rs201689565

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_025137.4(SPG11):c.5381T>C(p.Leu1794Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000602 in 1,612,628 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000056 ( 0 hom. )

Consequence

SPG11
NM_025137.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16U:3O:1

Conservation

PhyloP100: 8.34

Variant links:

Genes affected

SPG11 (HGNC:11226): (SPG11 vesicle trafficking associated, spatacsin) The protein encoded by this gene is a potential transmembrane protein that is phosphorylated upon DNA damage. Defects in this gene are a cause of spastic paraplegia type 11 (SPG11). Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2009]

SPG11 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.948

PP5

Variant 15-44584299-A-G is Pathogenic according to our data. Variant chr15-44584299-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 374112.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPG11	NM_025137.4 link	c.5381T>C	p.Leu1794Pro	missense_variant	Exon 30 of 40	ENST00000261866.12	NP_079413.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPG11	ENST00000261866.12 link	c.5381T>C	p.Leu1794Pro	missense_variant	Exon 30 of 40	1	NM_025137.4	ENSP00000261866.7		Q96JI7-1

Frequencies

GnomAD3 genomes

AF:

0.0000985

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000220

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000479

AC:

AN:

250508

Hom.:

AF XY:

0.0000369

AC XY:

AN XY:

135410

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.0000972

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000561

AC:

AN:

1460416

Hom.:

Cov.:

AF XY:

0.0000606

AC XY:

AN XY:

726342

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000711

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000985

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000220

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000132

Hom.:

Bravo

AF:

0.0000793

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:16Uncertain:3Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5Uncertain:1

Mar 26, 2019

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNA sequence analysis of the SPG11 gene demonstrated a c.5381T>C in exon 30, results in an amino acid change, p.Leu1794Pro. The p.Leu1794Pro change affects a highly conserved amino acid residue located in a domain of the SPG11 protein that is not known to be functional. The p.Leu1794Pro substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This particular amino acid change has been reported in the compound heterozygous state with a truncating variant in three unrelated families with spastic paraplegia (Lynch et al., 2016). This sequence change has been described in the gnomAD database with a global population frequency of 0.0057% (dbSNP rs201689565). -

Oct 19, 2020

Athena Diagnostics

Significance: Likely 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). 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. -

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

- -

Dec 29, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); 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: 27790088, 26374131, 31407473, 34426522, 31589614, 33098801, 35254204, 35872528, 36549973, 36139378, 35906604, 34983064) -

Jun 14, 2023

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM3, PP4, PP3, PM2_SUP, PP1 -

Jan 26, 2021

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

- -

Hereditary spastic paraplegia 11

Pathogenic:5Uncertain:1

Feb 23, 2023

3billion, Medical Genetics

Significance: Likely 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: 0.006%). Protein truncation variants are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.90; 3Cnet: 0.63). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000374112). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Paris Brain Institute, Inserm - ICM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 10, 2018

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 05, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change in SPG11 is predicted to replace leucine with proline at codon 1794, p.(Leu1794Pro). The leucine residue is highly conserved (100 vertebrates, UCSC), and is not located in an annotated functional domain. There is a moderate physicochemical difference between leucine and proline. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.01% (15/128,650 alleles) in the European (non-Finnish) population, which is consistent with a recessive disease. The variant has been identified in a homozygous state and compound heterozygous with a second pathogenic allele in multiple cases diagnosed with complicated/pure hereditary spastic paraplegia (HSP) and segregates with the condition in at least one family (PMID: 26374131, 31407473, 35254204, 36139378). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.897). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PM2_Supporting, PP1, PP3. -

Mar 10, 2020

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

This variant was classified as: Uncertain significance. The available evidence favors the pathogenic nature of this variant, however the currently available data is insufficient to conclusively support its pathogenic nature. Thus this variant is classified as Uncertain significance - favor pathogenic. The following ACMG criteria were applied in classifying this variant: PP3,PP5. -

Nov 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1794 of the SPG11 protein (p.Leu1794Pro). This variant is present in population databases (rs201689565, gnomAD 0.01%). This missense change has been observed in individuals with hereditary spastic paraplegia (PMID: 26374131, 31407473; internal data). ClinVar contains an entry for this variant (Variation ID: 374112). 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 expected to disrupt SPG11 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Hereditary spastic paraplegia

Pathogenic:2

May 01, 2018

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 13, 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: SPG11 c.5381T>C (p.Leu1794Pro) results in a non-conservative amino acid change in 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 4.8e-05 in 250508 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in SPG11 causing Hereditary Spastic Paraplegia, Type 11 (4.8e-05 vs 0.0011), allowing no conclusion about variant significance. c.5381T>C has been reported in the literature as a biallelic genotype in multiple individuals affected with Hereditary Spastic Paraplegia, Type 11 (e.g. Lynch_2016, Zech_2020, Krenn_2020, Peric_2022). 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. The following publications have been ascertained in the context of this evaluation (PMID: 31407473, 26374131, 36139378, 33098801). ClinVar contains an entry for this variant (Variation ID: 374112). Based on the evidence outlined above, the variant was classified as pathogenic. -

Spastic paraparesis;C0311394:Difficulty walking;C0575081:Gait disturbance;C4024949:Generalized hyperreflexia

Pathogenic:1

May 05, 2015

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Pathogenic:1

Jan 09, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5381T>C (p.L1794P) alteration is located in exon 30 (coding exon 30) of the SPG11 gene. This alteration results from a T to C substitution at nucleotide position 5381, causing the leucine (L) at amino acid position 1794 to be replaced by a proline (P). Based on data from gnomAD, the C allele has an overall frequency of 0.006% (16/281906) total alleles studied. The highest observed frequency was 0.012% (15/128650) of European (non-Finnish) alleles. This mutation has been reported in the homozygous and compound heterozygous state in individuals with spastic paraplegia (Lynch, 2015; Krenn, 2020; Doleckova, 2022; Peri, 2022). It was also identified in the homozygous state in an individual with childhood-onset dystonia (Zech, 2020) and in the heterozygous state in an individual with amyotrophic lateral sclerosis with no second SPG11 variant (Krüger, 2016). 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 11;C1865864:Amyotrophic lateral sclerosis type 5;C5569024:Charcot-Marie-Tooth disease axonal type 2X

Pathogenic:1

Apr 23, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Charcot-Marie-Tooth disease axonal type 2X

Pathogenic:1

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 -

Amyotrophic lateral sclerosis

Uncertain:1

UM ALS/MND Lab, University Of Malta

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: research

- -

Hereditary spastic paraplegia 11;C3468114:Juvenile amyotrophic lateral sclerosis;C5569024:Charcot-Marie-Tooth disease axonal type 2X

Other:1

GenomeConnect - Invitae Patient Insights Network

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Pathogenic and reported on 12-19-2020 by Lab 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.78

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.39

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.49

T;.;T;.

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.84

T;T;T;T

M_CAP

Uncertain

0.17

MetaRNN

Pathogenic

0.95

D;D;D;D

MetaSVM

Uncertain

0.54

MutationAssessor

Uncertain

2.6

M;M;.;M

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-3.7

D;D;D;D

REVEL

Pathogenic

0.90

Sift

Uncertain

0.0010

D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

D;.;D;.

Vest4

0.94

MVP

0.92

MPC

0.32

ClinPred

0.86

GERP RS

5.8

Varity_R

0.85

gMVP

0.89

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over