NM_014946.4(SPAST):c.1173+1G>A AND Hereditary spastic paraplegia 4

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jun 20, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000472388.8

Allele description [Variation Report for NM_014946.4(SPAST):c.1173+1G>A]

NM_014946.4(SPAST):c.1173+1G>A

Gene:

SPAST:spastin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2p22.3

Genomic location:

Preferred name:

NM_014946.4(SPAST):c.1173+1G>A

HGVS:

NC_000002.12:g.32127023G>A
NG_008730.1:g.68413G>A
NM_001363823.2:c.1170+1G>A
NM_001363875.2:c.1074+1G>A
NM_001377959.1:c.1077+1G>A
NM_014946.4:c.1173+1G>AMANE SELECT
NM_199436.2:c.1077+1G>A
LRG_714t1:c.1173+1G>A
LRG_714:g.68413G>A
NC_000002.11:g.32352092G>A
NM_014946.3:c.1173+1G>A

Links:

dbSNP: rs1060502226

NCBI 1000 Genomes Browser:

rs1060502226

Molecular consequence:

NM_001363823.2:c.1170+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001363875.2:c.1074+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001377959.1:c.1077+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_014946.4:c.1173+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_199436.2:c.1077+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]

Condition(s)

Name:: Hereditary spastic paraplegia 4
Synonyms:: Spastic paraplegia 4, autosomal dominant; Familial spastic paraplegia autosomal dominant 2
Identifiers:: MONDO: MONDO:0008438; MedGen: C1866855; Orphanet: 100985; OMIM: 182601

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000548908	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jun 20, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 10699187, 11015453, 16199547, 20932283, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000548908

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jun 20, 2022)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Help

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

Citations

PubMed

Spectrum of SPG4 mutations in autosomal dominant spastic paraplegia.

Fonknechten N, Mavel D, Byrne P, Davoine CS, Cruaud C, Bönsch D, Samson D, Coutinho P, Hutchinson M, McMonagle P, Burgunder JM, Tartaglione A, Heinzlef O, Feki I, Deufel T, Parfrey N, Brice A, Fontaine B, Prud'homme JF, Weissenbach J, Dürr A, Hazan J.

Hum Mol Genet. 2000 Mar 1;9(4):637-44. Erratum in: Hum Mol Genet. 2005 Feb 1;14(3):461. Boentsch, D [corrected to Bönsch, D].

PubMed [citation]

PMID:: 10699187

Mutation analysis of the spastin gene (SPG4) in patients with hereditary spastic paraparesis.

Lindsey JC, Lusher ME, McDermott CJ, White KD, Reid E, Rubinsztein DC, Bashir R, Hazan J, Shaw PJ, Bushby KM.

J Med Genet. 2000 Oct;37(10):759-65.

PubMed [citation]

PMID:: 11015453
PMCID:: PMC1757167

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000548908.5

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

Description

Disruption of this splice site has been observed in individuals with autosomal dominant hereditary spastic paraplegia (PMID: 10699187, 11015453). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 409030). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 8 of the SPAST gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SPAST are known to be pathogenic (PMID: 20932283).

#	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: Sep 29, 2024

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