NM_025137.4(SPG11):c.5381T>C (p.Leu1794Pro) AND Hereditary spastic paraplegia 11

Germline classification:: Conflicting interpretations of pathogenicity (6 submissions)
Last evaluated:: Jan 29, 2024
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000801301.23

Allele description [Variation Report for NM_025137.4(SPG11):c.5381T>C (p.Leu1794Pro)]

NM_025137.4(SPG11):c.5381T>C (p.Leu1794Pro)

Gene:

SPG11:SPG11 vesicle trafficking associated, spatacsin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

15q21.1

Genomic location:

Preferred name:

NM_025137.4(SPG11):c.5381T>C (p.Leu1794Pro)

HGVS:

NC_000015.10:g.44584299A>G
NG_008885.1:g.84380T>C
NM_001160227.2:c.5381T>C
NM_025137.4:c.5381T>CMANE SELECT
NP_001153699.1:p.Leu1794Pro
NP_079413.3:p.Leu1794Pro
NC_000015.9:g.44876497A>G
NM_025137.3:c.5381T>C

Protein change:

L1794P

Links:

dbSNP: rs201689565

NCBI 1000 Genomes Browser:

rs201689565

Molecular consequence:

NM_001160227.2:c.5381T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_025137.4:c.5381T>C - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

unknown functional consequence

Observations:

Condition(s)

Name:: Hereditary spastic paraplegia 11
Synonyms:: SPASTIC PARAPLEGIA, AUTOSOMAL RECESSIVE, COMPLICATED, WITH THIN CORPUS CALLOSUM; SPASTIC PARAPLEGIA, AUTOSOMAL RECESSIVE, WITH MENTAL IMPAIRMENT AND THIN CORPUS CALLOSUM; Spastic paraplegia 11, autosomal recessive; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0011445; MedGen: C1858479; Orphanet: 2822; OMIM: 604360

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000941072	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 29, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 26374131, 31407473, 28492532
SCV001149938	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	criteria provided, single submitter (Classification criteria August 2017)	Pathogenic (Jul 10, 2018)	germline	clinical testing	Citation Link,
SCV001368423	Centre for Mendelian Genomics, University Medical Centre Ljubljana	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 10, 2020)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001451262	Paris Brain Institute, Inserm - ICM	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002503783	Molecular Genetics, Royal Melbourne Hospital See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 5, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 26374131, 31407473, 35254204, 36139378, 25741868
SCV003841386	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Feb 23, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	1	not provided	not provided	1	not provided	clinical testing
not provided	unknown	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Hereditary spastic paraplegia in Greece: characterisation of a previously unexplored population using next-generation sequencing.

Lynch DS, Koutsis G, Tucci A, Panas M, Baklou M, Breza M, Karadima G, Houlden H.

Eur J Hum Genet. 2016 Jun;24(6):857-63. doi: 10.1038/ejhg.2015.200. Epub 2015 Sep 16.

PubMed [citation]

PMID:: 26374131
PMCID:: PMC4688955

See all PubMed Citations (6)

Details of each submission

From Invitae, SCV000941072.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

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; Invitae). ClinVar contains an entry for this variant (Variation ID: 374112). 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 SPG11 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München, SCV001149938.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	blood	not provided		1	not provided	not provided	not provided

From Centre for Mendelian Genomics, University Medical Centre Ljubljana, SCV001368423.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Paris Brain Institute, Inserm - ICM, SCV001451262.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Molecular Genetics, Royal Melbourne Hospital, SCV002503783.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From 3billion, SCV003841386.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 8, 2024

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