SPG7

Inheritance Pattern: AR

Disease ID:MONDO:0011803

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0020250

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0018155

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0011803

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0011803

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

Inheritance Pattern: AR

Disease ID:MONDO:0011803

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *SPG7* and autosomal dominant primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of February 19, 2026. The *SPG7* gene encodes paraplegin, a mitochondrial inner membrane metalloproteinase that is a component of the m-AAA protease along with *AFG3L2*. The m-AAA protease is an ATP-dependent proteolytic complex of the mitochondrial inner membrane that degrades misfolded proteins and regulates ribosome assembly. *SPG7* has been associated with one disease entity to date; spastic paraplegia 7, autosomal recessive [OMIM# 607259], however there have also been reports of an autosomal dominant *SPG7*-related disorder characterized by spasticity, ataxia, and/or optic atrophy (PMIDs: 11222789, 22571692, 39978794, 37983191). Per criteria outlined by the ClinGen Lumping and Splitting guidelines, this Expert Panel found a difference in inheritance pattern and phenotypic variability among these entities. Therefore, the autosomal recessive disease entity has been split, is curated separately, and has been renamed as autosomal recessive *SPG7*-related primary mitochondrial disease. The autosomal dominant disease entity is curated here. As described above, there have been reports of an autosomal dominant *SPG7*-related disorder characterized by spasticity, ataxia, and/or optic atrophy (PMIDs: 11222789, 22571692, 39978794, 37983191, 32548275). However, there is minimal functional evidence to support the deleterious nature of these variants in the heterozygous state, and many variants are now recognized to be too common in the general population to be associated with the reported phenotypes. In summary, the evidence supporting the relationship between *SPG7* and autosomal dominant primary mitochondrial disease has been disputed and no valid evidence remains to support the claim. More evidence is needed to either support or entirely refute the role this gene plays in this disease. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on February 19, 2026 (SOP Version 11).

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *SPG7* and autosomal recessive *SPG7*-related primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of February 19, 2026. The *SPG7* gene encodes paraplegin, a mitochondrial inner membrane metalloproteinase that is a component of the m-AAA protease along with AFG3L2. The m-AAA protease is an ATP-dependent proteolytic complex of the mitochondrial inner membrane that degrades misfolded proteins and regulates ribosome assembly. The *SPG7* gene was first reported in relation to autosomal recessive *SPG7*-related primary mitochondrial disease in 1998 (PMID: 9635427). *SPG7* has been associated with one disease entity to date; spastic paraplegia 7, autosomal recessive [OMIM# 607259], however there have also been reports of an autosomal dominant *SPG7*-related disorder characterized by spasticity, ataxia, and/or optic atrophy (PMIDs: 11222789, 22571692, 39978794, 37983191). Per criteria outlined by the ClinGen Lumping and Splitting guidelines, this Expert Panel found a difference in inheritance pattern and phenotypic variability among these entities. Therefore, the autosomal recessive disease entity is considered distinct and is curated here. This has been renamed as autosomal recessive *SPG7*-related primary mitochondrial disease. The autosomal dominant disease entity has been split and curated separately. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included 11 unique variants (four missense, two frameshift, one initiation codon, three nonsense, one intronic) identified in seven unrelated cases from six publications (PMIDs: 20186691, 24727571, 26260707, 31854126, 35243150, 39978794), although more affected individuals have been reported in the medical literature. Disease onset is typically in adulthood but can occur earlier in life. Clinical features in affected individuals include spasticity, ataxia, myopathy, neuropathy, ophthalmoplegia, ptosis, and optic atrophy. Multiple mitochondrial DNA deletions are seen in skeletal muscle. The mechanism of disease is loss of function. This gene-disease relationship is also supported by a functional alteration in patient cells (PMIDs: 24466038, 9635427), cell culture model (PMID: 37766787), mouse model (PMIDs: 14722615, 16357941), and *Drosophila melanogaster* model (PMID: 29467464). In summary, there is definitive evidence to support the relationship between *SPG7* and autosomal recessive *SPG7*-related primary mitochondrial disease. This relationship has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on February 19, 2026 (SOP Version 11).

Inheritance Pattern: AD

Disease ID:MONDO:0011803

Submitter: Orphanet