NM_025137.4(SPG11):c.1621C>T (p.Gln541Ter) AND Hereditary spastic paraplegia 11

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Jan 29, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000757917.9

Allele description [Variation Report for NM_025137.4(SPG11):c.1621C>T (p.Gln541Ter)]

NM_025137.4(SPG11):c.1621C>T (p.Gln541Ter)

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.1621C>T (p.Gln541Ter)

HGVS:

NC_000015.10:g.44633619G>A
NG_008885.1:g.35060C>T
NM_001160227.2:c.1621C>T
NM_025137.4:c.1621C>TMANE SELECT
NP_001153699.1:p.Gln541Ter
NP_079413.3:p.Gln541Ter
NC_000015.9:g.44925817G>A
NM_025137.3:c.1621C>T

Protein change:

Q541*

Links:

dbSNP: rs765061840

NCBI 1000 Genomes Browser:

rs765061840

Molecular consequence:

NM_001160227.2:c.1621C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_025137.4:c.1621C>T - nonsense - [Sequence Ontology: SO:0001587]

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
SCV000886427	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology - AGHI-WGS-HudsonAlpha	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 20, 2018)	paternal	research	PubMed (1) [See all records that cite this PMID]
SCV001411210	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 29, 2024)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 19105190, 20110243, 22154821, 26556829, 25299611, 28554332, 29246610, 28492532
SCV002764116	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000886427

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology - AGHI-WGS-HudsonAlpha

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jul 20, 2018)

paternal

research

PubMed (1)
[See all records that cite this PMID]

SCV001411210

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 29, 2024)

germline

clinical testing

PubMed (8)
[See all records that cite these PMIDs]

SCV002764116

Genome-Nilou Lab

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

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

Citations

PubMed

Screening of ARHSP-TCC patients expands the spectrum of SPG11 mutations and includes a large scale gene deletion.

Denora PS, Schlesinger D, Casali C, Kok F, Tessa A, Boukhris A, Azzedine H, Dotti MT, Bruno C, Truchetto J, Biancheri R, Fedirko E, Di Rocco M, Bueno C, Malandrini A, Battini R, Sickl E, de Leva MF, Boespflug-Tanguy O, Silvestri G, Simonati A, Said E, et al.

Hum Mutat. 2009 Mar;30(3):E500-19. doi: 10.1002/humu.20945.

PubMed [citation]

PMID:: 19105190

SPATACSIN mutations cause autosomal recessive juvenile amyotrophic lateral sclerosis.

Orlacchio A, Babalini C, Borreca A, Patrono C, Massa R, Basaran S, Munhoz RP, Rogaeva EA, St George-Hyslop PH, Bernardi G, Kawarai T.

Brain. 2010 Feb;133(Pt 2):591-8. doi: 10.1093/brain/awp325. Epub 2010 Jan 28.

PubMed [citation]

PMID:: 20110243
PMCID:: PMC2822627

See all PubMed Citations (9)

Details of each submission

From HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology - AGHI-WGS-HudsonAlpha, SCV000886427.1

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

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

From Invitae, SCV001411210.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This sequence change creates a premature translational stop signal (p.Gln541*) in the SPG11 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SPG11 are known to be pathogenic (PMID: 19105190, 20110243, 22154821, 26556829). This variant is present in population databases (rs765061840, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with hereditary spastic paraplegia or amyotrophic lateral sclerosis (PMID: 25299611, 28554332, 29246610). ClinVar contains an entry for this variant (Variation ID: 235891). 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 Genome-Nilou Lab, SCV002764116.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	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	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Mar 16, 2024

ClinVar

Relating variation to medicine