ClinVar Miner

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

gnomAD frequency: 0.00361  dbSNP: rs61755320
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 56
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000034858 SCV000219172 pathogenic Hereditary spastic paraplegia 7 2024-01-28 criteria provided, single submitter clinical testing 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000515835 SCV000221215 pathogenic Hereditary spastic paraplegia 2023-03-23 criteria provided, single submitter clinical testing 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.
Eurofins Ntd Llc (ga) RCV000195683 SCV000225309 likely pathogenic not provided 2015-03-04 criteria provided, single submitter clinical testing
Neurogenetics of motion laboratory, Montreal Neurological Institute RCV000034858 SCV000245719 pathogenic Hereditary spastic paraplegia 7 criteria provided, single submitter case-control
GeneDx RCV000195683 SCV000252339 pathogenic not provided 2021-05-03 criteria provided, single submitter clinical testing 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)
Illumina Laboratory Services, Illumina RCV000270813 SCV000399754 pathogenic Spastic Paraplegia, Recessive 2016-06-14 criteria provided, single submitter clinical testing 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; Sánchez-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.
Unit for Genetic & Epidemiological Research on Neurological Disorders, Instituto de Investigação e Inovação em Saúde RCV000515835 SCV000574457 pathogenic Hereditary spastic paraplegia 2017-03-07 criteria provided, single submitter research
Fulgent Genetics, Fulgent Genetics RCV000034858 SCV000611242 likely pathogenic Hereditary spastic paraplegia 7 2017-05-18 criteria provided, single submitter clinical testing
Athena Diagnostics RCV000195683 SCV000615433 pathogenic not provided 2022-05-03 criteria provided, single submitter clinical testing 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.
Center of Genomic medicine, Geneva, University Hospital of Geneva RCV000034858 SCV000693453 pathogenic Hereditary spastic paraplegia 7 2017-08-07 criteria provided, single submitter clinical testing This recessive SPG7 variant was found in compound heterozygosity with one another recessive SPG7 variant in a female patient with spastic paraplegia 7
Ambry Genetics RCV000623796 SCV000742948 pathogenic Inborn genetic diseases 2021-07-23 criteria provided, single submitter clinical testing 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.
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000034858 SCV000745330 pathogenic Hereditary spastic paraplegia 7 2017-05-31 criteria provided, single submitter clinical testing
Undiagnosed Diseases Network, NIH RCV000034858 SCV000746604 pathogenic Hereditary spastic paraplegia 7 2018-10-05 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana RCV000626837 SCV000747540 pathogenic Dysarthria; Gait ataxia; Cerebral cortical atrophy; Spastic paraparesis 2017-01-01 criteria provided, single submitter clinical testing
SIB Swiss Institute of Bioinformatics RCV000034858 SCV000803517 likely pathogenic Hereditary spastic paraplegia 7 2018-05-31 criteria provided, single submitter curation 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).
Raymond Lab, University of Cambridge RCV000850200 SCV000897738 likely pathogenic Intellectual disability 2019-02-13 criteria provided, single submitter research
CeGaT Center for Human Genetics Tuebingen RCV000195683 SCV001151097 pathogenic not provided 2024-03-01 criteria provided, single submitter clinical testing SPG7: PM3:Very Strong, PP1:Strong, PM2:Supporting, PS3:Supporting
Centre for Mendelian Genomics, University Medical Centre Ljubljana RCV000034858 SCV001368404 likely pathogenic Hereditary spastic paraplegia 7 2019-12-03 criteria provided, single submitter clinical testing This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PM3,PP2,PP3,PP5.
Institute of Human Genetics, University of Leipzig Medical Center RCV000034858 SCV001440297 likely pathogenic Hereditary spastic paraplegia 7 2021-04-08 criteria provided, single submitter clinical testing This variant was identified as compound heterozygous with NM_003119.4:c.1552+1G>T.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000195683 SCV001447388 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital RCV000195683 SCV001450317 pathogenic not provided 2016-02-24 criteria provided, single submitter clinical testing
Paris Brain Institute, Inserm - ICM RCV000034858 SCV001451052 pathogenic Hereditary spastic paraplegia 7 criteria provided, single submitter clinical testing
Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris RCV000034858 SCV001519205 pathogenic Hereditary spastic paraplegia 7 2021-01-04 criteria provided, single submitter research
Baylor Genetics RCV000034858 SCV001522924 pathogenic Hereditary spastic paraplegia 7 2021-10-20 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000195683 SCV001715175 pathogenic not provided 2022-03-09 criteria provided, single submitter clinical testing PP3
Genomics England Pilot Project, Genomics England RCV000034858 SCV001760391 pathogenic Hereditary spastic paraplegia 7 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV000034858 SCV002023626 likely pathogenic Hereditary spastic paraplegia 7 2023-01-26 criteria provided, single submitter clinical testing
Centogene AG - the Rare Disease Company RCV000034858 SCV002059504 pathogenic Hereditary spastic paraplegia 7 2021-09-10 criteria provided, single submitter clinical testing
DASA RCV000034858 SCV002061281 pathogenic Hereditary spastic paraplegia 7 2022-01-05 criteria provided, single submitter clinical testing 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.
New York Genome Center RCV000034858 SCV002098960 pathogenic Hereditary spastic paraplegia 7 2021-03-15 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children RCV000515835 SCV002105846 pathogenic Hereditary spastic paraplegia 2022-01-04 criteria provided, single submitter clinical testing
Mendelics RCV000034858 SCV002519810 pathogenic Hereditary spastic paraplegia 7 2022-05-04 criteria provided, single submitter clinical testing
3billion RCV000034858 SCV002573329 pathogenic Hereditary spastic paraplegia 7 2022-09-01 criteria provided, single submitter clinical testing 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.
Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin RCV000034858 SCV002574835 pathogenic Hereditary spastic paraplegia 7 2022-09-22 criteria provided, single submitter clinical testing
MGZ Medical Genetics Center RCV000034858 SCV002581047 pathogenic Hereditary spastic paraplegia 7 2022-07-27 criteria provided, single submitter clinical testing
Human Genetics Bochum, Ruhr University Bochum RCV002463623 SCV002758630 pathogenic Frontotemporal dementia and/or amyotrophic lateral sclerosis 2 2022-09-02 criteria provided, single submitter clinical testing ACMG criteria used to clasify this variant: PS3, PM2, PS4, PP1, PM1, PP3
Genetics and Molecular Pathology, SA Pathology RCV000034858 SCV002761564 pathogenic Hereditary spastic paraplegia 7 2020-06-29 criteria provided, single submitter clinical testing
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München RCV000034858 SCV002764908 pathogenic Hereditary spastic paraplegia 7 2021-11-09 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000034858 SCV003922888 pathogenic Hereditary spastic paraplegia 7 2023-03-28 criteria provided, single submitter clinical testing 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.
Neurogenomics Lab, Neuroscience Institute, University Of Cape Town RCV000034858 SCV003930338 pathogenic Hereditary spastic paraplegia 7 2024-05-22 criteria provided, single submitter research 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/.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center RCV000034858 SCV004099090 pathogenic Hereditary spastic paraplegia 7 2023-08-31 criteria provided, single submitter clinical testing PS3_Moderate, PM3_VeryStrong, PP3
PreventionGenetics, part of Exact Sciences RCV003421943 SCV004118612 likely pathogenic SPG7-related disorder 2023-12-06 criteria provided, single submitter clinical testing The SPG7 c.1529C>T variant is predicted to result in the amino acid substitution p.Ala510Val. In the compound heterozygous and homozygous states, this variant has been repeatedly reported 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000034858 SCV004563041 pathogenic Hereditary spastic paraplegia 7 2023-10-06 criteria provided, single submitter clinical testing 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.
Molecular Genetics, Royal Melbourne Hospital RCV000034858 SCV004812497 pathogenic Hereditary spastic paraplegia 7 2023-07-07 criteria provided, single submitter clinical testing 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.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000034858 SCV005016514 likely pathogenic Hereditary spastic paraplegia 7 2023-12-07 criteria provided, single submitter clinical testing
OMIM RCV000034858 SCV000058462 pathogenic Hereditary spastic paraplegia 7 2013-03-01 no assertion criteria provided literature only
GenomeConnect, ClinGen RCV000034858 SCV000607222 not provided Hereditary spastic paraplegia 7 no assertion provided phenotyping only 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.
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000677252 SCV000681423 uncertain significance Optic nerve hypoplasia 2018-02-14 flagged submission research 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000195683 SCV000733558 pathogenic not provided no assertion criteria provided clinical testing
NIHR Bioresource Rare Diseases, University of Cambridge RCV001003619 SCV001162030 pathogenic Spastic ataxia; Sensorimotor neuropathy no assertion criteria provided research
Clinical Genomics Program, Stanford Medicine RCV000034858 SCV001427239 pathogenic Hereditary spastic paraplegia 7 2020-06-19 no assertion criteria provided clinical testing 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]
GenomeConnect - Invitae Patient Insights Network RCV000034858 SCV001749915 not provided Hereditary spastic paraplegia 7 no assertion provided phenotyping only 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.
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000195683 SCV001808652 pathogenic not provided no assertion criteria provided clinical testing
Genetic Services Laboratory, University of Chicago RCV000034858 SCV002064525 pathogenic Hereditary spastic paraplegia 7 2021-08-09 no assertion criteria provided clinical testing 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.
GeneReviews RCV000034858 SCV004034077 not provided Hereditary spastic paraplegia 7 no assertion provided literature only
GenomeConnect - Brain Gene Registry RCV000034858 SCV004176873 not provided Hereditary spastic paraplegia 7 no assertion provided phenotyping only 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/.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.