Submissions for variant NM_025137.4(SPG11):c.3075dup (p.Glu1026fs)

dbSNP: rs312262752

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000001176	SCV000784243	pathogenic	Hereditary spastic paraplegia 11	2018-03-05	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000001176	SCV000823844	pathogenic	Hereditary spastic paraplegia 11	2024-11-05	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu1026Argfs*4) 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 (rs312262752, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with autosomal recessive juvenile amyotrophic lateral sclerosis, and hereditary spastic paraplegia (PMID: 18067136, 19105190, 19194956, 20110243, 27071356, 27084228, 28991695). It has also been observed to segregate with disease in related individuals. This variant is also known as c.3076insA, c.3076_3077insA, and c.3075_3076insA,. ClinVar contains an entry for this variant (Variation ID: 1117). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Paris Brain Institute, Inserm - ICM	RCV000001176	SCV001451255	pathogenic	Hereditary spastic paraplegia 11		criteria provided, single submitter	clinical testing
Kariminejad - Najmabadi Pathology & Genetics Center	RCV001813929	SCV001755384	pathogenic	Abnormal central motor function	2021-07-10	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV002247231	SCV002010947	pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV002247231	SCV002520053	pathogenic	not provided	2021-12-10	criteria provided, single submitter	clinical testing	PM2, PM3, PS4_moderate, PVS1_strong
Genome-Nilou Lab	RCV001762029	SCV002764002	pathogenic	Amyotrophic lateral sclerosis type 5		criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000001176	SCV002764003	pathogenic	Hereditary spastic paraplegia 11		criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000001176	SCV003761347	pathogenic	Hereditary spastic paraplegia 11	2023-01-25	criteria provided, single submitter	curation	The homozygous p.Glu1026ArgfsTer4 variant in SPG11 was identified by our study in two siblings with spastic paraplegia. The p.Glu1026ArgfsTer4 variant in SPG11 has been previously reported in 17 unrelated individuals with hereditary spastic paraplegia 11 (PMID: 29983107, PMID: 35906604, PMID: 35348942, PMID: 32383541, PMID: 18067136, PMID: 19105190, PMID: 19194956, PMID: 20110243, PMID: 27071356, PMID: 27084228, PMID: 28991695) and segregated with disease in 7 affected members from 3 families (PMID: 35348942, PMID: 19194956, PMID: 20110243), but has been identified in 0.01% (3/21626) of European (Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs312262752). 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 17 unrelated affected individuals (PMID: 29983107, PMID: 35906604, PMID: 35348942, PMID: 32383541, PMID: 18067136, PMID: 19105190, PMID: 19194956, PMID: 20110243, PMID: 27071356, PMID: 27084228, PMID: 28991695), 8 were homozygotes (PMID: 19194956, PMID: 20110243, PMID: 32383541, PMID: 18067136) and 8 were compound heterozygotes who carried pathogenic or likely pathogenic variants in trans (PMID: 29983107, PMID: 35906604, PMID: 35348942, PMID: 32383541, PMID: 19105190, ClinVar ID: 41313; PMID: 27071356 , PMID: 27084228, PMID: 28991695), which increases the likelihood that the p.Glu1026ArgfsTer4 variant is pathogenic. This variant has also been reported in ClinVar (Variation ID: 1117) 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 1026 and leads to a premature termination codon 4 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 SPG11-related neurologic disease. 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_VeryStrong, PP1_Moderate (Richards 2015).
Neurogenomics Lab, Neuroscience Institute, University Of Cape Town	RCV000001176	SCV003930340	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 0.0001095 (0.001%; 7/63948 alleles in European Finnish 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. 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. 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. Sequencing funded by the International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD): https://www.ucl.ac.uk/genomic-medicine-neuromuscular-diseases/.
GeneDx	RCV002247231	SCV004022990	pathogenic	not provided	2023-01-24	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: 28991695, 29983107, 32383541, 27071356, 35254204, 20110243, 18067136)
CeGaT Center for Human Genetics Tuebingen	RCV002247231	SCV004136525	pathogenic	not provided	2022-10-01	criteria provided, single submitter	clinical testing	SPG11: PVS1, PM2, PM3, PS4:Moderate
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV002247231	SCV005198341	pathogenic	not provided	2022-07-13	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005007806	SCV005637903	pathogenic	Amyotrophic lateral sclerosis type 5; Hereditary spastic paraplegia 11; Charcot-Marie-Tooth disease axonal type 2X	2024-03-21	criteria provided, single submitter	clinical testing
OMIM	RCV000001176	SCV000021326	pathogenic	Hereditary spastic paraplegia 11	2009-10-05	no assertion criteria provided	literature only
GeneReviews	RCV000001176	SCV000058141	not provided	Hereditary spastic paraplegia 11		no assertion provided	literature only
PreventionGenetics, part of Exact Sciences	RCV004748491	SCV005350127	pathogenic	SPG11-related disorder	2024-03-05	no assertion criteria provided	clinical testing	The SPG11 c.3075dupA variant is predicted to result in a frameshift and premature protein termination (p.Glu1026Argfs*4). This variant has been reported in the homozygous or compound heterozygous state in individuals with hereditary spastic paraplegia (see for example, Balicza et al. 2016. PubMed ID: 27084228; Khani et al. 2020. PubMed ID: 32383541; Schneider-Gold et al. 2017. PubMed ID: 28991695). This variant is reported in 0.014% of alleles in individuals of European (Finnish) descent in gnomAD. Frameshift variants in SPG11 are expected to be pathogenic. This variant is interpreted as pathogenic.