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rs61755320

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 6P and 6B. PM1PM5PP3PP5BP4BS1_SupportingBS2

The NM_003119.4(SPG7):c.1529C>T(p.Ala510Val) variant causes a missense change. The variant allele was found at a frequency of 0.0058 in 1,611,950 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A510L) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0036 ( 2 hom., cov: 32)
Exomes 𝑓: 0.0060 ( 42 hom. )

Consequence

SPG7
NM_003119.4 missense

Scores

8
3
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:49U:1O:4

Conservation

PhyloP100: 4.97
Variant links:
Genes affected
SPG7 (HGNC:11237): (SPG7 matrix AAA peptidase subunit, paraplegin) This gene encodes a mitochondrial metalloprotease protein that is a member of the AAA family. Members of this protein family share an ATPase domain and have roles in diverse cellular processes including membrane trafficking, intracellular motility, organelle biogenesis, protein folding, and proteolysis. Mutations in this gene cause autosomal recessive spastic paraplegia 7. Two transcript variants encoding distinct isoforms have been identified. [provided by RefSeq, Mar 2014]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance.

PM1
In a helix (size 9) in uniprot entity SPG7_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_003119.4
PM5
Other missense variant is known to change same aminoacid residue: Variant chr16-89546736-GC-TT is described in ClinVar as [Pathogenic]. Clinvar id is 989124.Status of the report is criteria_provided_single_submitter, 1 stars.
PP3
Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Dann, Eigen, M_CAP, REVEL [when MetaRNN, MutationTaster was below the threshold]
PP5
Variant 16-89546737-C-T is Pathogenic according to our data. Variant chr16-89546737-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 42016.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=33, Likely_pathogenic=9, not_provided=4, Uncertain_significance=1}. Variant chr16-89546737-C-T is described in Lovd as [Pathogenic]. Variant chr16-89546737-C-T is described in Lovd as [Likely_pathogenic].
BP4
Computational evidence support a benign effect (MetaRNN=0.030638576).. Strength limited to SUPPORTING due to the PP5.
BS1
Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.00603 (8795/1459650) while in subpopulation NFE AF= 0.00733 (8141/1110008). AF 95% confidence interval is 0.0072. There are 42 homozygotes in gnomad4_exome. There are 4197 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SPG7NM_003119.4 linkuse as main transcriptc.1529C>T p.Ala510Val missense_variant 11/17 ENST00000645818.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SPG7ENST00000645818.2 linkuse as main transcriptc.1529C>T p.Ala510Val missense_variant 11/17 NM_003119.4 P2Q9UQ90-1

Frequencies

GnomAD3 genomes
AF:
0.00359
AC:
546
AN:
152182
Hom.:
2
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00150
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00288
Gnomad ASJ
AF:
0.00173
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000830
Gnomad FIN
AF:
0.000848
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00613
Gnomad OTH
AF:
0.00192
GnomAD3 exomes
AF:
0.00292
AC:
735
AN:
251478
Hom.:
2
AF XY:
0.00299
AC XY:
407
AN XY:
135920
show subpopulations
Gnomad AFR exome
AF:
0.00123
Gnomad AMR exome
AF:
0.00208
Gnomad ASJ exome
AF:
0.00188
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000751
Gnomad FIN exome
AF:
0.00106
Gnomad NFE exome
AF:
0.00495
Gnomad OTH exome
AF:
0.00244
GnomAD4 exome
AF:
0.00603
AC:
8795
AN:
1459650
Hom.:
42
Cov.:
31
AF XY:
0.00578
AC XY:
4197
AN XY:
726296
show subpopulations
Gnomad4 AFR exome
AF:
0.000987
Gnomad4 AMR exome
AF:
0.00221
Gnomad4 ASJ exome
AF:
0.00203
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000661
Gnomad4 FIN exome
AF:
0.00137
Gnomad4 NFE exome
AF:
0.00733
Gnomad4 OTH exome
AF:
0.00557
GnomAD4 genome
AF:
0.00359
AC:
547
AN:
152300
Hom.:
2
Cov.:
32
AF XY:
0.00306
AC XY:
228
AN XY:
74478
show subpopulations
Gnomad4 AFR
AF:
0.00149
Gnomad4 AMR
AF:
0.00287
Gnomad4 ASJ
AF:
0.00173
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00104
Gnomad4 FIN
AF:
0.000848
Gnomad4 NFE
AF:
0.00613
Gnomad4 OTH
AF:
0.00190
Alfa
AF:
0.00490
Hom.:
3
Bravo
AF:
0.00371
TwinsUK
AF:
0.00620
AC:
23
ALSPAC
AF:
0.00467
AC:
18
ESP6500AA
AF:
0.00136
AC:
6
ESP6500EA
AF:
0.00453
AC:
39
ExAC
AF:
0.00252
AC:
306
Asia WGS
AF:
0.000866
AC:
3
AN:
3478
EpiCase
AF:
0.00594
EpiControl
AF:
0.00581

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:49Uncertain:1Other:4
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Hereditary spastic paraplegia 7 Pathogenic:30Other:4
Pathogenic, criteria provided, single submitterresearchMolecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella MarisJan 04, 2021- -
Pathogenic, no assertion criteria providedliterature onlyOMIMMar 01, 2013- -
Likely pathogenic, criteria provided, single submittercurationSIB Swiss Institute of BioinformaticsMay 31, 2018This 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 submitterclinical testingGenomics England Pilot Project, Genomics England-- -
Pathogenic, criteria provided, single submittercase-controlNeurogenetics of motion laboratory, Montreal Neurological Institute-- -
Likely pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsMay 18, 2017- -
Likely pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityJan 26, 2023- -
not provided, no classification providedliterature onlyGeneReviews-- -
not provided, no classification providedphenotyping onlyGenomeConnect, 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 submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMar 28, 2023Variant 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, no assertion criteria providedclinical testingClinical Genomics Program, Stanford MedicineJun 19, 2020The 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] -
not provided, no classification providedphenotyping onlyGenomeConnect - 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/. -
not provided, no classification providedphenotyping onlyGenomeConnect - 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 submitterclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical CenterMay 31, 2017- -
Pathogenic, no assertion criteria providedresearchNeurogenomics Lab, Neuroscience Institute, University Of Cape TownMay 31, 2023PM2_supporting: the highest population allele frequency in gnomAD v2.1.1 is 0.004808 (0.48%; 621/129168 alleles in European non-Finnish population) and in gnomAD v3.1.2 is 0.006129 (0.61%; 417/68040 alleles in European non-Finnish population) and the variant is absent from an internal database of 1074 control alleles. The heterozygous carrier frequency in gnomad v2.1.1 is 619/64584=~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. -
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsOct 20, 2021- -
Pathogenic, criteria provided, single submitterclinical testingInvitaeJan 28, 2024This 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 submitterclinical testingGreenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic CenterAug 31, 2023PS3_Moderate, PM3_VeryStrong, PP3 -
Pathogenic, criteria provided, single submitterclinical testingInstitute Of Human Genetics Munich, Klinikum Rechts Der Isar, Tu MünchenNov 09, 2021- -
Pathogenic, criteria provided, single submitterclinical testingUndiagnosed Diseases Network, NIHOct 05, 2018- -
Pathogenic, criteria provided, single submitterclinical testing3billionSep 01, 2022It 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. -
Pathogenic, criteria provided, single submitterclinical testingInstitute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin BerlinSep 22, 2022- -
Pathogenic, criteria provided, single submitterclinical testingMendelicsMay 04, 2022- -
Pathogenic, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesOct 06, 2023The 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 submitterclinical testingGenetics and Molecular Pathology, SA PathologyJun 29, 2020- -
Pathogenic, criteria provided, single submitterclinical testingParis Brain Institute, Inserm - ICM-- -
Pathogenic, criteria provided, single submitterclinical testingMGZ Medical Genetics CenterJul 27, 2022- -
Likely pathogenic, criteria provided, single submitterclinical testingCentre for Mendelian Genomics, University Medical Centre LjubljanaDec 03, 2019This 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 submitterclinical testingCentogene AG - the Rare Disease CompanySep 10, 2021- -
Pathogenic, criteria provided, single submitterclinical testingDASAJan 05, 2022The 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 providedclinical testingGenetic Services Laboratory, University of ChicagoAug 09, 2021DNA 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 submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterApr 08, 2021This variant was identified as compound heterozygous with NM_003119.4:c.1552+1G>T. -
Pathogenic, criteria provided, single submitterclinical testingNew York Genome CenterMar 15, 2021- -
Pathogenic, criteria provided, single submitterclinical testingCenter of Genomic medicine, Geneva, University Hospital of GenevaAug 07, 2017This recessive SPG7 variant was found in compound heterozygosity with one another recessive SPG7 variant in a female patient with spastic paraplegia 7 -
not provided Pathogenic:9
Pathogenic, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicMar 09, 2022PP3 -
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenDec 01, 2023SPG7: PM3:Very Strong, PP1:Strong, PM2:Supporting, PS3:Supporting -
Likely pathogenic, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Mar 04, 2015- -
Pathogenic, criteria provided, single submitterclinical testingClinical Genetics and Genomics, Karolinska University HospitalFeb 24, 2016- -
Pathogenic, criteria provided, single submitterclinical testingAthena Diagnostics IncMay 03, 2022This 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. -
Pathogenic, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, Amsterdam University Medical Center-- -
Pathogenic, criteria provided, single submitterclinical testingGeneDxMay 03, 2021Yeast 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) -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Medical Genetics and Applied Genomics, University Hospital TübingenOct 23, 2020- -
Pathogenic, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Hereditary spastic paraplegia Pathogenic:3
Pathogenic, criteria provided, single submitterclinical testingGenome Diagnostics Laboratory, The Hospital for Sick ChildrenJan 04, 2022- -
Likely pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineAug 09, 2018The 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 dinstitute.org). 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. -
Pathogenic, criteria provided, single submitterresearchUnit for Genetic & Epidemiological Research on Neurological Disorders, Instituto de Investigação e Inovação em SaúdeMar 07, 2017- -
SPG7-related condition Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesDec 06, 2023The 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. -
Frontotemporal dementia and/or amyotrophic lateral sclerosis 2 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingHuman Genetics Bochum, Ruhr University BochumSep 02, 2022ACMG criteria used to clasify this variant: PS3, PM2, PS4, PP1, PM1, PP3 -
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsJul 23, 2021The 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. -
Sensorimotor neuropathy;C1849156:Spastic ataxia Pathogenic:1
Pathogenic, no assertion criteria providedresearchNIHR Bioresource Rare Diseases, University of Cambridge-- -
Dysarthria;C0037771:Spastic paraparesis;C0751837:Gait ataxia;C4551583:Cerebral cortical atrophy Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingCentre for Mendelian Genomics, University Medical Centre LjubljanaJan 01, 2017- -
Spastic Paraplegia, Recessive Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016The 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. -
Intellectual disability Pathogenic:1
Likely pathogenic, criteria provided, single submitterresearchRaymond Lab, University of CambridgeFeb 13, 2019- -
Optic nerve hypoplasia Uncertain:1
Uncertain significance, criteria provided, single submitterresearchRare Disease Group, Clinical Genetics, Karolinska InstitutetFeb 14, 2018This 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.95
BayesDel_addAF
Pathogenic
0.18
D
BayesDel_noAF
Pathogenic
0.49
Cadd
Pathogenic
26
Dann
Pathogenic
1.0
Eigen
Pathogenic
0.70
Eigen_PC
Uncertain
0.62
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Pathogenic
0.99
D;D;D;D;D;D;D;D;D
M_CAP
Pathogenic
0.56
D
MetaRNN
Benign
0.031
T;T;T;T;T;T;T;T;T
MetaSVM
Pathogenic
1.1
D
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.54
T
Polyphen
1.0
.;.;D;.;.;.;.;.;.
MVP
0.97
MPC
0.78
ClinPred
0.018
T
GERP RS
5.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.81
gMVP
0.78

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs61755320; hg19: chr16-89613145; COSMIC: COSV51947555; COSMIC: COSV51947555; API