Submissions for variant NM_025137.4(SPG11):c.6832_6833del (p.Ser2278fs)

dbSNP: rs312262784

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Mendelics	RCV000034252	SCV001139567	pathogenic	Hereditary spastic paraplegia 11	2019-05-28	criteria provided, single submitter	clinical testing
Invitae	RCV000034252	SCV001399998	pathogenic	Hereditary spastic paraplegia 11	2024-01-03	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser2278Leufs*61) 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 (rs312262784, gnomAD 0.006%). This premature translational stop signal has been observed in individuals with SPG11-related conditions (PMID: 18079167, 21035867, 22237444, 26556829, 27084228). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 41351). For these reasons, this variant has been classified as Pathogenic.
Consultorio y Laboratorio de Neurogenética, Hospital JM Ramos Mejia	RCV000034252	SCV001424048	pathogenic	Hereditary spastic paraplegia 11		criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001781341	SCV002021931	pathogenic	not provided	2021-03-06	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002362610	SCV002664753	pathogenic	Inborn genetic diseases	2021-11-15	criteria provided, single submitter	clinical testing	The c.6832_6833delAG pathogenic mutation, located in coding exon 37 of the SPG11 gene, results from a deletion of two nucleotides at nucleotide positions 6832 to 6833, causing a translational frameshift with a predicted alternate stop codon (p.S2278Lfs*61). This variant has been reported in the homozygous and compound heterozygous states in multiple patients with hereditary spastic paraplegia and/or Charcot-Marie-Tooth disease (Stevanin G et al. Brain, 2008 Mar;131:772-84; Conceição Pereira M et al. Genet Med, 2012 Jan;14:143-51; Balicza P et al. J Neurol Sci, 2016 May;364:116-21; 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). 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	RCV000034252	SCV002763666	pathogenic	Hereditary spastic paraplegia 11		criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV001781341	SCV002771253	pathogenic	not provided	2021-12-22	criteria provided, single submitter	clinical testing	This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000034252	SCV003761345	pathogenic	Hereditary spastic paraplegia 11	2023-01-25	criteria provided, single submitter	curation	The homozygous p.Ser2278LeufsTer61 variant in SPG11 was identified by our study in one individual with spastic paraplegia. The p.Ser2278LeufsTer61 variant in SPG11 has been previously reported in 4 unrelated individuals with hereditary spastic paraplegia 11 (PMID: 27084228, PMID: 26556829, PMID: 22237444, PMID: 18079167) and segregated with disease in 4 affected relatives from 2 families (PMID: 26556829, PMID: 18079167), but has been identified in 0.005% (1/18390) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs312262784). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. Of these 4 affected unrelated individuals PMID: 27084228, PMID: 26556829, PMID: 22237444, PMID: 18079167), two were homozygotes (PMID: 18079167, PMID: 26556829), one was a compound heterozygote who carried a likely pathogenic variant in trans (PMID: 27084228) and one was a compound heterozygote who carried a likely pathogenic variant in unknown phase (PMID: 22237444). This variant has also been reported in ClinVar (Variation ID: 41351) and has been interpreted as pathogenic by multiple submitters. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 2278 and leads to a premature termination codon 61 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the SPG11 gene is an established disease mechanism in autosomal recessive spastic paraplegia 11. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive spastic paraplegia 11. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PM3_Strong, PP1_Moderate (Richards 2015).
GeneReviews	RCV000034252	SCV000058192	not provided	Hereditary spastic paraplegia 11		no assertion provided	literature only