rs61755320

chr16-89546737-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 13P and 2B. PM1 PM5 PP3 PP5_Very_Strong BP4 BS1_Supporting

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 Likely pathogenic (★★). 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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:51 U:1 O:4
• Conservation: PhyloP100: 4.97

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• 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 max_spliceai, 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 [Likely_pathogenic]. Clinvar id is 42016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPG7	NM_003119.4	c.1529C>T	p.Ala510Val	missense_variant	11/17	ENST00000645818.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPG7	ENST00000645818.2	c.1529C>T	p.Ala510Val	missense_variant	11/17		NM_003119.4	P2

Frequencies

GnomAD3 genomes AF: 0.00359 AC: 546 AN: 152182 Hom.: 2 Cov.: 32

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

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

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

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: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:51 Uncertain:1 Other:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia 7 Pathogenic:32 Other:4

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	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Nov 09, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Undiagnosed Diseases Network, NIH	Oct 05, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	Mar 15, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Paris Brain Institute, Inserm - ICM	-	- -
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/. -
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	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	Sep 10, 2021	- -
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	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	Mendelics	May 04, 2022	- -
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, 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 - 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	Fulgent Genetics, Fulgent Genetics	May 18, 2017	- -
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	Baylor Genetics	Oct 20, 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	Genetics and Molecular Pathology, SA Pathology	Jun 29, 2020	- -
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. -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genomics Program, 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] -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Aug 31, 2023	PS3_Moderate, PM3_VeryStrong, PP3 -
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	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 26, 2023	- -
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. -
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, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jul 27, 2022	- -
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. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	case-control	Neurogenetics of motion laboratory, Montreal Neurological Institute	-	- -
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. -
Pathogenic, criteria provided, single submitter	clinical testing	Genomics England Pilot Project, Genomics England	-	- -

not provided Pathogenic:9

Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 04, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 03, 2021	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Feb 24, 2016	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 03, 2022	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. -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 09, 2022	PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	SPG7: PM3:Very Strong, PP1:Strong, PM2:Supporting, PS3:Supporting -

Hereditary spastic paraplegia Pathogenic:3

Pathogenic, criteria provided, single submitter	research	Unit for Genetic & Epidemiological Research on Neurological Disorders, Instituto de Investigação e Inovação em Saúde	Mar 07, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Jan 04, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 23, 2023	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. -

Frontotemporal dementia and/or amyotrophic lateral sclerosis 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Human Genetics Bochum, Ruhr University Bochum

Sep 02, 2022

ACMG criteria used to clasify this variant: PS3, PM2, PS4, PP1, PM1, PP3 -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 23, 2021

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. -

Sensorimotor neuropathy;C1849156:Spastic ataxia Pathogenic:1

Pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

-

- -

SPG7-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 06, 2023

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. -

Dysarthria;C0037771:Spastic paraparesis;C0751837:Gait ataxia;C4551583:Cerebral cortical atrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2017

- -

Spastic Paraplegia, Recessive Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

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. -

Intellectual disability Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Raymond Lab, University of Cambridge

Feb 13, 2019

- -

Optic nerve hypoplasia Uncertain:1

Uncertain significance, flagged submission

research

Rare Disease Group, Clinical Genetics, Karolinska Institutet

Feb 14, 2018

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. -

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

Other links and lift over

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