rs121918358

Variant names:

• chr16-89510539-T-A
• rs121918358
• NM_003119.4:c.233T>A

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 16P and 1B. PVS1 PP5_Very_Strong BS2_Supporting

The NM_003119.4(SPG7):​c.233T>A​(p.Leu78*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00027 in 1,613,200 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00028 (5 hom.)
• Consequence: SPG7 NM_003119.4 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:28 U:1
• Conservation: PhyloP100: 0.782
• Publications: 17 publications found

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 Gene-Disease associations (from GenCC):

• hereditary spastic paraplegia 7

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• lateral sclerosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 16-89510539-T-A is Pathogenic according to our data. Variant chr16-89510539-T-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 6816.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 5 AD,AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003119.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPG7	NM_003119.4	MANE Select	c.233T>A	p.Leu78*	stop_gained	Exon 2 of 17	NP_003110.1
	SPG7	NM_001363850.1		c.233T>A	p.Leu78*	stop_gained	Exon 2 of 18	NP_001350779.1
	SPG7	NM_199367.3		c.233T>A	p.Leu78*	stop_gained	Exon 2 of 10	NP_955399.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPG7	ENST00000645818.2	MANE Select	c.233T>A	p.Leu78*	stop_gained	Exon 2 of 17	ENSP00000495795.2
	SPG7	ENST00000268704.7	TSL:1	c.233T>A	p.Leu78*	stop_gained	Exon 2 of 17	ENSP00000268704.3
	SPG7	ENST00000341316.6	TSL:1	c.233T>A	p.Leu78*	stop_gained	Exon 2 of 10	ENSP00000341157.2

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 152074 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000418 AC: 105 AN: 251260 AF XY: 0.000589

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000278 AC: 406 AN: 1461008 Hom.: 5 Cov.: 34 AF XY: 0.000355 AC XY: 258 AN XY: 726850

African (AFR) AF: 0.0000597 AC: 2 AN: 33474

American (AMR) AF: 0.000157 AC: 7 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00279 AC: 241 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53222

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.000127 AC: 141 AN: 1111364

Other (OTH) AF: 0.000215 AC: 13 AN: 60378

GnomAD4 genome AF: 0.000197 AC: 30 AN: 152192 Hom.: 0 Cov.: 32 AF XY: 0.000255 AC XY: 19 AN XY: 74438

African (AFR) AF: 0.0000482 AC: 2 AN: 41528

American (AMR) AF: 0.000131 AC: 2 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00249 AC: 12 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 67994

Other (OTH) AF: 0.000474 AC: 1 AN: 2108

Alfa AF: 0.000146 Hom.: 0

Bravo AF: 0.000102

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000469 AC: 57

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:28 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia 7 Pathogenic:20

Nov 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Leu78*) in the SPG7 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SPG7 are known to be pathogenic (PMID: 21623769, 22964162). This variant is present in population databases (rs121918358, gnomAD 0.3%), including at least one homozygous and/or hemizygous individual. This premature translational stop signal has been observed in individual(s) with clinical features of autosomal recessive hereditary spastic paraplegia (PMID: 18200586, 22571692, 24727571). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6816). For these reasons, this variant has been classified as Pathogenic.

Apr 01, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Jan 01, 2022

PROSPAX: an integrated multimodal progression chart in spastic ataxias, Center for Neurology; Hertie-Institute for Clinical Brain Research

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Sep 02, 2020

Genetics and Genomic Medicine Centre, NeuroGen Healthcare, NeuroGen Healthcare

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 01, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SPG7 c.233T>A (p.Leu78X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00042 in 251260 control chromosomes in the gnomAD database, including 2 homozygotes. c.233T>A has been reported in the literature in multiple homozygous individuals affected with Hereditary Spastic Paraplegia (e.g. Arnoldi_2008). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating enzyme activity in homozygous patient fibroblasts with varied results between patients (e.g. Arnoldi_2008). The most pronounced variant effect results in 30%-50% of normal activity. The following publication has been ascertained in the context of this evaluation (PMID: 18200586). ClinVar contains an entry for this variant (Variation ID: 6816). Based on the evidence outlined above, the variant was classified as pathogenic.

Jan 22, 2022

Kariminejad - Najmabadi Pathology & Genetics Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

___

Mar 14, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 08, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (v2: 108 heterozygotes, 2 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as pathogenic, and observed in compound heterozygous and homozygous individuals with spastic paraplegia (ClinVar, PMIDs: 23065789, 36139378). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Mar 14, 2025

Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Paris Brain Institute, Inserm - ICM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 20, 2025

Institute of Human Genetics Munich, TUM University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Neurogenetics of motion laboratory, Montreal Neurological Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: case-control

Feb 27, 2024

Service de Génétique Médicale, Centre Hospitalier Universitaire de Nice-Université Côte d'Azur

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_003119.2:c.1529C>T in the same patient

Feb 24, 2021

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was identified as compound heterozygous with NM_003119.4:c.1529C>T.

Jul 22, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The observed missense variant c.233T>Ap.Leu78Ter in SPG7 gene has been reported in homozygous/compound heterozygous state in multiple individuals with Ataxia/Hereditary Spastic Paraplegia 7 Perić S, et al., 2022, Hewamadduma CA, et al., 2018. The p.Leu78Ter variant has 0.04% allele frequency in gnomAD Exomes. It has been submitted to ClinVar as Uncertain Significance/Likely Pathogenic/ Pathogenic multiple submissions. The nucleotide change c.233T>A in SPG7 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Computational evidence Mutation Taster - Disease causing predicts damaging effect on protein structure and function for this variant. This variant is predicted to cause loss of normal protein function through

Feb 20, 2023

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 03, 2020

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 01, 2022

Solve-RD Consortium

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

Variant confirmed as disease-causing by referring clinical team

Feb 02, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Jan 16, 2020

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].

not provided Pathogenic:4

Nov 05, 2024

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity. (http://gnomad.broadinstitute.org) This variant has been identified in multiple unrelated individuals with clinical features associated with this gene.

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 07, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25525159, 27084228, 28362824, 29482223, 18200586, 23065789, 22571692, 26626314, 22964162, 25681447, 25976027, 31433872, 31407473, 33300680, 31589614, 33084218, 33624863)

Jul 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SPG7: PM3:Very Strong, PVS1, PM2

SPG7-related disorder Pathogenic:1

Aug 30, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The SPG7 c.233T>A variant is predicted to result in premature protein termination (p.Leu78*). This variant has been reported in the homozygous state in individuals with hereditary spastic paraplegia (Arnoldi et al. 2008. PubMed ID: 18200586; Iqbal et al. 2017. PubMed ID: 28362824). In addition, one study suggested that this variant may act in a dominant fashion, although no evidence was provided to support this claim beyond segregation of the variant with the disease in the family (Sánchez-Ferrero et al. 2013. PubMed ID: 22571692). This variant is reported in 0.28% of alleles in individuals of South Asian descent in gnomAD. Nonsense variants in SPG7 are expected to be pathogenic. This variant is interpreted as pathogenic.

Hereditary spastic paraplegia Pathogenic:1

Mar 01, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary ataxia Pathogenic:1

Apr 29, 2020

Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Retinal dystrophy Pathogenic:1

Jan 01, 2023

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Proximal spinal muscular atrophy Uncertain:1

Apr 26, 2018

Institute of Human Genetics, Cologne University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.24
CADD	Pathogenic	34
DANN	Benign	0.91
Eigen	Benign	-0.074
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.13	N
PhyloP100		0.78
Vest4		0.87
GERP RS		0.040
PromoterAI		-0.010	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=5/195	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121918358; hg19: chr16-89576947;