ClinVar Miner

Submissions for variant NM_003119.2(SPG7):c.1529C>T (rs61755320)

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Total submissions: 22
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000034858 SCV000219172 pathogenic Spastic paraplegia 7 2018-12-06 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 510 of the SPG7 protein (p.Ala510Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs61755320, ExAC 0.3%). However, presence of this variant in the general population is not necessarily evidence against pathogenicity, as mutations in SPG7 have been associated with mild disease severity, variable phenotype, and late age of onset (PMID: 23269439, 16534102). This sequence change has been shown to segregate with disease in two large families affected with hereditary spastic paraplegia (PMID: 23269439, 16534102) and has been reported in the homozygous or compound heterozygous state in many affected families (PMID: 23269439, 16534102, 18200586, 18799786, 22571692, 22964162). ClinVar contains an entry for this variant (Variation ID: 42016). Experimental studies in yeast demonstrate that this missense change disrupts protein function (PMID: 20186691). In summary, this missense variant has been reported to disrupt protein function and segregate with disease in multiple families. While there is some debate in the literature over this variant, the available evidence indicates that it is causative for hereditary spastic paraplegia when homozygous or in combination with a second pathogenic variant. For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000515835 SCV000221215 likely pathogenic Hereditary spastic paraplegia 2018-08-09 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 200 6, Brugman 2008, Bonn 2010, Schlipf 2011, Roxburgh 2013, Sanchez-Ferrero 2013, Y oon 2013, Gass 2017, Bhattacharjee 2017, Morais 2017, Iqbal 2017). Though the va riant is a common cause of spastic paraplegia type 7 in individuals of British a ncestry, it may be associated with a late age of onset and/or reduced penetrance (Roxburugh 2013). This variant has been identified in 0.47% (599/126692) of Eur opean chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broa Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Functional assays suggest the p.Ala510Val variant may lead to proteolytic defic iency (Bonn 2010); however, these types of assays may not accurately reflect bio logical function. In summary, although additional studies are required to fully establish its clinical significance, the p.Ala510Val variant is likely pathogeni c. ACMG/AMP Criteria applied: PS3_Supporting, PS4, PM3_VeryStrong.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics 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 Spastic paraplegia 7 criteria provided, single submitter case-control
Genetic Services Laboratory, University of Chicago RCV000034858 SCV000249017 pathogenic Spastic paraplegia 7 2017-05-17 criteria provided, single submitter clinical testing
GeneDx RCV000195683 SCV000252339 pathogenic not provided 2017-09-12 criteria provided, single submitter clinical testing The A510V variant in the SPG7 gene has been reported as a common pathogenic variant identified along with a second variant in patients with spastic paraplegia or ataxia (Schlipf, et al., 2011, van Gassen et al., 2012, Sanchez-Ferrero et al., 2013; Pfeffer et al., 2015). The A510V variant has subsequently been found to segregate with disease in multiple populations and yeast expression studies found that A510V perturbs the function of the SPG7 protein (Bonn et al., 2010; Roxburgh et al., 2013; Schlipf et al., 2011). The A510V variant is observed in 267/66,688 (0.4%) alleles from individuals of European (Non-Finnish) background in the ExAC dataset, including two homozygous individuals (Lek et al., 2016). The A510V variant is a conservative amino acid substitution occurring at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, we interpret A510V as a pathogenic variant.
Illumina Clinical Services Laboratory,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 Spastic paraplegia 7 2017-05-18 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000195683 SCV000615433 pathogenic not provided 2018-06-01 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics,Karolinska Institutet RCV000677252 SCV000681423 uncertain significance Optic nerve hypoplasia 2018-02-14 criteria provided, single submitter 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.
Center of Genomic medicine, Geneva,University Hospital of Geneva RCV000034858 SCV000693453 pathogenic 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 2017-09-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000034858 SCV000745330 pathogenic Spastic paraplegia 7 2017-05-31 criteria provided, single submitter clinical testing
Undiagnosed Diseases Network,NIH RCV000034858 SCV000746604 pathogenic 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 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 Praxis fuer Humangenetik Tuebingen RCV000195683 SCV001151097 likely pathogenic not provided 2016-08-01 criteria provided, single submitter clinical testing
OMIM RCV000034858 SCV000058462 pathogenic Spastic paraplegia 7 2013-03-01 no assertion criteria provided literature only
GenomeConnect, ClinGen RCV000034858 SCV000607222 not provided 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.
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000034858 SCV000733558 likely pathogenic Spastic paraplegia 7 no assertion criteria provided clinical testing

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