript) in a gene where LOF is a known mechanism of disease. PS4 not evaluated as literature probands counted under PM3. PP1_moderate: variant segregates with 2 informative meioses in 1 family. PM3_strong: 3 points awarded for 2 homozygous occurrences, 2 observations with pathogenic variant but phase unknown and 1 observation with pathogenic variant confirmed in trans (PMID 21625935, 18079167, 24571105, 18337587, 22237444). Sequencing funded by the International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD): https://www.ucl.ac.uk/genomic-medicine-neuromuscular-diseases/.
Mayo Clinic Laboratories, Mayo Clinic	RCV002254905	SCV004224001	pathogenic	not provided	2022-12-06	criteria provided, single submitter	clinical testing	PM2, PM3, PVS1
GeneReviews	RCV000034236	SCV000058178	not provided	Hereditary spastic paraplegia 11		no assertion provided	literature only
GenomeConnect - Invitae Patient Insights Network	RCV003483446	SCV004228761	not provided	Amyotrophic lateral sclerosis type 5; Hereditary spastic paraplegia 11; Charcot-Marie-Tooth disease axonal type 2X		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 03-05-2021 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.