VCV000042016.112 - ClinVar

NM_003119.4(SPG7):c.1529C>T (p.Ala510Val)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(61)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

This variant is part of a Genotype

NM_003119.3(SPG7):c.[1529C>T];[2120delTinsCCAAGTCTGTA]

Identifiers

NM_003119.4(SPG7):c.1529C>T (p.Ala510Val)

Variation ID: 42016 Accession: VCV000042016.112

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 16q24.3 16: 89546737 (GRCh38) [ NCBI UCSC ] 16: 89613145 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jun 29, 2015	Nov 24, 2024	Aug 22, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_003119.4:c.1529C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_003110.1:p.Ala510Val	missense
NM_001363850.1:c.1529C>T	NP_001350779.1:p.Ala510Val	missense
NC_000016.10:g.89546737C>T
NC_000016.9:g.89613145C>T
NG_008082.1:g.43341C>T
	Q9UQ90:p.Ala510Val

... more HGVS ... less HGVS

Protein change

A510V

Other names

SPG7, ALA510VAL (rs61755320)
p.A510V:GCA>GTA
NM_003119.3(SPG7):c.1529C>T(p.Ala510Val)

Canonical SPDI

NC_000016.10:89546736:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

variation affecting protein; Variation Ontology [ VariO:0002]

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00220 (T)

Allele frequency Help The frequency of the allele represented by this VCV record.

Exome Aggregation Consortium (ExAC) 0.00252

The Genome Aggregation Database (gnomAD), exomes 0.00292

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00346

The Genome Aggregation Database (gnomAD) 0.00361

Trans-Omics for Precision Medicine (TOPMed) 0.00371

1000 Genomes Project 30x 0.00203

1000 Genomes Project 0.00220

Links

UniProtKB: Q9UQ90#VAR_063609 OMIM: 602783.0012 dbSNP: rs61755320 ClinGen: CA090884 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
SPG7		-	-	GRCh38 GRCh37	979	1151

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Hereditary spastic paraplegia 7	Pathogenic/Likely pathogenic (40)	criteria provided, multiple submitters, no conflicts	Aug 22, 2024	RCV000034858.78
Hereditary spastic paraplegia	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Mar 23, 2023	RCV000515835.18
not provided	Pathogenic/Likely pathogenic (10)	criteria provided, multiple submitters, no conflicts	Jul 1, 2024	RCV000195683.59
Spastic Paraplegia, Recessive	Pathogenic (1)	criteria provided, single submitter	Jun 14, 2016	RCV000270813.14
Cerebral cortical atrophy Dysarthria Gait ataxia Spastic paraparesis	Pathogenic (1)	criteria provided, single submitter	Jan 1, 2017	RCV000626837.10
Optic nerve hypoplasia	no classifications from unflagged records (1)	no classifications from unflagged records	Jan 25, 2024	RCV000677252.12
Intellectual disability	Likely pathogenic (1)	criteria provided, single submitter	Feb 13, 2019	RCV000850200.10
Sensorimotor neuropathy Spastic ataxia	Pathogenic (1)	no assertion criteria provided	-	RCV001003619.9
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Jul 23, 2021	RCV000623796.12
Frontotemporal dementia and/or amyotrophic lateral sclerosis 2	Pathogenic (1)	criteria provided, single submitter	Sep 2, 2022	RCV002463623.8
SPG7-related disorder	Likely pathogenic (1)	no assertion criteria provided	Aug 30, 2024	RCV003421943.7
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Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: case-control	Spastic paraplegia 7 Affected status: yes Allele origin: germline	Neurogenetics of motion laboratory, Montreal Neurological Institute Additional submitter: McGill Innovation Center, McGill University Study: Care4Rare - Neurogenetics of motion laboratory Accession: SCV000245719.1 First in ClinVar: Jul 24, 2016 Last updated: Jul 24, 2016	Publications: PubMed (1) PubMed: 26626314 Observation 1: Clinical Features: Ataxia (present) , Spasticity (present) , Dysarthria (present) , Nystagmus (present) Family history: yes Age: 50-59 years Ethnicity/Population group: French-Canadian Geographic origin: Quebec, Canada Segregation observed: yes Observation 2: Clinical Features: Ataxia (present) , Spasticity (present) , Dysarthria (present) , Nystagmus (present) Family history: yes Age: 60-69 years Ethnicity/Population group: French-Canadian Geographic origin: Quebec, Canada Segregation observed: yes Observation 3: Clinical Features: Ataxia (present) , Spasticity (present) , Dysarthria (present) , Nystagmus (present) Family history: yes Age: 50-59 years Ethnicity/Population group: French-Canadian Geographic origin: Quebec, Canada Segregation observed: yes Observation 4: Clinical Features: Ataxia (present) , Spasticity (present) , Dysarthria (present) , Nystagmus (present) Family history: yes Age: 40-49 years Ethnicity/Population group: French-Canadian Geographic origin: Quebec, Canada Segregation observed: yes Observation 5: Clinical Features: Ataxia (present) , Spasticity (present) , Dysarthria (present) , Nystagmus (present) Family history: yes Age: 50-59 years Ethnicity/Population group: French-Canadian Geographic origin: Quebec, Canada Segregation observed: yes Observation 6: Clinical Features: Ataxia (present) , Spasticity (present) , Dysarthria (present) , Nystagmus (present) Family history: yes Age: 60-69 years Ethnicity/Population group: French-Canadian Geographic origin: Quebec, Canada Segregation observed: yes Observation 7: Clinical Features: Ataxia (present) , Spasticity (present) , Dysarthria (present) , Nystagmus (present) Family history: yes Age: 70-79 years Ethnicity/Population group: French-Canadian Geographic origin: Quebec, Canada Segregation observed: yes Observation 8: Clinical Features: Ataxia (present) , Spasticity (present) , Dysarthria (present) , Nystagmus (present) Family history: yes Age: 60-69 years Ethnicity/Population group: French-Canadian Geographic origin: Quebec, Canada Segregation observed: yes Observation 9: Clinical Features: Ataxia (present) , Spasticity (present) , Dysarthria (present) , Nystagmus (present) Family history: yes Age: 40-49 years Ethnicity/Population group: French-Canadian Geographic origin: Quebec, Canada Segregation observed: yes Observation 10: Clinical Features: Ataxia (present) , Spasticity (present) , Dysarthria (present) , Nystagmus (present) Family history: yes Age: 60-69 years Ethnicity/Population group: French-Canadian Geographic origin: Quebec, Canada Segregation observed: yes Observation 11: Clinical Features: Ataxia (present) , Spasticity (present) , Dysarthria (present) , Nystagmus (present) Family history: yes Age: 50-59 years Ethnicity/Population group: Acadian Geographic origin: New Brunswick, Canada Segregation observed: yes Observation 12: Clinical Features: Ataxia (present) , Spasticity (present) , Dysarthria (present) , Nystagmus (present) Family history: yes Age: 20-29 years Ethnicity/Population group: Acadian Geographic origin: New Brunswick, Canada Segregation observed: yes
Pathogenic (Aug 07, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary spastic paraplegia 7 Affected status: yes Allele origin: paternal	Center of Genomic medicine, Geneva, University Hospital of Geneva Accession: SCV000693453.2 First in ClinVar: Dec 26, 2017 Last updated: Dec 11, 2022	Comment: This recessive SPG7 variant was found in compound heterozygosity with one another recessive SPG7 variant in a female patient with spastic paraplegia 7 Age: 40-49 years Sex: female
Pathogenic (Jun 14, 2016)	criteria provided, single submitter (ICSL Variant Classification 20161018) Method: clinical testing	Spastic Paraplegia, Recessive Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000399754.2 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016	Publications: PubMed (12) PubMed: 18799786‚ 17661097‚ 23269439‚ 20186691‚ 21623769‚ 22571692‚ 26626314‚ 24727571‚ 18200586‚ 23733235‚ 25497598‚ 23065789 Comment: The c.1529C>T (p.Ala510Val) variant has been reported in at least 12 studies in which it is found in at least 70 patients, including 13 in … (more) The c.1529C>T (p.Ala510Val) variant has been reported in at least 12 studies in which it is found in at least 70 patients, including 13 in a homozygous state, 47 in a compound heterozygous state, and ten in a heterozygous state with no second variant identified. The variant was also found in a heterozygous state in four unaffected siblings of patients (Elleuch et al. 2007; Arnoldi et al. 2008; Brugman et al. 2008; Bonn et al. 2010; Schlipf et al. 2011; Klebe et al. 2012; Roxburgh et al. 2013; SÃ¡nchez-Ferrero et al. 2013; Yoon et al. 2013; Pfeffer et al. 2014; Pyle et al. 2015; Choquet et al. 2016). The p.Ala510Val variant was identified in a heterozygous state in five of 777 control individuals and in two of 200 control chromosomes, and is reported at a frequency of 0.00497 in the European population of the 1000 Genomes Project. Of note, this variant is also reported in a homozygous state in two individuals in the Exome Aggregation Consortium, however, given the wide variability in age of onset seen in this disorder, the presence of two homozygotes in this database does not provide evidence against pathogenicity. Bonn et al. (2010) conducted yeast complementation assays to study the activity of paraplegin variants identified in their study, and found that the p.Ala510Val variant demonstrated impaired proteolytic function in this assay. Based on the collective evidence, the p.Ala510Val variant is classified as pathogenic for spastic paraplegia. (less)
Pathogenic (Mar 07, 2017)	criteria provided, single submitter (Morais et al. (Eur J Hum Genet. 2017)) Method: research	Hereditary spastic paraplegia Affected status: yes Allele origin: inherited	Unit for Genetic & Epidemiological Research on Neurological Disorders, Instituto de Investigação e Inovação em Saúde Accession: SCV000574457.1 First in ClinVar: Dec 10, 2017 Last updated: Dec 10, 2017	Publications: PubMed (1) PubMed: 28832565
Likely pathogenic (May 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Hereditary spastic paraplegia 7 Affected status: unknown Allele origin: unknown	SIB Swiss Institute of Bioinformatics Accession: SCV000803517.1 First in ClinVar: Apr 28, 2018 Last updated: Apr 28, 2018	Publications: PubMed (6) PubMed: 20186691‚ 25681447‚ 22571692‚ 26626314‚ 26506339‚ 23065789 Comment: This variant is interpreted as a Likely Pathogenic, for Spastic paraplegia 7, autosomal recessive, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PP3 … (more) This variant is interpreted as a Likely Pathogenic, for Spastic paraplegia 7, autosomal recessive, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS3-Moderate => Functional assay shows a deleterious effect. (PMID:20186691). PM3 => For recessive disorders, detected in trans with a pathogenic variant (PMID:25681447). PS4-Moderate => Recurrent mutation (PMID:22571692,26626314,26506339,25681447). PP1-Moderate => PP1 upgraded in strength to Moderate (PMID:26626314,23065789,26506339). (less)
Likely pathogenic (Mar 04, 2015)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000225309.5 First in ClinVar: Jun 29, 2015 Last updated: Dec 15, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SPG7 Number of individuals with the variant: 6 Sex: mixed
Pathogenic (Oct 05, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary spastic paraplegia 7 (Autosomal recessive inheritance) Affected status: yes Allele origin: unknown, maternal	Undiagnosed Diseases Network, NIH Accession: SCV000746604.2 First in ClinVar: Apr 28, 2018 Last updated: Oct 10, 2018	Observation 1: Clinical Features: Weight loss (present) , Vertigo (present) , Spinal cord compression (present) , Poor gross motor coordination (present) , Poor fine motor coordination (present) , Nystagmus … (more) Weight loss (present) , Vertigo (present) , Spinal cord compression (present) , Poor gross motor coordination (present) , Poor fine motor coordination (present) , Nystagmus (present) , Muscular hypotonia (present) , Migraine (present) , Limb dysmetria (present) , Intervertebral disc degeneration (present) , Increased muscle fatiguability (present) , Hydronephrosis (present) , Herniation of intervertebral nuclei (present) , Hand muscle weakness (present) , Gait disturbance (present) , Dysarthria (present) , Diffuse cerebellar atrophy (present) , Cerebellar ataxia associated with quadrupedal gait (present) , Ankle clonus (present) (less) Age: 50-59 years Sex: female Ethnicity/Population group: White Tissue: blood Testing laboratory: HudsonAlpha Clinical Services Lab, LLC,HudsonAlpha Clinical Services Lab, LLC Date variant was reported to submitter: 2018-07-31 Testing laboratory interpretation: Pathogenic Observation 2: Clinical Features: Unsteady gait (present) , Spasticity (present) , Primary Caesarian section (present) , Nystagmus (present) , Muscle weakness (present) , Gait ataxia (present) , Dysdiadochokinesis (present) … (more) Unsteady gait (present) , Spasticity (present) , Primary Caesarian section (present) , Nystagmus (present) , Muscle weakness (present) , Gait ataxia (present) , Dysdiadochokinesis (present) , Dysarthria (present) , Caesarian section (present) , Abnormality of the optic nerve (present) , Abnormal delivery (present) (less) Age: 30-39 years Sex: male Ethnicity/Population group: White Tissue: blood Testing laboratory: Baylor Genetics Date variant was reported to submitter: 2017-05-08 Testing laboratory interpretation: Pathogenic
Pathogenic (Oct 23, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided (Autosomal unknown) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001447388.1 First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020	Clinical Features: Cerebellar ataxia (present) Sex: female
Likely pathogenic (Apr 08, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary spastic paraplegia 7 Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV001440297.2 First in ClinVar: Oct 31, 2020 Last updated: Oct 02, 2021	Comment: This variant was identified as compound heterozygous with NM_003119.4:c.1552+1G>T.
Pathogenic (Sep 22, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary spastic paraplegia 7 (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin Additional submitter: CUBI - Core Unit Bioinformatics, Berlin Institute of Health Accession: SCV002574835.1 First in ClinVar: Sep 24, 2022 Last updated: Sep 24, 2022	Clinical Features: Spastic paraplegia (present) , Gait disturbance (present) , Dystonic disorder (present) , Paresthesia (present) Sex: male Tissue: Blood
Pathogenic (Jul 27, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary spastic paraplegia 7 Affected status: yes Allele origin: germline	MGZ Medical Genetics Center Accession: SCV002581047.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 Comment: ACMG criteria applied: PS4, PM3_STR, PS3_SUP, PP1, PP3	Number of individuals with the variant: 6 Sex: female
Pathogenic (Jun 29, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary spastic paraplegia 7 (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Genetics and Molecular Pathology, SA Pathology Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002761564.1 First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022
Pathogenic (May 03, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000252339.12 First in ClinVar: Oct 11, 2015 Last updated: Mar 04, 2023	Comment: Yeast expression studies found that the A510V variant perturbs the proteolytic function of paraplegin (Bonn et al., 2010); This variant is associated with the following … (more) Yeast expression studies found that the A510V variant perturbs the proteolytic function of paraplegin (Bonn et al., 2010); This variant is associated with the following publications: (PMID: 20186691, 31316545, 25681447, 22571692, 21623769, 11222789, 27081526, 22964162, 23269439, 20981092, 22995991, 18799786, 16534102, 31433872, 31692161, 32040484, 32161564, 31980526, 32581362, 33059505, 34426522, 32893728, 33144682, 33300680, 32447552, 33157434, 33084218, 33841295, 29867446, 33726816) (less)
Pathogenic (Oct 20, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary spastic paraplegia 7 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV001522924.2 First in ClinVar: Mar 22, 2021 Last updated: Mar 11, 2023
Pathogenic (May 03, 2022)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Athena Diagnostics Accession: SCV000615433.6 First in ClinVar: Dec 19, 2017 Last updated: Jan 26, 2024	Publications: PubMed (19) PubMed: 23065789‚ 29915382‚ 28444220‚ 28362824‚ 27165006‚ 27084228‚ 11222789‚ 14985266‚ 16534102‚ 20186691‚ 21623769‚ 23269439‚ 26626314‚ 24727571‚ 23733235‚ 25681447‚ 22964162‚ 22571692‚ 30098094 Comment: This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls, and is reported in the literature as the … (more) This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls, and is reported in the literature as the most common pathogenic SPG7 variant (PMID: 30098094, 24727571, 27165006, 28444220; Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant associates with disease in multiple families (PMID: 16534102, 25681447). A yeast complementation study demonstrated that this variant disrupts proteolytic function (PMID: 20186691). 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. (less)
Pathogenic (Mar 23, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary spastic paraplegia (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000221215.5 First in ClinVar: Apr 01, 2015 Last updated: Apr 20, 2024	Publications: PubMed (13) PubMed: 23269439‚ 16534102‚ 18799786‚ 20186691‚ 21623769‚ 29026558‚ 27957547‚ 22571692‚ 29057857‚ 23065789‚ 23733235‚ 28832565‚ 28362824 Comment: The p.Ala510Val variant in SPG7 has been previously identified in >25 homozygous or compound heterozygous individuals with spastic paraplegia type 7 (Elluch 2006 PMID: 16534102, … (more) The p.Ala510Val variant in SPG7 has been previously identified in >25 homozygous or compound heterozygous individuals with spastic paraplegia type 7 (Elluch 2006 PMID: 16534102, Brugman 2008 PMID: 18799786, Bonn 2010 PMID: 20186691, Schlipf 2011 PMID: 21623769, Roxburgh 2013 PMID: 23269439, Sanchez-Ferrero 2013 PMID: 22571692, Yoon 2013 PMID: 23733235, Gass 2017 PMID: 29026558, Bhattacharjee 2017 PMID: 29057857, Morais 2017 PMID: 28832565, Iqbal 2017 PMID: 28362824). Though the variant is a common cause of spastic paraplegia type 7 in individuals of British ancestry, it may be associated with a late age of onset and/or reduced penetrance (Roxburgh 2013 PMID: 23269439). This variant has been identified in 0.6% (417/68040) of European chromosomes (including 2 homozygotes) by gnomAD v3.1.2 (http://gnomad.broadinstitute.org). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. It has also been reported in ClinVar (Variation ID 42016). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Functional assays suggest the p.Ala510Val variant may lead to proteolytic deficiency (Bonn 2010 PMID: 20186691); however, these types of assays may not accurately reflect biological function. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive spastic paraplegia type 7. ACMG/AMP Criteria applied: PS3_Supporting, PP3, PM3_VeryStrong. (less)
Likely pathogenic (Dec 07, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary spastic paraplegia 7 Affected status: yes Allele origin: unknown	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne Accession: SCV005016514.1 First in ClinVar: May 01, 2024 Last updated: May 01, 2024
Pathogenic (Jan 01, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Hereditary spastic paraplegia 7 Affected status: yes Allele origin: germline	PROSPAX: an integrated multimodal progression chart in spastic ataxias, Center for Neurology; Hertie-Institute for Clinical Brain Research Accession: SCV005044614.1 First in ClinVar: Oct 20, 2024 Last updated: Oct 20, 2024	Number of individuals with the variant: 62
Pathogenic (May 22, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Hereditary spastic paraplegia 7 (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Neurogenomics Lab, Neuroscience Institute, University Of Cape Town Accession: SCV003930338.2 First in ClinVar: Aug 19, 2023 Last updated: May 26, 2024	Publications: PubMed (5) PubMed: 37712079‚ 23269439‚ 22964162‚ 32973427‚ 20186691 Comment: PM2_supporting: the highest population allele frequency in gnomAD v4.0 is 0.007265 (0.72%; 8558/1178040 alleles in European non-Finnish population). 41 homozygotes present. The heterozygous carrier frequency … (more) PM2_supporting: the highest population allele frequency in gnomAD v4.0 is 0.007265 (0.72%; 8558/1178040 alleles in European non-Finnish population). 41 homozygotes present. The heterozygous carrier frequency is 8558/1178040=~1% which should give rise to a disease prevalence of 2.5/100,000 which is not inconsistent with reported figures (the prevalence of SPG7 is estimated at between 1:100,000 and 9:100,000 for most countries https://www.ncbi.nlm.nih.gov/books/NBK1107/). This variant is the most common mutation causing adult onset neurogenetic disease in patients of British ancestry (PMID 23269439). PP3_moderate: REVEL score is 0.92. PM3_very_strong: >4 points: max 1 point awarded for multiple homozygous occurrences of the variant in affected unrelated probands (PMID 23269439, PMID 22964162) and >3 points awarded for co-occurrence of the variant with other pathogenic/likely pathogenic SPG7 variants in multiple unrelated probands (compound heterozygotes) (PMID 22964162, PMID 32973427). PS3_supporting: functional studies provide supportive evidence that this variant has a damaging effect on the gene or gene product (PMID 20186691, PMID 32973427). PS4 not evaluated as literature probands counted under PM3. Sequencing funded by the International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD): https://www.ucl.ac.uk/genomic-medicine-neuromuscular-diseases/. (less) Number of individuals with the variant: 1 Sex: female Geographic origin: South Africa
Pathogenic (Jul 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001151097.27 First in ClinVar: Feb 03, 2020 Last updated: Oct 20, 2024	Comment: SPG7: PM3:Very Strong, PP1:Strong, PM2:Supporting, PS3:Supporting Number of individuals with the variant: 54
Likely pathogenic (May 18, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary spastic paraplegia 7 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000611242.1 First in ClinVar: Apr 16, 2017 Last updated: Apr 16, 2017
Pathogenic (May 31, 2017)	criteria provided, single submitter (ACGS Guidelines, 2013) Method: clinical testing	Hereditary spastic paraplegia 7 Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Study: VKGL Data-share Consensus Accession: SCV000745330.1 First in ClinVar: Apr 19, 2018 Last updated: Apr 19, 2018
Pathogenic (Jan 01, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cerebral cortical atrophy Dysarthria Gait ataxia Spastic paraparesis Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV000747540.1 First in ClinVar: May 12, 2018 Last updated: May 12, 2018
Likely pathogenic (Feb 13, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Intellectual disability Affected status: yes Allele origin: unknown	Raymond Lab, University of Cambridge Accession: SCV000897738.1 First in ClinVar: Sep 14, 2019 Last updated: Sep 14, 2019	Number of individuals with the variant: 2 Family history: yes
Pathogenic (Feb 24, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics and Genomics, Karolinska University Hospital Accession: SCV001450317.1 First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020	Number of individuals with the variant: 1
Likely pathogenic (Dec 03, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary spastic paraplegia 7 Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV001368404.2 First in ClinVar: Jul 06, 2020 Last updated: Dec 12, 2020	Comment: This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PM3,PP2,PP3,PP5.
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary spastic paraplegia 7 Affected status: yes Allele origin: unknown	Paris Brain Institute, Inserm - ICM Accession: SCV001451052.1 First in ClinVar: May 16, 2021 Last updated: May 16, 2021	Number of individuals with the variant: 50
Pathogenic (Jan 04, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Hereditary spastic paraplegia 7 Affected status: yes Allele origin: inherited	Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris Accession: SCV001519205.1 First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021
Pathogenic (-)	criteria provided, single submitter (ACGS Guidelines, 2016) Method: clinical testing	Hereditary spastic paraplegia 7 Affected status: yes Allele origin: germline	Genomics England Pilot Project, Genomics England Accession: SCV001760391.1 First in ClinVar: Jul 31, 2021 Last updated: Jul 31, 2021
Pathogenic (Sep 10, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary spastic paraplegia 7 Affected status: yes Allele origin: germline	Centogene AG - the Rare Disease Company Accession: SCV002059504.1 First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022
Pathogenic (Jan 05, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary spastic paraplegia 7 Affected status: yes Allele origin: germline	DASA Accession: SCV002061281.1 First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022	Publications: PubMed (8) PubMed: 18799786‚ 22571692‚ 29246844‚ 30537300‚ 26626314‚ 25681447‚ 23065789‚ 20186691 Comment: The c.1529C>T;p.(Ala510Val) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID 42016; OMIM 602783.0012; PMID 18799786; … (more) The c.1529C>T;p.(Ala510Val) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID 42016; OMIM 602783.0012; PMID 18799786; 22571692; 29246844; 30537300; 26626314; 25681447; 23065789; 25681447) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 20186691) - PS3_moderate. The p.(Ala510Val) was detected in trans with a pathogenic variant (PMID 25681447) - PM3. The variant co-segregated with disease in multiple affected family members (PMID:26626314; 23065789; 26506339) - PP1_moderate. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. and allele frequency is greater than expected for disorder -BS1. In summary, the currently available evidence indicates that the variant is pathogenic. (less) Number of individuals with the variant: 3 Sex: mixed Geographic origin: Brazil;Argentina;Uruguay
Pathogenic (Mar 15, 2021)	criteria provided, single submitter (NYGC Assertion Criteria 2020) Method: clinical testing	Hereditary spastic paraplegia 7 (Autosomal recessive inheritance) Affected status: unknown Allele origin: inherited	New York Genome Center Study: CSER-NYCKidSeq Accession: SCV002098960.1 First in ClinVar: Feb 26, 2022 Last updated: Feb 26, 2022	Clinical Features: Seizure (present) , Intellectual disability (present) Secondary finding: no
Pathogenic (Jan 04, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary spastic paraplegia Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, The Hospital for Sick Children Accession: SCV002105846.1 First in ClinVar: Mar 19, 2022 Last updated: Mar 19, 2022
Pathogenic (May 04, 2022)	criteria provided, single submitter (Mendelics Assertion Criteria 2019) Method: clinical testing	Hereditary spastic paraplegia 7 Affected status: unknown Allele origin: germline	Mendelics Accession: SCV002519810.1 First in ClinVar: May 21, 2022 Last updated: May 21, 2022
Pathogenic (Sep 01, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary spastic paraplegia 7 Affected status: yes Allele origin: germline	3billion Accession: SCV002573329.1 First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022	Publications: PubMed (5) PubMed: 30098094‚ 26626314‚ 20186691‚ 16534102‚ 23269439 Comment: It is observed in the gnomAD v2.1.1 ( https://gnomad.broadinstitute.org ) dataset at total allele frequency of 0.290%. Functional studies provide strong evidence of the variant … (more) It is observed in the gnomAD v2.1.1 ( https://gnomad.broadinstitute.org ) dataset at total allele frequency of 0.290%. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 20186691). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.92). The variant has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000042016). A different missense change at the same codon (p.Ala510Leu) has been reported to be associated with SPG7-related disorder (ClinVar ID: VCV000989124). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Spastic ataxia (present)
Pathogenic (Sep 02, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Frontotemporal dementia and/or amyotrophic lateral sclerosis 2 Affected status: yes Allele origin: germline	Human Genetics Bochum, Ruhr University Bochum Accession: SCV002758630.1 First in ClinVar: Dec 11, 2022 Last updated: Dec 11, 2022	Comment: ACMG criteria used to clasify this variant: PS3, PM2, PS4, PP1, PM1, PP3
Pathogenic (Nov 09, 2021)	criteria provided, single submitter (Classification criteria August 2017) Method: clinical testing	Hereditary spastic paraplegia 7 (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München Accession: SCV002764908.1 First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022	Number of individuals with the variant: 1 Clinical Features: Abnormal pyramidal sign (present) , Dystonic disorder (present) , Dyskinesia (present) , Cerebellar ataxia (present)
Pathogenic (Aug 31, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary spastic paraplegia 7 Affected status: yes Allele origin: germline	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center Accession: SCV004099090.1 First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023	Comment: PS3_Moderate, PM3_VeryStrong, PP3
Pathogenic (Mar 09, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV001715175.3 First in ClinVar: Jun 15, 2021 Last updated: Jan 26, 2024	Comment: PP3 Number of individuals with the variant: 17
Likely pathogenic (Jan 26, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary spastic paraplegia 7 Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002023626.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Jan 28, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Hereditary spastic paraplegia 7 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000219172.13 First in ClinVar: Mar 29, 2015 Last updated: Feb 20, 2024	Publications: PubMed (8) PubMed: 28492532‚ 16534102‚ 18200586‚ 18799786‚ 22571692‚ 22964162‚ 23269439‚ 20186691 Comment: This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 510 of the SPG7 protein (p.Ala510Val). … (more) This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 510 of the SPG7 protein (p.Ala510Val). This variant is present in population databases (rs61755320, gnomAD 0.5%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with autosomal recessive hereditary spastic paraplegia (PMID: 16534102, 18200586, 18799786, 22571692, 22964162, 23269439). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 42016). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SPG7 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SPG7 function (PMID: 20186691). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Oct 06, 2023)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	Hereditary spastic paraplegia 7 Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV004563041.1 First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024	Comment: The SPG7 c.1529C>T; p.Ala510Val variant (ClinVar Variation ID: 42016) is one of the most common SPG7 variants found in late onset, recessively inherited ataxia. Numerous … (more) The SPG7 c.1529C>T; p.Ala510Val variant (ClinVar Variation ID: 42016) is one of the most common SPG7 variants found in late onset, recessively inherited ataxia. Numerous homozygous individuals and individuals shown to be bialleleic or presumed to be biallelic with additional SPG7 variants have been identified in cohorts of ataxia patients (Gass 2017, Mancini 2019, Pfeffer 2015, Roxburgh 2013). This variant is found in the general population with an overall allele frequency of 0.29% (820/282,858 alleles, including 2 homozygotes) in the Genome Aggregation Database (v2.1.1). This variant is usually associated with a late age of onset (44 years) with initial symptoms related to gait disturbances (Mancini 20019). Functional analyses have demonstrated impaired respiratory growth and proteolytic processing of MrpL32 in a yeast complementation assay (Bonn 2010). Based on the available information, this variant is considered pathogenic. References: Bonn F et al. Functional evaluation of paraplegin mutations by a yeast complementation assay. Hum Mutat. 2010 May;31(5):617-21. Gass J et al. Expanded phenotype in a patient with spastic paraplegia 7. Clin Case Rep. 2017 Aug 24;5(10):1620-1622. Mancini C et al. Prevalence and phenotype of the c.1529C>T SPG7 variant in adult-onset cerebellar ataxia in Italy. Eur J Neurol. 2019 Jan;26(1):80-86. Pfeffer G et al. SPG7 mutations are a common cause of undiagnosed ataxia. Neurology. 2015 Mar 17;84(11):1174-6. Roxburgh RH et al. The p.Ala510Val mutation in the SPG7 (paraplegin) gene is the most common mutation causing adult onset neurogenetic disease in patients of British ancestry. J Neurol. 2013 May;260(5):1286-94. (less)
Pathogenic (Jul 07, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary spastic paraplegia 7 (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Molecular Genetics, Royal Melbourne Hospital Additional submitter: Shariant Australia, Australian Genomics Accession: SCV004812497.1 First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024	Publications: PubMed (4) PubMed: 20186691‚ 23269439‚ 30098094‚ 32153140 Comment: This sequence change in SPG7 is predicted to replace alanine with valine at codon 510, p.(Ala510Val). The alanine residue is highly conserved (100 vertebrates, UCSC), … (more) This sequence change in SPG7 is predicted to replace alanine with valine at codon 510, p.(Ala510Val). The alanine residue is highly conserved (100 vertebrates, UCSC), and is located in the AAA domain. There is a moderate physicochemical difference between alanine and valine. The highest population minor allele frequency in gnomAD v2.1 is 0.5% (621/129,168 alleles, 1 homozygote) in the European (non-Finnish) population, which is higher than expected for a recessive disorder. This variant has been detected as homozygous and compound heterozygous with a second pathogenic variant in many individuals with hereditary spastic paraplegia and adult-onset cerebellar ataxia (PMID: 20186691, 23269439, 30098094, 32153140). The variant has been reported to segregate with spastic paraplegia/ataxia in multiple families (PMID: 23269439, 30098094). Complementation assays in yeast showed impaired respiratory growth indicating that this variant impacts protein function (PMID: 20186691). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.923). Based on the classification scheme RMH Modified ACMG Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PP1_Strong, PS3_Supporting, PP3, BS1. (less)
Pathogenic (Jul 23, 2021)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000742948.5 First in ClinVar: Apr 15, 2018 Last updated: May 01, 2024	Publications: PubMed (6) PubMed: 20186691‚ 22571692‚ 23269439‚ 25681447‚ 26626314‚ 30098094 Comment: The c.1529C>T (p.A510V) alteration is located in coding exon 11 of the SPG7 gene. This alteration results from a C to T substitution at nucleotide … (more) The c.1529C>T (p.A510V) alteration is located in coding exon 11 of the SPG7 gene. This alteration results from a C to T substitution at nucleotide position 1529, causing the alanine (A) at amino acid position 510 to be replaced by a valine (V). Based on data from the Genome Aggregation Database (gnomAD), the SPG7 c.1529C>T alteration was observed in 0.29% (820/282858) of total alleles studied, with two homozygotes observed, and a frequency of 0.48% (621/129168) in the European (non-Finnish) subpopulation. This mutation, which is the most frequently identified SPG7 mutation, has been detected in the homozygous and compound heterozygous states in multiple unrelated patients affected with SPG7-related spastic paraplegia and has been shown to segregate with disease in multiple families (Bonn, 2010; Roxburgh, 2013; Sánchez-Ferrero, 2013; Pfeffer, 2015; Choquet, 2016; Mancini, 2019). Variable expressivity has been reported, even among family members with the same genotype (Roxburgh, 2013). In addition, this variant is present at significantly higher rates in patients versus controls (Sanchez-Ferror, 2013; Mancini, 2019). This amino acid position is highly conserved in available vertebrate species. A yeast complementation assay demonstrated loss of of proteolytic activity of the A510V mutant protein under certain conditions (Bonn, 2010). The p.A510V alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. (less)
Pathogenic (May 30, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Skane University Hospital Lund Accession: SCV005198343.1 First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024
Pathogenic (Aug 22, 2024)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Hereditary spastic paraplegia 7 Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV003922888.2 First in ClinVar: May 13, 2023 Last updated: Oct 26, 2024	Publications: PubMed (6) PubMed: 30098094‚ 25497598‚ 20186691‚ 23269439‚ 22571692‚ 32973427 Comment: Variant summary: SPG7 c.1529C>T (p.Ala510Val) results in a non-conservative amino acid change located in the AAA ATPase, AAA+ lid domain (IPR041569) of the encoded protein … (more) Variant summary: SPG7 c.1529C>T (p.Ala510Val) results in a non-conservative amino acid change located in the AAA ATPase, AAA+ lid domain (IPR041569) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0029 in 251478 control chromosomes in the gnomAD database, including 2 homozygotes. This frequency does not allow conclusions about variant significance as age-related reduced penetrance in adults with this variant has been observed (example, Roxburgh_2013). c.1529C>T has been widely reported in the literature as biallelic homozygous or compound heterozygous genotypes in multiple individuals affected with Hereditary Spastic Paraplegia 7 (example, Roxburgh_20013, Sanchez-Ferrero_2013, Bonn_2010, Pyle_2015, Mancini_2019, Wali_2020). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence in a yeast complementation assay system that this missense change perturbs the proteotypic function of the hetero-oligomeric m-AAA protease (Bonn_2010). Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Pathogenic (May 23, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary spastic paraplegia 7 (Autosomal unknown) Affected status: yes Allele origin: germline	Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center Accession: SCV005397772.1 First in ClinVar: Nov 17, 2024 Last updated: Nov 17, 2024	Publications: PubMed (17) PubMed: 37213040‚ 22571692‚ 20186691‚ 35586535‚ 30537300‚ 30098094‚ 31068484‚ 23269439‚ 32040484‚ 20301286‚ 33598982‚ 28444220‚ 29246844‚ 29915382‚ 26506339‚ 23065789‚ 32973427 Comment: This sequence variant is a single nucleotide substitution (C>T) at position 1529 of the coding sequence of the SPG7 gene that results in an alanine … (more) This sequence variant is a single nucleotide substitution (C>T) at position 1529 of the coding sequence of the SPG7 gene that results in an alanine to valine amino acid change at residue 510 of the SPG7 encoded protein, paraplegin. The 510 residue falls in the AAA+ Lid domain which plays a role in paraplegin's ATPase activity (PMID: 32973427). This is a previously reported variant (ClinVar 42016) that has been observed in homozygous, compound heterozygous, and monoallelic heterozygous individuals affected by a variety of movement disorders including hereditary spastic paraplegia, Parkingson's disease, progressive muscle atrophy, and ataxia (PMID: 32973427, 35586535, 28444220, 22571692, 37213040, 20301286, 29246844, 29915382, 30098094, 32040484, 20186691, 26506339, 31068484). In addition, this variant has been shown to be associated with an increased risk of developing hereditary spastic paraplegia (PMID: 33598982) or Parkingson's disease (PMID: 30537300) and has cosegregated with hereditary spastic paraplegia in several families (PMID: 23269439, 22571692, 23065789). This variant is present in 9342 of 1611950 alleles (0.5795%) in the gnomAD v4.1.0 population dataset. Several studies have suggested that this variant may have reduced penetrance and/or variable expressivity (PMID: 37213040, 33598982). Multiple bioinformatic tools predict that this amino acid change would be damaging, and the Ala510 residue at this position is highly conserved across the vertebrate species examined. Studies in yeast and patient-derived stem cells indicate that this variant confers an increased expression of paraplegin and multiple mitochondrial dysfunctions (PMID: 32973427, 20186691). Based upon the evidence, we consider this a pathogenic variant with reduced penetrance and/or variable expressivity. ACMG Criteria: PM3, PP1, PP3, PS3, PS4 (less)
Pathogenic (Jul 16, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary spastic paraplegia 7 (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV005399924.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Publications: PubMed (5) PubMed: 20186691‚ 24727571‚ 30098094‚ 31854126‚ 32548275 Comment: Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more) Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with spastic paraplegia 7 (MIM#607259) and optical atrophy (MONDO#0003608). (I) 0108 - This gene is associated with both recessive and dominant disease. This gene is associated with autosomal recessive spastic paraplegia 7 and autosomal dominant optical atrophy (PMIDs: 31854126, 32548275). (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to valine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 (816 heterozygotes, 2 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (p.(Ala510Thr): 1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated AAA+ lid domain (DECIPHER). (I) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. This variant has previously been reported as likely pathogenic or pathogenic in at least ten individuals with spastic paraplegia 7 and is the most common pathogenic variant found across different populations (ClinVar, GeneReviews, PMIDs: 24727571, 30098094). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional studies show that this variant impairs protein function (PMID: 20186691). (SP) 1206 - This variant has been shown to be paternally inherited (by segregation analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
Pathogenic (Aug 09, 2021)	no assertion criteria provided Method: clinical testing	Hereditary spastic paraplegia 7 Affected status: yes Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV002064525.3 First in ClinVar: Jan 29, 2022 Last updated: Dec 11, 2022	Comment: DNA sequence analysis of the SPG7 gene demonstrated a sequence change, c.1529C>T, in exon 11 that results in an amino acid change, p.Ala510Val. This sequence … (more) DNA sequence analysis of the SPG7 gene demonstrated a sequence change, c.1529C>T, in exon 11 that results in an amino acid change, p.Ala510Val. This sequence change has been described in the gnomAD database with a frequency of 0.48% in the non-Finnish European subpopulation (dbSNP rs61755320). This sequence change has previously been identified in the homozygous and compound heterozygous states in individuals and families with hereditary spastic paraplegia (PMIDs: 26626314, 30098094, 23269439, 16534102) and is one of the common pathogenic variants described in the SPG7 gene. The p.Ala510Val change affects a highly conserved amino acid residue located in a known functional domain of the SPG7 protein. The p.Ala510Val substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Functional studies show p.Ala510Val impairs the function of the SPG7 protein (PMID: 20186691). Collectively this evidence suggests p.Ala510Val is pathogenic. (less)
Pathogenic (Mar 01, 2013)	no assertion criteria provided Method: literature only	SPASTIC PARAPLEGIA 7, AUTOSOMAL RECESSIVE Affected status: not provided Allele origin: germline	OMIM Accession: SCV000058462.3 First in ClinVar: May 03, 2013 Last updated: Jun 29, 2015	Publications: PubMed (2) PubMed: 22571692‚ 20186691 Comment on evidence: In 8 Spanish probands with autosomal recessive spastic paraplegia-7 (SPG7; 607259), Sanchez-Ferrero et al. (2013) identified a 1529C-T transition in the SPG7 gene, resulting in … (more) In 8 Spanish probands with autosomal recessive spastic paraplegia-7 (SPG7; 607259), Sanchez-Ferrero et al. (2013) identified a 1529C-T transition in the SPG7 gene, resulting in an ala510-to-val (A510V) substitution at a highly conserved residue (rs61755320). Four patients carried the mutation in compound heterozygous state with another pathogenic mutation in the SPG7 gene, 1 patient was homozygous for A510V, and 3 patients carried A510V as a single heterozygous mutation. In the whole cohort, A510H was present in 8 (3%) of 285 Spanish patients with spastic paraplegia compared to 1% of controls. The findings suggested that A510H likely contributes to the pathogenesis of SPG7. Sanchez-Ferrero et al. (2013) noted that although A510V had initially been reported as a rare polymorphism, yeast complementation assays by Bonn et al. (2010) showed that this missense change would perturb the proteolytic function of the heterooligomeric m-AAA protease. (less)
Pathogenic (-)	no assertion criteria provided Method: research	Spastic ataxia Sensorimotor neuropathy Affected status: yes Allele origin: unknown	NIHR Bioresource Rare Diseases, University of Cambridge Accession: SCV001162030.1 First in ClinVar: Feb 27, 2020 Last updated: Feb 27, 2020	Publications: PubMed (1) PubMed: 32581362 Observation 1: Number of individuals with the variant: 1 Sex: female Observation 2: Number of individuals with the variant: 1 Sex: male
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV000733558.4 First in ClinVar: Apr 09, 2018 Last updated: Sep 08, 2021
Likely pathogenic (Jun 01, 2022)	no assertion criteria provided Method: provider interpretation	Hereditary spastic paraplegia 7 Affected status: yes Allele origin: inherited	Solve-RD Consortium Accession: SCV005091279.1 First in ClinVar: Oct 26, 2024 Last updated: Oct 26, 2024 Comment: Variant identified during reanalysis of unsolved cases by the Solve-RD project. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and … (more) Variant identified during reanalysis of unsolved cases by the Solve-RD project. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 779257. (less)	Comment: Variant confirmed as disease-causing by referring clinical team
Likely pathogenic (Aug 30, 2024)	no assertion criteria provided Method: clinical testing	SPG7-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004118612.3 First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024	Comment: The SPG7 c.1529C>T variant is predicted to result in the amino acid substitution p.Ala510Val. This variant has been repeatedly reported in the compound heterozygous and … (more) The SPG7 c.1529C>T variant is predicted to result in the amino acid substitution p.Ala510Val. This variant has been repeatedly reported in the compound heterozygous and homozygous states to be causative for hereditary spastic paraplegia with variable age of onset and severity (Sánchez-Ferrero et al. 2013. PubMed ID: 22571692; van Gassen et al. 2012. PubMed ID: 22964162; Roxburgh et al. 2013. PubMed ID: 23269439). This variant has been reported at a subpopulation frequency of ≤0.48% in a database of individuals with unknown phenotype, including two homozygous individuals. This allele frequency is slightly high for a pathogenic variant; but, given the wide range in age of onset, does not rule out pathogenicity. This variant is significantly more frequent in patients than healthy controls (3% vs 1%) (Sánchez-Ferrero et al. 2013. PubMed ID: 22571692). Functional characterization of SPG7 variants by a yeast complementation assay suggests that this variant impairs protein function (Bonn et al. 2010. PubMed ID: 20186691). Taken together, these data indicate this variant is likely pathogenic in an autosomal recessive manner with variable age of onset and severity. (less)
Pathogenic (Jun 19, 2020)	no assertion criteria provided Method: clinical testing	Hereditary spastic paraplegia 7 (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Clinical Genomics Laboratory, Stanford Medicine Accession: SCV001427239.1 First in ClinVar: Aug 24, 2020 Last updated: Aug 24, 2020	Comment: The p.Ala510Val variant in the SPG7 gene has been previously reported in >30 unrelated individuals with ataxia and co-segregated with disease in 12 affected relatives … (more) The p.Ala510Val variant in the SPG7 gene has been previously reported in >30 unrelated individuals with ataxia and co-segregated with disease in 12 affected relatives from 5 families(Mancini et al., 2019; Ngo et al., 2020; Roxburgh et al., 2013;Sun et al., 2019). All affected individuals were homozygous/compound heterozygous. The p.Ala510Val variant has previously been identified in trans with multiple different disease-associated variants consistent with autosomal recessive inheritance.The presence of this variant with a likely disease causing variant on the opposite allele increases suspicion for its pathogenicity. This variant has been identified in 621/129,168 European (non-Finnish)chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org/).Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency.Computational tools predict that this variant is deleterious; however, the accuracy of in silico algorithms is limited.Functional studies of this variant are supportive of a deleterious effect to the protein; however, the current available evidence is not sufficient to support a disease-causing effect (Bonn et al., 2010).These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Ala510Val variant as pathogenic for autosomal recessive spastic paraplegia 7based on the information above. [ACMG evidence codes used: PM3_VeryStrong;PP3; PP1] (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, Amsterdam University Medical Center Study: VKGL Data-share Consensus Accession: SCV001808652.1 First in ClinVar: Aug 27, 2021 Last updated: Aug 27, 2021
not provided (-)	no classification provided Method: phenotyping only	Hereditary spastic paraplegia 7 Affected status: yes Allele origin: unknown	GenomeConnect, ClinGen Accession: SCV000607222.1 First in ClinVar: Apr 16, 2017 Last updated: Apr 16, 2017	Comment: GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical … (more) GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less) Clinical Features: Hypermetropia (present) , Abnormality of eye movement (present) , Abnormality of movement (present) , Memory impairment (present) , Hypertonia (present) , Abnormality of coordination (present) … (more) Hypermetropia (present) , Abnormality of eye movement (present) , Abnormality of movement (present) , Memory impairment (present) , Hypertonia (present) , Abnormality of coordination (present) , Cognitive impairment (present) , Morphological abnormality of the central nervous system (present) (less) Indication for testing: Diagnostic, Autosomal recessive spastic paraplegia type 7 Age: 50-59 years Sex: male Testing laboratory: Genetic Services Laboratory,University of Chicago Date variant was reported to submitter: 2017-06-13 Testing laboratory interpretation: Pathogenic
not provided (-)	no classification provided Method: phenotyping only	Hereditary spastic paraplegia 7 Affected status: unknown Allele origin: unknown	GenomeConnect - Invitae Patient Insights Network Accession: SCV001749915.1 First in ClinVar: Jul 18, 2021 Last updated: Jul 18, 2021	Comment: Variant interpreted as Pathogenic and reported on 12-16-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report … (more) Variant interpreted as Pathogenic and reported on 12-16-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. (less) Clinical Features: Abnormality of the nervous system (present) Indication for testing: Diagnostic Age: 40-49 years Sex: male Testing laboratory: Invitae Date variant was reported to submitter: 2020-12-16 Testing laboratory interpretation: Pathogenic
not provided (-)	no classification provided Method: literature only	Hereditary spastic paraplegia 7 Affected status: unknown Allele origin: germline	GeneReviews Accession: SCV004034077.1 First in ClinVar: Sep 16, 2023 Last updated: Sep 16, 2023	Publications: PubMed (3) PubMed: 22571692‚ 25681447‚ 26626314 Bookshelf: NBK1107 Bookshelf: NBK1107
not provided (-)	no classification provided Method: phenotyping only	Hereditary spastic paraplegia 7 Affected status: unknown Allele origin: unknown	GenomeConnect - Brain Gene Registry Accession: SCV004176873.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023	Comment: Variant classified as Pathogenic and reported on 11-08-2022 by Children's Hospital of Philadelphia. Assertions are reported exactly as they appear on the patient provided laboratory … (more) Variant classified as Pathogenic and reported on 11-08-2022 by Children's Hospital of Philadelphia. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. (less) Clinical Features: Abnormal brain morphology (present) , Dysplastic corpus callosum (present) , Ventriculomegaly (present) Indication for testing: Diagnostic Age: 0-9 years Sex: female Method: Exome Sequencing Testing laboratory: Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia Date variant was reported to submitter: 2022-11-08 Testing laboratory interpretation: Pathogenic
Uncertain significance (Feb 14, 2018)	Flagged submission flagged submission (ACMG Guidelines, 2015) Method: research Reason: Outlier claim with insufficient supporting evidence Source: ClinGen	Optic nerve hypoplasia (Autosomal dominant inheritance) Affected status: yes Allele origin: maternal	Rare Disease Group, Clinical Genetics, Karolinska Institutet Accession: SCV000681423.1 First in ClinVar: Aug 17, 2018 Last updated: Aug 17, 2018	Comment: This particular variant has been described previously in spastic paraplegia, both in autosomal recessive inheritance and some individuals with autosomal dominant inheritance. Another variant in … (more) This particular variant has been described previously in spastic paraplegia, both in autosomal recessive inheritance and some individuals with autosomal dominant inheritance. Another variant in SPG7 has been seen in autosomal dominant neuropathy. This individual has optic nerve hypoplasia, intellectual disability, bilateral spastic cerebral palsy, epilepsy, microcephaly and facial asymmetry. The significance for this variant for some of these phenotypes is uncertain. (less) Clinical Features: Intellectual disability (present) , Cerebral palsy (present) , Microcephaly (present) , Facial asymmetry (present) , Seizure (present) Age: 20-29 years Sex: male Ethnicity/Population group: Caucasian Geographic origin: Sweden
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Comment:

The c.1529C>T (p.Ala510Val) variant has been reported in at least 12 studies in which it is found in at least 70 patients, including 13 in a homozygous state, 47 in a compound heterozygous state, and ten in a heterozygous state with no second variant identified. The variant was also found in a heterozygous state in four unaffected siblings of patients (Elleuch et al. 2007; Arnoldi et al. 2008; Brugman et al. 2008; Bonn et al. 2010; Schlipf et al. 2011; Klebe et al. 2012; Roxburgh et al. 2013; SÃ¡nchez-Ferrero et al. 2013; Yoon et al. 2013; Pfeffer et al. 2014; Pyle et al. 2015; Choquet et al. 2016). The p.Ala510Val variant was identified in a heterozygous state in five of 777 control individuals and in two of 200 control chromosomes, and is reported at a frequency of 0.00497 in the European population of the 1000 Genomes Project. Of note, this variant is also reported in a homozygous state in two individuals in the Exome Aggregation Consortium, however, given the wide variability in age of onset seen in this disorder, the presence of two homozygotes in this database does not provide evidence against pathogenicity. Bonn et al. (2010) conducted yeast complementation assays to study the activity of paraplegin variants identified in their study, and found that the p.Ala510Val variant demonstrated impaired proteolytic function in this assay. Based on the collective evidence, the p.Ala510Val variant is classified as pathogenic for spastic paraplegia.

Comment:

This variant is interpreted as a Likely Pathogenic, for Spastic paraplegia 7, autosomal recessive, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS3-Moderate => Functional assay shows a deleterious effect. (PMID:20186691). PM3 => For recessive disorders, detected in trans with a pathogenic variant (PMID:25681447). PS4-Moderate => Recurrent mutation (PMID:22571692,26626314,26506339,25681447). PP1-Moderate => PP1 upgraded in strength to Moderate (PMID:26626314,23065789,26506339).

Comment:

Yeast expression studies found that the A510V variant perturbs the proteolytic function of paraplegin (Bonn et al., 2010); This variant is associated with the following publications: (PMID: 20186691, 31316545, 25681447, 22571692, 21623769, 11222789, 27081526, 22964162, 23269439, 20981092, 22995991, 18799786, 16534102, 31433872, 31692161, 32040484, 32161564, 31980526, 32581362, 33059505, 34426522, 32893728, 33144682, 33300680, 32447552, 33157434, 33084218, 33841295, 29867446, 33726816)

Comment:

This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls, and is reported in the literature as the most common pathogenic SPG7 variant (PMID: 30098094, 24727571, 27165006, 28444220; Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant associates with disease in multiple families (PMID: 16534102, 25681447). A yeast complementation study demonstrated that this variant disrupts proteolytic function (PMID: 20186691). 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.

Comment:

The p.Ala510Val variant in SPG7 has been previously identified in >25 homozygous or compound heterozygous individuals with spastic paraplegia type 7 (Elluch 2006 PMID: 16534102, Brugman 2008 PMID: 18799786, Bonn 2010 PMID: 20186691, Schlipf 2011 PMID: 21623769, Roxburgh 2013 PMID: 23269439, Sanchez-Ferrero 2013 PMID: 22571692, Yoon 2013 PMID: 23733235, Gass 2017 PMID: 29026558, Bhattacharjee 2017 PMID: 29057857, Morais 2017 PMID: 28832565, Iqbal 2017 PMID: 28362824). Though the variant is a common cause of spastic paraplegia type 7 in individuals of British ancestry, it may be associated with a late age of onset and/or reduced penetrance (Roxburgh 2013 PMID: 23269439). This variant has been identified in 0.6% (417/68040) of European chromosomes (including 2 homozygotes) by gnomAD v3.1.2 (http://gnomad.broadinstitute.org). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. It has also been reported in ClinVar (Variation ID 42016). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Functional assays suggest the p.Ala510Val variant may lead to proteolytic deficiency (Bonn 2010 PMID: 20186691); however, these types of assays may not accurately reflect biological function. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive spastic paraplegia type 7. ACMG/AMP Criteria applied: PS3_Supporting, PP3, PM3_VeryStrong.

Comment:

PM2_supporting: the highest population allele frequency in gnomAD v4.0 is 0.007265 (0.72%; 8558/1178040 alleles in European non-Finnish population). 41 homozygotes present. The heterozygous carrier frequency is 8558/1178040=~1% which should give rise to a disease prevalence of 2.5/100,000 which is not inconsistent with reported figures (the prevalence of SPG7 is estimated at between 1:100,000 and 9:100,000 for most countries https://www.ncbi.nlm.nih.gov/books/NBK1107/). This variant is the most common mutation causing adult onset neurogenetic disease in patients of British ancestry (PMID 23269439). PP3_moderate: REVEL score is 0.92. PM3_very_strong: >4 points: max 1 point awarded for multiple homozygous occurrences of the variant in affected unrelated probands (PMID 23269439, PMID 22964162) and >3 points awarded for co-occurrence of the variant with other pathogenic/likely pathogenic SPG7 variants in multiple unrelated probands (compound heterozygotes) (PMID 22964162, PMID 32973427). PS3_supporting: functional studies provide supportive evidence that this variant has a damaging effect on the gene or gene product (PMID 20186691, PMID 32973427). PS4 not evaluated as literature probands counted under PM3. Sequencing funded by the International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD): https://www.ucl.ac.uk/genomic-medicine-neuromuscular-diseases/.

Comment:

The c.1529C>T;p.(Ala510Val) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID 42016; OMIM 602783.0012; PMID 18799786; 22571692; 29246844; 30537300; 26626314; 25681447; 23065789; 25681447) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 20186691) - PS3_moderate. The p.(Ala510Val) was detected in trans with a pathogenic variant (PMID 25681447) - PM3. The variant co-segregated with disease in multiple affected family members (PMID:26626314; 23065789; 26506339) - PP1_moderate. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. and allele frequency is greater than expected for disorder -BS1. In summary, the currently available evidence indicates that the variant is pathogenic.

Comment:

It is observed in the gnomAD v2.1.1 ( https://gnomad.broadinstitute.org ) dataset at total allele frequency of 0.290%. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 20186691). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.92). The variant has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000042016). A different missense change at the same codon (p.Ala510Leu) has been reported to be associated with SPG7-related disorder (ClinVar ID: VCV000989124). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 510 of the SPG7 protein (p.Ala510Val). This variant is present in population databases (rs61755320, gnomAD 0.5%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with autosomal recessive hereditary spastic paraplegia (PMID: 16534102, 18200586, 18799786, 22571692, 22964162, 23269439). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 42016). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SPG7 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SPG7 function (PMID: 20186691). For these reasons, this variant has been classified as Pathogenic.

Comment:

The SPG7 c.1529C>T; p.Ala510Val variant (ClinVar Variation ID: 42016) is one of the most common SPG7 variants found in late onset, recessively inherited ataxia. Numerous homozygous individuals and individuals shown to be bialleleic or presumed to be biallelic with additional SPG7 variants have been identified in cohorts of ataxia patients (Gass 2017, Mancini 2019, Pfeffer 2015, Roxburgh 2013). This variant is found in the general population with an overall allele frequency of 0.29% (820/282,858 alleles, including 2 homozygotes) in the Genome Aggregation Database (v2.1.1). This variant is usually associated with a late age of onset (44 years) with initial symptoms related to gait disturbances (Mancini 20019). Functional analyses have demonstrated impaired respiratory growth and proteolytic processing of MrpL32 in a yeast complementation assay (Bonn 2010). Based on the available information, this variant is considered pathogenic. References: Bonn F et al. Functional evaluation of paraplegin mutations by a yeast complementation assay. Hum Mutat. 2010 May;31(5):617-21. Gass J et al. Expanded phenotype in a patient with spastic paraplegia 7. Clin Case Rep. 2017 Aug 24;5(10):1620-1622. Mancini C et al. Prevalence and phenotype of the c.1529C>T SPG7 variant in adult-onset cerebellar ataxia in Italy. Eur J Neurol. 2019 Jan;26(1):80-86. Pfeffer G et al. SPG7 mutations are a common cause of undiagnosed ataxia. Neurology. 2015 Mar 17;84(11):1174-6. Roxburgh RH et al. The p.Ala510Val mutation in the SPG7 (paraplegin) gene is the most common mutation causing adult onset neurogenetic disease in patients of British ancestry. J Neurol. 2013 May;260(5):1286-94.

Comment:

This sequence change in SPG7 is predicted to replace alanine with valine at codon 510, p.(Ala510Val). The alanine residue is highly conserved (100 vertebrates, UCSC), and is located in the AAA domain. There is a moderate physicochemical difference between alanine and valine. The highest population minor allele frequency in gnomAD v2.1 is 0.5% (621/129,168 alleles, 1 homozygote) in the European (non-Finnish) population, which is higher than expected for a recessive disorder. This variant has been detected as homozygous and compound heterozygous with a second pathogenic variant in many individuals with hereditary spastic paraplegia and adult-onset cerebellar ataxia (PMID: 20186691, 23269439, 30098094, 32153140). The variant has been reported to segregate with spastic paraplegia/ataxia in multiple families (PMID: 23269439, 30098094). Complementation assays in yeast showed impaired respiratory growth indicating that this variant impacts protein function (PMID: 20186691). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.923). Based on the classification scheme RMH Modified ACMG Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PP1_Strong, PS3_Supporting, PP3, BS1.

Comment:

The c.1529C>T (p.A510V) alteration is located in coding exon 11 of the SPG7 gene. This alteration results from a C to T substitution at nucleotide position 1529, causing the alanine (A) at amino acid position 510 to be replaced by a valine (V). Based on data from the Genome Aggregation Database (gnomAD), the SPG7 c.1529C>T alteration was observed in 0.29% (820/282858) of total alleles studied, with two homozygotes observed, and a frequency of 0.48% (621/129168) in the European (non-Finnish) subpopulation. This mutation, which is the most frequently identified SPG7 mutation, has been detected in the homozygous and compound heterozygous states in multiple unrelated patients affected with SPG7-related spastic paraplegia and has been shown to segregate with disease in multiple families (Bonn, 2010; Roxburgh, 2013; Sánchez-Ferrero, 2013; Pfeffer, 2015; Choquet, 2016; Mancini, 2019). Variable expressivity has been reported, even among family members with the same genotype (Roxburgh, 2013). In addition, this variant is present at significantly higher rates in patients versus controls (Sanchez-Ferror, 2013; Mancini, 2019). This amino acid position is highly conserved in available vertebrate species. A yeast complementation assay demonstrated loss of of proteolytic activity of the A510V mutant protein under certain conditions (Bonn, 2010). The p.A510V alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.

Comment:

Variant summary: SPG7 c.1529C>T (p.Ala510Val) results in a non-conservative amino acid change located in the AAA ATPase, AAA+ lid domain (IPR041569) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0029 in 251478 control chromosomes in the gnomAD database, including 2 homozygotes. This frequency does not allow conclusions about variant significance as age-related reduced penetrance in adults with this variant has been observed (example, Roxburgh_2013). c.1529C>T has been widely reported in the literature as biallelic homozygous or compound heterozygous genotypes in multiple individuals affected with Hereditary Spastic Paraplegia 7 (example, Roxburgh_20013, Sanchez-Ferrero_2013, Bonn_2010, Pyle_2015, Mancini_2019, Wali_2020). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence in a yeast complementation assay system that this missense change perturbs the proteotypic function of the hetero-oligomeric m-AAA protease (Bonn_2010). Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

This sequence variant is a single nucleotide substitution (C>T) at position 1529 of the coding sequence of the SPG7 gene that results in an alanine to valine amino acid change at residue 510 of the SPG7 encoded protein, paraplegin. The 510 residue falls in the AAA+ Lid domain which plays a role in paraplegin's ATPase activity (PMID: 32973427). This is a previously reported variant (ClinVar 42016) that has been observed in homozygous, compound heterozygous, and monoallelic heterozygous individuals affected by a variety of movement disorders including hereditary spastic paraplegia, Parkingson's disease, progressive muscle atrophy, and ataxia (PMID: 32973427, 35586535, 28444220, 22571692, 37213040, 20301286, 29246844, 29915382, 30098094, 32040484, 20186691, 26506339, 31068484). In addition, this variant has been shown to be associated with an increased risk of developing hereditary spastic paraplegia (PMID: 33598982) or Parkingson's disease (PMID: 30537300) and has cosegregated with hereditary spastic paraplegia in several families (PMID: 23269439, 22571692, 23065789). This variant is present in 9342 of 1611950 alleles (0.5795%) in the gnomAD v4.1.0 population dataset. Several studies have suggested that this variant may have reduced penetrance and/or variable expressivity (PMID: 37213040, 33598982). Multiple bioinformatic tools predict that this amino acid change would be damaging, and the Ala510 residue at this position is highly conserved across the vertebrate species examined. Studies in yeast and patient-derived stem cells indicate that this variant confers an increased expression of paraplegin and multiple mitochondrial dysfunctions (PMID: 32973427, 20186691). Based upon the evidence, we consider this a pathogenic variant with reduced penetrance and/or variable expressivity. ACMG Criteria: PM3, PP1, PP3, PS3, PS4

Comment:

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with spastic paraplegia 7 (MIM#607259) and optical atrophy (MONDO#0003608). (I) 0108 - This gene is associated with both recessive and dominant disease. This gene is associated with autosomal recessive spastic paraplegia 7 and autosomal dominant optical atrophy (PMIDs: 31854126, 32548275). (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to valine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 (816 heterozygotes, 2 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (p.(Ala510Thr): 1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated AAA+ lid domain (DECIPHER). (I) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. This variant has previously been reported as likely pathogenic or pathogenic in at least ten individuals with spastic paraplegia 7 and is the most common pathogenic variant found across different populations (ClinVar, GeneReviews, PMIDs: 24727571, 30098094). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional studies show that this variant impairs protein function (PMID: 20186691). (SP) 1206 - This variant has been shown to be paternally inherited (by segregation analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Comment:

DNA sequence analysis of the SPG7 gene demonstrated a sequence change, c.1529C>T, in exon 11 that results in an amino acid change, p.Ala510Val. This sequence change has been described in the gnomAD database with a frequency of 0.48% in the non-Finnish European subpopulation (dbSNP rs61755320). This sequence change has previously been identified in the homozygous and compound heterozygous states in individuals and families with hereditary spastic paraplegia (PMIDs: 26626314, 30098094, 23269439, 16534102) and is one of the common pathogenic variants described in the SPG7 gene. The p.Ala510Val change affects a highly conserved amino acid residue located in a known functional domain of the SPG7 protein. The p.Ala510Val substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Functional studies show p.Ala510Val impairs the function of the SPG7 protein (PMID: 20186691). Collectively this evidence suggests p.Ala510Val is pathogenic.

Comment:

The SPG7 c.1529C>T variant is predicted to result in the amino acid substitution p.Ala510Val. This variant has been repeatedly reported in the compound heterozygous and homozygous states to be causative for hereditary spastic paraplegia with variable age of onset and severity (Sánchez-Ferrero et al. 2013. PubMed ID: 22571692; van Gassen et al. 2012. PubMed ID: 22964162; Roxburgh et al. 2013. PubMed ID: 23269439). This variant has been reported at a subpopulation frequency of ≤0.48% in a database of individuals with unknown phenotype, including two homozygous individuals. This allele frequency is slightly high for a pathogenic variant; but, given the wide range in age of onset, does not rule out pathogenicity. This variant is significantly more frequent in patients than healthy controls (3% vs 1%) (Sánchez-Ferrero et al. 2013. PubMed ID: 22571692). Functional characterization of SPG7 variants by a yeast complementation assay suggests that this variant impairs protein function (Bonn et al. 2010. PubMed ID: 20186691). Taken together, these data indicate this variant is likely pathogenic in an autosomal recessive manner with variable age of onset and severity.

Comment:

The p.Ala510Val variant in the SPG7 gene has been previously reported in >30 unrelated individuals with ataxia and co-segregated with disease in 12 affected relatives from 5 families(Mancini et al., 2019; Ngo et al., 2020; Roxburgh et al., 2013;Sun et al., 2019). All affected individuals were homozygous/compound heterozygous. The p.Ala510Val variant has previously been identified in trans with multiple different disease-associated variants consistent with autosomal recessive inheritance.The presence of this variant with a likely disease causing variant on the opposite allele increases suspicion for its pathogenicity. This variant has been identified in 621/129,168 European (non-Finnish)chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org/).Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency.Computational tools predict that this variant is deleterious; however, the accuracy of in silico algorithms is limited.Functional studies of this variant are supportive of a deleterious effect to the protein; however, the current available evidence is not sufficient to support a disease-causing effect (Bonn et al., 2010).These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Ala510Val variant as pathogenic for autosomal recessive spastic paraplegia 7based on the information above. [ACMG evidence codes used: PM3_VeryStrong;PP3; PP1]

Comment:

This particular variant has been described previously in spastic paraplegia, both in autosomal recessive inheritance and some individuals with autosomal dominant inheritance. Another variant in SPG7 has been seen in autosomal dominant neuropathy. This individual has optic nerve hypoplasia, intellectual disability, bilateral spastic cerebral palsy, epilepsy, microcephaly and facial asymmetry. The significance for this variant for some of these phenotypes is uncertain.

Comment:

Variant interpreted as Pathogenic and reported on 12-16-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

Comment:

Variant classified as Pathogenic and reported on 11-08-2022 by Children's Hospital of Philadelphia. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/.

Germline Functional Evidence

Functional Help The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence	Method Help A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter.	Result Help A brief description of the result of this method for this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
variation affecting protein (VariO:0002)	Method not provided	Result not provided	Rare Disease Group, Clinical Genetics, Karolinska Institutet Accession: SCV000681423.1

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
The mutational profile in a South African cohort with inherited neuropathies and spastic paraplegia.	Mahungu AC	Frontiers in neurology	2023	PMID: 37712079
An SPG7 mutation as a novel cause of monogenic progressive muscular atrophy.	Pereira Â	Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology	2023	PMID: 37213040
Spastic Paraplegia Type 7 and Movement Disorders: Beyond the Spastic Paraplegia.	Sáenz-Farret M	Movement disorders clinical practice	2022	PMID: 35586535
Evidence for Non-Mendelian Inheritance in Spastic Paraplegia 7.	Estiar MA	Movement disorders : official journal of the Movement Disorder Society	2021	PMID: 33598982
Mitochondrial Function in Hereditary Spastic Paraplegia: Deficits in SPG7 but Not SPAST Patient-Derived Stem Cells.	Wali G	Frontiers in neuroscience	2020	PMID: 32973427
Whole-genome sequencing of patients with rare diseases in a national health system.	Turro E	Nature	2020	PMID: 32581362
Mutations in the m-AAA proteases AFG3L2 and SPG7 are causing isolated dominant optic atrophy.	Charif M	Neurology. Genetics	2020	PMID: 32548275
Targeted gene panel use in 2249 neuromuscular patients: the Australasian referral center experience.	Beecroft SJ	Annals of clinical and translational neurology	2020	PMID: 32153140
Whole genome sequencing unveils genetic heterogeneity in optic nerve hypoplasia.	Dahl S	PloS one	2020	PMID: 32040484
A deep intronic splice variant advises reexamination of presumably dominant SPG7 Cases.	Verdura E	Annals of clinical and translational neurology	2020	PMID: 31854126
Loss of paraplegin drives spasticity rather than ataxia in a cohort of 241 patients with SPG7.	Coarelli G	Neurology	2019	PMID: 31068484
Utility and implications of exome sequencing in early-onset Parkinson's disease.	Trinh J	Movement disorders : official journal of the Movement Disorder Society	2019	PMID: 30537300
Prevalence and phenotype of the c.1529C>T SPG7 variant in adult-onset cerebellar ataxia in Italy.	Mancini C	European journal of neurology	2019	PMID: 30098094
Targeted exome analysis identifies the genetic basis of disease in over 50% of patients with a wide range of ataxia-related phenotypes.	Sun M	Genetics in medicine : official journal of the American College of Medical Genetics	2019	PMID: 29915382
SPG7 with parkinsonism responsive to levodopa and dopaminergic deficit.	Pedroso JL	Parkinsonism & related disorders	2018	PMID: 29246844
Spastic Paraplegia 7.	Adam MP	-	2018	PMID: 20301286
Case series of autosomal recessive hereditary spastic paraparesis with novel mutation in SPG 7 gene.	Bhattacharjee S	Neurosciences (Riyadh, Saudi Arabia)	2017	PMID: 29057857
Expanded phenotype in a patient with spastic paraplegia 7.	Gass J	Clinical case reports	2017	PMID: 29026558
Massive sequencing of 70 genes reveals a myriad of missing genes or mechanisms to be uncovered in hereditary spastic paraplegias.	Morais S	European journal of human genetics : EJHG	2017	PMID: 28832565
A panel study on patients with dominant cerebellar ataxia highlights the frequency of channelopathies.	Coutelier M	Brain : a journal of neurology	2017	PMID: 28444220
Targeted high throughput sequencing in hereditary ataxia and spastic paraplegia.	Iqbal Z	PloS one	2017	PMID: 28362824
Clinical and genetic study of hereditary spastic paraplegia in Canada.	Chrestian N	Neurology. Genetics	2016	PMID: 27957547
Clinical exome sequencing for cerebellar ataxia and spastic paraplegia uncovers novel gene-disease associations and unanticipated rare disorders.	van de Warrenburg BP	European journal of human genetics : EJHG	2016	PMID: 27165006
Genetic background of the hereditary spastic paraplegia phenotypes in Hungary - An analysis of 58 probands.	Balicza P	Journal of the neurological sciences	2016	PMID: 27084228
SPG7 mutations explain a significant proportion of French Canadian spastic ataxia cases.	Choquet K	European journal of human genetics : EJHG	2016	PMID: 26626314
Abnormal Paraplegin Expression in Swollen Neurites, τ- and α-Synuclein Pathology in a Case of Hereditary Spastic Paraplegia SPG7 with an Ala510Val Mutation.	Thal DR	International journal of molecular sciences	2015	PMID: 26506339
SPG7 mutations are a common cause of undiagnosed ataxia.	Pfeffer G	Neurology	2015	PMID: 25681447
Exome sequencing in undiagnosed inherited and sporadic ataxias.	Pyle A	Brain : a journal of neurology	2015	PMID: 25497598
Mutations in the SPG7 gene cause chronic progressive external ophthalmoplegia through disordered mitochondrial DNA maintenance.	Pfeffer G	Brain : a journal of neurology	2014	PMID: 24727571
Autosomal recessive hereditary spastic paraplegia-clinical and genetic characteristics of a well-defined cohort.	Yoon G	Neurogenetics	2013	PMID: 23733235
The p.Ala510Val mutation in the SPG7 (paraplegin) gene is the most common mutation causing adult onset neurogenetic disease in patients of British ancestry.	Roxburgh RH	Journal of neurology	2013	PMID: 23269439
SPG7 mutational screening in spastic paraplegia patients supports a dominant effect for some mutations and a pathogenic role for p.A510V.	Sánchez-Ferrero E	Clinical genetics	2013	PMID: 22571692
Spastic paraplegia gene 7 in patients with spasticity and/or optic neuropathy.	Klebe S	Brain : a journal of neurology	2012	PMID: 23065789
Genotype-phenotype correlations in spastic paraplegia type 7: a study in a large Dutch cohort.	van Gassen KL	Brain : a journal of neurology	2012	PMID: 22964162
Amplicon-based high-throughput pooled sequencing identifies mutations in CYP7B1 and SPG7 in sporadic spastic paraplegia patients.	Schlipf NA	Clinical genetics	2011	PMID: 21623769
Functional evaluation of paraplegin mutations by a yeast complementation assay.	Bonn F	Human mutation	2010	PMID: 20186691
Paraplegin mutations in sporadic adult-onset upper motor neuron syndromes.	Brugman F	Neurology	2008	PMID: 18799786
A clinical, genetic, and biochemical characterization of SPG7 mutations in a large cohort of patients with hereditary spastic paraplegia.	Arnoldi A	Human mutation	2008	PMID: 18200586
Refinement of the SPG15 candidate interval and phenotypic heterogeneity in three large Arab families.	Elleuch N	Neurogenetics	2007	PMID: 17661097
Mutation analysis of the paraplegin gene (SPG7) in patients with hereditary spastic paraplegia.	Elleuch N	Neurology	2006	PMID: 16534102
A clinical, genetic and biochemical study of SPG7 mutations in hereditary spastic paraplegia.	Wilkinson PA	Brain : a journal of neurology	2004	PMID: 14985266
Paraplegin gene analysis in hereditary spastic paraparesis (HSP) pedigrees in northeast England.	McDermott CJ	Neurology	2001	PMID: 11222789
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SPG7	-	-	-	-
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Text-mined citations for rs61755320 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_003119.4(SPG7):c.1529C>T (p.Ala510Val)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs61755320 ...