chr16-89546656-AGGAGAGGCG-A
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2PM4PP3PP5_Very_Strong
The NM_003119.4(SPG7):c.1454_1462delGGCGGGAGA(p.Arg485_Glu487del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000354 in 1,606,364 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: 𝑓 0.00040 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00035 ( 0 hom. )
Consequence
SPG7
NM_003119.4 disruptive_inframe_deletion
NM_003119.4 disruptive_inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.91
Genes affected
SPG7 (HGNC:11237): (SPG7 matrix AAA peptidase subunit, paraplegin) This gene encodes a mitochondrial metalloprotease protein that is a member of the AAA family. Members of this protein family share an ATPase domain and have roles in diverse cellular processes including membrane trafficking, intracellular motility, organelle biogenesis, protein folding, and proteolysis. Mutations in this gene cause autosomal recessive spastic paraplegia 7. Two transcript variants encoding distinct isoforms have been identified. [provided by RefSeq, Mar 2014]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 13 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_003119.4.
PP3
No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
PP5
Variant 16-89546656-AGGAGAGGCG-A is Pathogenic according to our data. Variant chr16-89546656-AGGAGAGGCG-A is described in ClinVar as [Pathogenic]. Clinvar id is 411680.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-89546656-AGGAGAGGCG-A is described in Lovd as [Pathogenic]. Variant chr16-89546656-AGGAGAGGCG-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.000402 AC: 61AN: 151660Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.000259 AC: 65AN: 251444Hom.: 0 AF XY: 0.000228 AC XY: 31AN XY: 135892
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GnomAD4 exome AF: 0.000349 AC: 507AN: 1454586Hom.: 0 AF XY: 0.000338 AC XY: 245AN XY: 723946
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GnomAD4 genome 0.000402 AC: 61AN: 151778Hom.: 0 Cov.: 31 AF XY: 0.000418 AC XY: 31AN XY: 74172
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:30Uncertain:1Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hereditary spastic paraplegia 7 Pathogenic:17Other:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 27, 2025 | This variant, c.1454_1462del, results in the deletion of 3 amino acid(s) of the SPG7 protein (p.Arg485_Glu487del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs768823392, gnomAD 0.08%). This variant has been observed in individual(s) with hereditary spastic paraplegia (PMID: 11222789, 22964162, 23065789, 23269439, 23812641, 24466038, 24727571, 26756429, 27165006). 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. ClinVar contains an entry for this variant (Variation ID: 411680). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Paris Brain Institute, Inserm - ICM | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Paris Brain Institute, Inserm - ICM | - | - - |
| Pathogenic, criteria provided, single submitter | research | PROSPAX: an integrated multimodal progression chart in spastic ataxias, Center for Neurology; Hertie-Institute for Clinical Brain Research | Jan 01, 2022 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust | May 03, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Centogene AG - the Rare Disease Company | Jun 26, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Jun 11, 2019 | - - |
| not provided, no classification provided | literature only | GeneReviews | - | - - |
| Pathogenic, criteria provided, single submitter | research | HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology | Aug 25, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Sep 13, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | 3billion, Medical Genetics | Sep 01, 2022 | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.028%). Canonical splice site is predicted to alter splicing and result in a loss or disruption of normal protein function. Multiple pathogenic loss-of-function variants are reported downstream of the variant. The variant is in trans with the other pathogenic variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000411680 / PMID: 11222789 / 3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. - |
| Likely pathogenic, no assertion criteria provided | clinical testing | Genetic Services Laboratory, University of Chicago | Dec 15, 2020 | DNA sequence analysis of the SPG7 gene demonstrated a nine-base pair deletion in exon 11, c.1454_1462del. This in-frame deletion is predicted to result in the deletion of three amino acid residues, p.Arg485_Glu487del. This in-frame deletion has been described in the homozygous and compound heterozygous states in patients with spastic paraplegia 7 or ataxia (PMIDs: 22964162, 23065789, 11222789). It has been described in the gnomAD population database with a global allele frequency of 0.028% and in the Finnish European subgroup with an allele frequency of 0.080% (rs768823392). Collectively this evidence suggests that this p.Arg485_Glu487del variant is likely pathogenic, however functional studies have not been performed to prove this conclusively - |
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jan 12, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jun 13, 2018 | - - |
| Pathogenic, criteria provided, single submitter | research | Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL) | Apr 27, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 02, 2024 | Variant summary: SPG7 c.1454_1462delGGCGGGAGA (p.Arg485_Glu487del, also known as c.1450-1_1457del) results in an in-frame deletion that is predicted to remove 3 amino acids from the encoded protein. The variant allele was found at a frequency of 0.00026 in 251444 control chromosomes. c.1454_1462delGGCGGGAGA has been reported in the literature as a common pathogenic variant in multiple individuals affected with Hereditary Spastic Paraplegia 7 (example, Burguez_2017, van Gassen_2012). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 29246610, 22964162). ClinVar contains an entry for this variant (Variation ID: 411680). Based on the evidence outlined above, the variant was classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin | Sep 22, 2022 | - - |
| Likely pathogenic, no assertion criteria provided | provider interpretation | Solve-RD Consortium | Jun 01, 2022 | Variant confirmed as disease-causing by referring clinical team - |
not provided Pathogenic:7
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 17, 2017 | The c.1454_1462delGGCGGGAGA (also reported as c.1450_1458del due to alternativenomenclature) in the SPG7 gene has been reported previously in association with spastic paraplegia. Most affectedindividuals were homozygous or compound heterozyogous for SPG7 variants and had typical features of spasticparaplegia 7 (McDermott et al., 2001; van Gassen et al., 2012; Klebe et al., 2012). When reported in theheterozygous state, some individuals had a later onset and milder presentation, sometimes with a cerebellar phenotypewithout spasticity (McDermott et al., 2001; Klebe et al., 2012). The c.1454_1462delGGCGGGAGA variant resultsin an in-frame deletion of three amino acid residues from the resulting protein starting with codon Arginine 485 andending with codon Glutamine 487, denoted p.Arg485_Glu487del. The c.1454_1462delGGCGGGAGA variant wasobserved in approximately 0.15% (12/8254 alleles) in individuals of European ancestry in the NHLBI ExomeSequencing Project. Therefore, we interpret c.1454_1462delGGCGGGAGA variant as a pathogenic variant. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Sep 21, 2020 | The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). In some published literature, this variant is referred to as c.1450_1458del or c.1450-1_1457del. Pathogenic variants in the SPG7 gene classically exhibit an autosomal recessive mode of disease inheritance, however there is also evidence for autosomal dominant transmission in some families. Consistent with this, some individuals carrying this variant in the heterozygous state display a late onset and/or mild disease (PMID: 11222789, 23065789, 31068484). In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. The variant is located in a region that is considered important for protein function and/or structure. - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2022 | SPG7: PS1, PS4, PM2 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | Jul 13, 2022 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Hereditary spastic paraplegia Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Jul 01, 2018 | - - |
| Pathogenic, criteria provided, single submitter | research | Unit for Genetic & Epidemiological Research on Neurological Disorders, Instituto de Investigação e Inovação em Saúde | Mar 07, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 26, 2020 | The p.Arg485_Glu487 del variant in SPG7 is a common pathogenic variant in spastic paraplegia type 7 and it has been reported in the homozygous or compound heterozygous state with another SPG7 pathogenic variant in over 20 individuals with spastic paraplegia (McDermott 2001 PMID: 11222789, van Gassen 2012 PMID: 22964162, Klebe 2012 PMID: 23065789, Pfeffer 2014 PMID: 24727571, van de Warrenburg 2016 PMID: 27165006, Gass 2017 PMID: 29026558, Hewamadduma 2018 PMID: 30533525, Sun 2019 PMID: 29915382, Ngo 2019 PMID: 31692161). This variant also segregated with disease in 4 affected relatives from 4 families (van Gassen PMID: 22964162). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 411680) and has been identified in 0.08% (20/25116) of Finnish chromosomes and 0.04% (55/129114) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant is a deletion of 3 amino acids at position 485 and is not predicted to alter the protein reading-frame. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive spastic paraplegia type 7. ACMG/AMP Criteria applied: PM3_VeryStrong, PM4, PP1_Strong. - |
Inborn genetic diseases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 18, 2016 | Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected - |
Dysarthria;C0037771:Spastic paraparesis;C0751837:Gait ataxia;C4551583:Cerebral cortical atrophy Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 01, 2017 | - - |
Seizure;C0037772:Spastic paraplegia;C0233794:Memory impairment;C0751837:Gait ataxia Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 01, 2017 | - - |
Distal spinal muscular atrophy Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | Institute of Human Genetics, Cologne University | Apr 26, 2018 | - - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at