rs141659620

Positions:

• chr16-89531961-G-A
• chr16-89531961-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PP5_Very_Strong

The NM_003119.4(SPG7):​c.1045G>A​(p.Gly349Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00159 in 1,613,926 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (3 hom.)
• Consequence: SPG7 NM_003119.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:35
• Conservation: PhyloP100: 9.65

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]

SPG7 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PP5: Variant 16-89531961-G-A is Pathogenic according to our data. Variant chr16-89531961-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 6819.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-89531961-G-A is described in Lovd as [Pathogenic]. Variant chr16-89531961-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPG7	NM_003119.4	c.1045G>A	p.Gly349Ser	missense_variant	8/17	ENST00000645818.2	NP_003110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPG7	ENST00000645818.2	c.1045G>A	p.Gly349Ser	missense_variant	8/17		NM_003119.4	ENSP00000495795.2

Frequencies

GnomAD3 genomes AF: 0.00101 AC: 154 AN: 152222 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00172

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000834 AC: 209 AN: 250588 Hom.: 0 AF XY: 0.000796 AC XY: 108 AN XY: 135656

Gnomad AFR exome AF: 0.000186

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.000232

Gnomad NFE exome AF: 0.00162

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00165 AC: 2410 AN: 1461586 Hom.: 3 Cov.: 31 AF XY: 0.00158 AC XY: 1150 AN XY: 727116

Gnomad4 AFR exome AF: 0.000538

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000243

Gnomad4 FIN exome AF: 0.000131

Gnomad4 NFE exome AF: 0.00206

Gnomad4 OTH exome AF: 0.00106

GnomAD4 genome AF: 0.00101 AC: 154 AN: 152340 Hom.: 0 Cov.: 32 AF XY: 0.000819 AC XY: 61 AN XY: 74484

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00172

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00160 Hom.: 0

Bravo AF: 0.00107

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00174 AC: 15

ExAC AF: 0.000848 AC: 103

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00142

EpiControl AF: 0.00148

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:35

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia 7 Pathogenic:22

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Nov 09, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Oct 20, 2014	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 16, 2023	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with spastic paraplegia 7 (MIM#607259) and optical atrophy (MONDO#0003608). (I) 0108 - This gene is associated with both recessive and dominant disease. This gene is associated with autosomal recessive spastic paraplegia 7 and autosomal dominant optical atrophy (PMIDs: 31854126, 32548275). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to serine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 (232 heterozygotes, 0 homozygotes). (SP) 0309 - Alternative amino acid changes at the same position have been observed in gnomAD (v2) (p.(Gly349Arg): 2 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in a binding site within the AAA domain (DECIPHER). (I) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. The variant has previously been classified as likely pathogenic or pathogenic by multiple diagnostic laboratories and has been reported in multiple individuals with spastic paraplegia 7 (ClinVar, PMIDs: 30533525, 35959404). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Studies in mAAA protease-deficient yeast cells transfected with mutant human paraplegin, displayed impaired proteolytic enzyme activity (PMID: 20186691). (SP) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (NM_003119.3(SPG7):c.1529C>T; p.(Ala510Val)) in a recessive disease. (SP) 1205 - This variant has been shown to be maternally inherited (by segregation testing). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The SPG7 c.1045G>A (p.Gly349Ser) missense variant is reported in 11 studies in which it is found in at least 25 patients with spastic paraplegia, including in 19 patients in a compound heterozygous state and in six patients in a heterozygous state (Brugman et al. 2008; Bonn et al. 2010; Schlipf et al. 2011; Klebe et al. 2012; Van Gassen et al. 2012; Kumar et al. 2013; Roxburgh et al. 2013; Yoon et al. 2013; Fogel et al. 2014; Marcotulli et al. 2014; Choquet et al. 2016). The p.Gly349Ser variant was reported in seven of 1104 control chromosomes, and is found at a frequency of 0.00174 in the European American population of the Exome Sequencing Project. The Gly349 residue is conserved across species. Functional studies in yeast demonstrated that the variant results in impaired enzyme activity (Bonn et al. 2010). Based on the evidence, the p.Gly349Ser variant is classified as pathogenic for autosomal recessive spastic paraplegia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Apr 08, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 08, 2023	Variant summary: SPG7 c.1045G>A (p.Gly349Ser) results in a non-conservative amino acid change located in the AAA+ ATPase domain (IPR003593) 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 0.00083 in 250588 control chromosomes (gnomAD). c.1045G>A has been reported in the literature in multiple individuals affected with Hereditary Spastic Paraplegia 7 (example: Schlipf_2011, Bonn_2010, vanGassen_2012, Roxburgh_2013). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence that this variant disrupts normal protein function (Bonn_2010). The following publications have been ascertained in the context of this evaluation (PMID: 20186691, 23269439, 21623769, 22964162). Nineteen submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and all classified this variant pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genomics England Pilot Project, Genomics England	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, no assertion criteria provided	clinical testing	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	Nov 02, 2023	- -
Pathogenic, criteria provided, single submitter	not provided	Institute of Human Genetics, University Hospital of Duesseldorf	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 09, 2023	The SPG7 c.1045G>A; p.Gly349Ser variant (rs141659620) is reported in the literature in numerous compound heterozygous individuals affected with hereditary spastic paraplegia (Bonn 2010, Brugman 2008, Hewamadduma 2018, Mahoney 2020, Rizzo 2020). This variant is found in the non-Finnish European population with an allele frequency of 0.16% (201/128,548 alleles) in the Genome Aggregation Database. Computational analyses predict that this variant is deleterious (REVEL: 0.948). Consistent with these predictions, functional analysis of this variant in a heterologous yeast assay suggests it fails to complement yeast similar to wildtype SPG7 (Bonn 2010). Based on available information, this variant is considered to be pathogenic. References: Bonn F et al. Functional evaluation of paraplegin mutations by a yeast complementation assay. Hum Mutat. 2010 May;31(5):617-21. PMID: 20186691. Brugman F et al. Paraplegin mutations in sporadic adult-onset upper motor neuron syndromes. Neurology. 2008 Nov 4;71(19):1500-5. PMID: 18799786. Hewamadduma CA et al. Novel genotype-phenotype and MRI correlations in a large cohort of patients with SPG7 mutations. Neurol Genet. 2018 Oct 24;4(6):e279. PMID: 30533525. Mahoney CJ et al. A novel phenotype of hereditary spastic paraplegia type 7 associated with a compound heterozygous mutation in paraplegin. Muscle Nerve. 2020 Jul;62(1):E44-E45. PMID: 32270516. Rizzo G et al. ''Eye of tiger sign" mimic in patients with spastic paraplegia gene 7 (SPG7) mutations. Parkinsonism Relat Disord. 2020 Dec;81:158-160. PMID: 33157434. -
Pathogenic, criteria provided, single submitter	case-control	Neurogenetics of motion laboratory, Montreal Neurological Institute	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 29, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2010	- -
Pathogenic, criteria provided, single submitter	clinical testing	Paris Brain Institute, Inserm - ICM	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Jan 05, 2022	The c.1045G>A;p.(Gly349Ser) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 6819; PMID: 27790088;27016405; 26626314; 25133958; 25034272; 23812641; 23733235) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 20186691) - PS3_supporting. The variant is located in a mutational hot spot and/or critical and well-established functional domain (AAA domain) - PM1. The p.(Gly349Ser) was detected in trans with a pathogenic variant (PMID: 26626314; 25034272; 23733235; 20186691) - PM3_strong. The variant co-segregated with disease in multiple affected family members (PMID: 25133958 ; 20186691) - PP1_strong. 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jun 21, 2022	- -
Pathogenic, criteria provided, single submitter	research	PROSPAX: an integrated multimodal progression chart in spastic ataxias, Center for Neurology; Hertie-Institute for Clinical Brain Research	Jan 01, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	May 28, 2020	This sequence change is predicted to replace glycine with serine at codon 349 of the SPG7 protein (p.Gly349Ser). The glycine residue is highly conserved (100 vertebrates, UCSC), and located in the AAA ATPase domain (PMID: 19841671). There is a small physicochemical difference between glycine and serine. The variant is present in a large population cohort at a frequency of 0.08% (rs141659620, 232/281,994 alleles, 0 homozygotes in gnomAD v2.1). The variant has been identified in multiple individuals with a second pathogenic allele with phenotypes including pure/complex hereditary spastic paraplegia and spastic ataxia, and segregates with disease in at least two families (PM3_VeryStrong, PP1_Moderate; PMID: 20186691, 21623769, 23812641, 26626314, 30533525). Additionally, the missense change impairs proteolytic activity in a in vitro yeast complementation assay (PS3_Supporting; PMID: 20186691). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (PP3; 7/7 algorithms). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PP1_Moderate, PS3_Supporting, PP3. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 11, 2024	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 349 of the SPG7 protein (p.Gly349Ser). This variant is present in population databases (rs141659620, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individuals with autosomal recessive hereditary spastic paraplegia (PMID: 18799786, 20186691, 21623769, 22964162, 23065789, 23269439, 23733235, 23812641, 25034272, 25133958, 26626314, 27016405). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6819). 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	Genetic Services Laboratory, University of Chicago	Sep 02, 2015	- -

not provided Pathogenic:9

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 26, 2021	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). Assessment of experimental evidence suggests this variant results in abnormal protein function. Experiment showed impaired ATPase activity (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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 22, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 03, 2024	Reported as heterozygous in an individual with HSP in whom a second variant was not described (PMID: 18799786); Functional studies performed in yeast cells found that G349S perturbs the function of the SPG7 protein (PMID: 20186691); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27016405, 29431110, 32816195, 34662886, 34758253, 23065789, 23269439, 21623769, 23733235, 25133958, 26626314, 25034272, 23812641, 30747022, 32447552, 31980526, 32270516, 31589614, 33300680, 33157434, 33841295, 34531397, 30533525, 27790088, 22964162, 20186691, 18799786, 22571692, 34983064, 36781956) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	SPG7: PM3:Very Strong, PM2:Supporting, PP3, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 26, 2022	PS3, PS4, PM2, PM3_strong, PP3 -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 27, 2021

The c.1045G>A (p.G349S) alteration is located in exon 8 (coding exon 8) of the SPG7 gene. This alteration results from a G to A substitution at nucleotide position 1045, causing the glycine (G) at amino acid position 349 to be replaced by a serine (S). Based on data from the Genome Aggregation Database (gnomAD) database, the SPG7 c.1045G>A alteration was observed in 0.08% (232/281994) of total alleles studied, with a frequency of 0.16% (201/128548) in the European (non-Finnish) subpopulation. This alteration has been identified in the compound heterozygous state with various other SPG7 variants in multiple unrelated patients with spastic paraplegia and/or cerebellar ataxia (Bonn, 2010; Hewamadduma, 2018; Klebe, 2012; Kumar, 2013; Schlipf, 2011; van Gassen, 2012). This amino acid position is highly conserved in available vertebrate species. Functional studies in yeast showed that this alteration impairs enzyme activity (Bonn, 2010). The p.G349S alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Hereditary spastic paraplegia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Feb 01, 2019

- -

SPG7-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 23, 2024

The SPG7 c.1045G>A variant is predicted to result in the amino acid substitution p.Gly349Ser. This variant has been reported in the compound heterozygous state to be causative for autosomal recessive spastic paraplegia (Bonn et al. 2010. PubMed ID: 20186691; Schlipf et al. 2011. PubMed ID: 21623769; Klebe et al. 2012. PubMed ID: 23065789; Roxburgh et al. 2012. PubMed ID: 23269439; van Gassen et al. 2012. PubMed ID: 22964162; Choquet et al. 2015. PubMed ID: 26626314). It has also been reported in the heterozygous state alone in at least two patients affected with spastic paraplegia; however, other individuals who harbored this variant in the heterozygous state alone were asymptomatic (Brugman et al. 2008. PubMed ID: 18799786; Fogel et al. 2014. PubMed ID: 25133958; Bonn et al. 2010. PubMed ID: 20186691; Schlipf et al. 2011. PubMed ID: 21623769). Functional studies have shown that the p.Gly349Ser results in impaired enzyme activity in yeast cells (Bonn et al. 2010. PubMed ID: 20186691). This variant is reported in 0.16% of alleles in individuals of European (Non-Finnish) descent in gnomAD, which is likely too common to be responsible for an early-onset, autosomal dominant form of disease. Taken together, this variant is classified as pathogenic. -

Retinal dystrophy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Jan 01, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.61
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	.;.;D;.;.;.;.;.;.
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.78	D
MetaRNN	Uncertain	0.60	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	4.6	.;.;H;.;.;.;.;.;H
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-5.5	.;.;.;.;.;.;.;.;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	.;.;.;.;.;.;.;.;D
Sift4G	Pathogenic	0.0	.;.;.;.;.;.;.;.;D
Polyphen		1.0	.;.;D;.;.;.;.;.;D
Vest4		0.98
MVP		0.96
MPC		0.79
ClinPred		0.49	T
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs141659620; hg19: chr16-89598369;