16-89550545-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1PP3_ModeratePP5_Very_Strong

The NM_003119.4(SPG7):c.1715C>T(p.Ala572Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000682 in 1,613,970 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. A572A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00015 ( 1 hom., cov: 33)

Exomes 𝑓: 0.000060 ( 0 hom. )

Consequence

SPG7
NM_003119.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:14

Conservation

PhyloP100: 6.05

Publications

5 publications found

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]

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

SPG7 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_003119.4

PP3

MetaRNN computational evidence supports a deleterious effect, 0.884

PP5

Variant 16-89550545-C-T is Pathogenic according to our data. Variant chr16-89550545-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 217269.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
SPG7	NM_003119.4 link	c.1715C>T	p.Ala572Val	missense_variant	Exon 13 of 17	ENST00000645818.2	NP_003110.1
SPG7	NM_001363850.1 link	c.1715C>T	p.Ala572Val	missense_variant	Exon 13 of 18		NP_001350779.1
SPG7	XM_047434537.1 link	c.842C>T	p.Ala281Val	missense_variant	Exon 8 of 13		XP_047290493.1
SPG7	XM_047434540.1 link	c.401C>T	p.Ala134Val	missense_variant	Exon 5 of 9		XP_047290496.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPG7	ENST00000645818.2 link	c.1715C>T	p.Ala572Val	missense_variant	Exon 13 of 17		NM_003119.4	ENSP00000495795.2

Frequencies

GnomAD3 genomes

AF:

0.000151

AC:

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000916

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000358

AC:

AN:

251306

AF XY:

0.0000294

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000595

AC:

AN:

1461608

Hom.:

Cov.:

AF XY:

0.0000605

AC XY:

AN XY:

727120

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33476

American (AMR)

AF:

0.000224

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39696

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53234

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000504

AC:

AN:

1111944

Other (OTH)

AF:

0.000248

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000151

AC:

AN:

152362

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

74500

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41592

American (AMR)

AF:

0.000915

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000207

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

68040

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000177

Hom.:

Bravo

AF:

0.000280

ExAC

AF:

0.00000824

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary spastic paraplegia 7

Pathogenic:8

Sep 01, 2022

3billion

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.004%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.83; 3Cnet: 0.97). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000217269). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 14985266 , 23065789 , 25681447 , 26626314). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

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

- -

Nov 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 572 of the SPG7 protein (p.Ala572Val). This variant is present in population databases (rs72547551, gnomAD 0.005%). This missense change has been observed in individuals with autosomal recessive hereditary spastic paraplegia (PMID: 14985266, 23065789, 25681447, 26626314). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 217269). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt SPG7 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Jul 15, 2025

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

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

- -

May 29, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 26, 2023

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.1715C>T (p.Ala572Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 251306 control chromosomes. c.1715C>T has been reported in the literature as biallelic homozygous or compound heterozygous genotypes in multiple individuals affected with Hereditary Spastic Paraplegia 7 (example, Vural_2021, Burguez_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Jul 16, 2023

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) 0200 - Variant is predicted to result in a missense amino acid change from alanine to valine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3: 21 heterozygotes, 1 homozygote). (SP) 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 the annotated Peptidase family M41 domain (DICPHER). (I) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as pathogenic by clinical diagnostic laboratories and has also been identified as compound heterozygous in individuals with ataxia, cerebellar ataxia or hereditary spastic paraplegia (ClinVar, PMIDs: 26626314, 25681447, 29246610). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided

Pathogenic:4

Mar 11, 2022

Athena Diagnostics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls. 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. Computational tools predict that this variant is damaging. The variant is located in a region that is considered important for protein function and/or structure. -

Jun 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 02, 2025

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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: 14985266, 23065789, 25681447, 26626314, 22571692, 25497598, Campins-Romeu2021[Case Report], 29246610, Haj Saleem2021[Case report], 29482223, 30533525, 32816195, 33059505, 34405107, 33624863, 37090936) -

Apr 21, 2021

Genetic Services Laboratory, University of Chicago

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DNA sequence analysis of the SPG7 gene demonstrated a sequence change, c.1715C>T variant in exon 13 that results in an amino acid change, p.Ala572Val. This sequence change has been described in the gnomAD database with a low population frequency of 0.0036% (dbSNP rs72547551). This pathogenic sequence change has previously been described in several patients with SPG7-related spastic paraplegia and ataxia (Wilkinson et al., 2004; Klebe et al., 2012; Pfeffer et al., 2015; Choquet et al., 2015). The p.Ala572Val change affects a highly conserved amino acid residue located in a domain of the SPG7 protein that is known to be functional. The p.Ala572Val substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). -

Inborn genetic diseases

Pathogenic:1

Jan 31, 2025

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1715C>T (p.A572V) alteration is located in exon 13 (coding exon 13) of the SPG7 gene. This alteration results from a C to T substitution at nucleotide position 1715, causing the alanine (A) at amino acid position 572 to be replaced by a valine (V). Based on data from gnomAD, the T allele has an overall frequency of 0.004% (10/282716) total alleles studied. The highest observed frequency was 0.006% (2/35440) of Admixed American alleles. This variant has been identified in the homozygous and compound heterozygous states in individuals with features consistent with SPG7-related spastic paraplegia; in at least one instance, the variants were identified in trans (Klebe, 2012; Pfeffer, 2015; Pyle, 2015; Choquet, 2016; Hewamadduma, 2018; Bogdanova-Mihaylova, 2021; Campins-Romeu, 2021; Vural, 2021; Monfrini, 2023). This amino acid position is highly conserved in available vertebrate species. This 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

Nov 16, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.61

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.46

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.91

.;.;D;.;.;.;.;.;.

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

D;D;D;D;D;D;D;D;D

M_CAP

Pathogenic

0.54

MetaRNN

Pathogenic

0.88

D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.73

MutationAssessor

Pathogenic

3.6

.;.;H;.;.;.;.;.;.

PhyloP100

6.0

PrimateAI

Uncertain

0.58

REVEL

Pathogenic

0.83

Polyphen

0.99

.;.;D;.;.;.;.;.;.

MVP

0.95

MPC

0.78

ClinPred

0.98

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.80

gMVP

0.83

Mutation Taster

=38/62

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over