Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 18, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | DASA | Jan 05, 2022 | 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. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 2013 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Genetic Services Laboratory, University of Chicago | Aug 09, 2021 | 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jan 26, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Centogene AG - the Rare Disease Company | Sep 10, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 28, 2023 | 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 complimentation assay system that this missense change perturbs the protelotypic 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | New York Genome Center | Mar 15, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 28, 2024 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Genomics England Pilot Project, Genomics England | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Molecular Genetics, Royal Melbourne Hospital | Jul 07, 2023 | 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. - |
Pathogenic, criteria provided, single submitter | case-control | Neurogenetics of motion laboratory, Montreal Neurological Institute | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 20, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Center of Genomic medicine, Geneva, University Hospital of Geneva | Aug 07, 2017 | This recessive SPG7 variant was found in compound heterozygosity with one another recessive SPG7 variant in a female patient with spastic paraplegia 7 - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genomics Laboratory, Stanford Medicine | Jun 19, 2020 | 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] - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Apr 08, 2021 | This variant was identified as compound heterozygous with NM_003119.4:c.1552+1G>T. - |
not provided, no classification provided | phenotyping only | GenomeConnect - Invitae Patient Insights Network | - | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin | Sep 22, 2022 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Dec 03, 2019 | This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PM3,PP2,PP3,PP5. - |
not provided, no classification provided | phenotyping only | GenomeConnect, ClinGen | - | 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. - |
Pathogenic, criteria provided, single submitter | research | Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris | Jan 04, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Paris Brain Institute, Inserm - ICM | - | - - |
Pathogenic, criteria provided, single submitter | research | Neurogenomics Lab, Neuroscience Institute, University Of Cape Town | May 22, 2024 | 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/. - |
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Jul 27, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Jun 29, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Aug 31, 2023 | PS3_Moderate, PM3_VeryStrong, PP3 - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Nov 09, 2021 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | Dec 07, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Undiagnosed Diseases Network, NIH | Oct 05, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 06, 2023 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | May 31, 2017 | - - |
not provided, no classification provided | phenotyping only | GenomeConnect - Brain Gene Registry | - | 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/. - |
Likely pathogenic, criteria provided, single submitter | curation | SIB Swiss Institute of Bioinformatics | May 31, 2018 | 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). - |
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Sep 01, 2022 | 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. - |