chr16-89546656-AGGAGAGGCG-A

Variant names:

• chr16-89546656-AGGAGAGGCG-A
• rs768823392
• NM_003119.4:c.1454_1462delGGCGGGAGA

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2 PM4 PP3 PP5_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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:30 U:1 O:1
• 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]

ACMG classification

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

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPG7	NM_003119.4	c.1454_1462delGGCGGGAGA	p.Arg485_Glu487del	disruptive_inframe_deletion	Exon 11 of 17	ENST00000645818.2	NP_003110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPG7	ENST00000645818.2	c.1454_1462delGGCGGGAGA	p.Arg485_Glu487del	disruptive_inframe_deletion	Exon 11 of 17		NM_003119.4	ENSP00000495795.2

Frequencies

GnomAD3 genomes AF: 0.000402 AC: 61 AN: 151660 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00123

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000559

Gnomad OTH AF: 0.000961

GnomAD3 exomes AF: 0.000259 AC: 65 AN: 251444 Hom.: 0 AF XY: 0.000228 AC XY: 31 AN XY: 135892

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000739

Gnomad NFE exome AF: 0.000404

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000349 AC: 507 AN: 1454586 Hom.: 0 AF XY: 0.000338 AC XY: 245 AN XY: 723946

Gnomad4 AFR exome AF: 0.0000902

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000565

Gnomad4 NFE exome AF: 0.000410

Gnomad4 OTH exome AF: 0.000300

GnomAD4 genome AF: 0.000402 AC: 61 AN: 151778 Hom.: 0 Cov.: 31 AF XY: 0.000418 AC XY: 31 AN XY: 74172

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00123

Gnomad4 NFE AF: 0.000559

Gnomad4 OTH AF: 0.000951

Alfa AF: 0.0000464 Hom.: 0

EpiCase AF: 0.000436

EpiControl AF: 0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:30 Uncertain:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia 7 Pathogenic:17 Other:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

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Paris Brain Institute, Inserm - ICM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Paris Brain Institute, Inserm - ICM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2022

PROSPAX: an integrated multimodal progression chart in spastic ataxias, Center for Neurology; Hertie-Institute for Clinical Brain Research

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

May 03, 2019

Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 26, 2020

Centogene AG - the Rare Disease Company

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 11, 2019

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Aug 25, 2023

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

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Sep 13, 2021

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 01, 2022

3billion, Medical Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Dec 15, 2020

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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 -

Jan 12, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Jun 13, 2018

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 27, 2023

Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Feb 02, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Sep 22, 2022

Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 01, 2022

Solve-RD Consortium

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

Variant confirmed as disease-causing by referring clinical team -

not provided Pathogenic:7

Oct 17, 2017

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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Sep 21, 2020

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Nov 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SPG7: PS1, PS4, PM2 -

Jul 13, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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Hereditary spastic paraplegia Pathogenic:3

Jul 01, 2018

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Mar 07, 2017

Unit for Genetic & Epidemiological Research on Neurological Disorders, Instituto de Investigação e Inovação em Saúde

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

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Jun 26, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jul 18, 2016

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 01, 2017

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Seizure;C0037772:Spastic paraplegia;C0233794:Memory impairment;C0751837:Gait ataxia Pathogenic:1

Jan 01, 2017

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Distal spinal muscular atrophy Uncertain:1

Apr 26, 2018

Institute of Human Genetics, Cologne University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs768823392; hg19: chr16-89613064;