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NM_014946.4(SPAST):c.1493+1G>A AND Hereditary spastic paraplegia 4

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Jul 26, 2019
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:
RCV001219396.5

Allele description [Variation Report for NM_014946.4(SPAST):c.1493+1G>A]

NM_014946.4(SPAST):c.1493+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.1493+1G>A
HGVS:
  • NC_000002.12:g.32137189G>A
  • NG_008730.1:g.78579G>A
  • NM_001363823.2:c.1490+1G>A
  • NM_001363875.2:c.1394+1G>A
  • NM_001377959.1:c.1397+1G>A
  • NM_014946.4:c.1493+1G>AMANE SELECT
  • NM_199436.2:c.1397+1G>A
  • LRG_714t1:c.1493+1G>A
  • LRG_714:g.78579G>A
  • NC_000002.11:g.32362258G>A
  • NM_014946.3:c.1493+1G>A
Links:
dbSNP: rs1553318351
NCBI 1000 Genomes Browser:
rs1553318351
Molecular consequence:
  • NM_001363823.2:c.1490+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001363875.2:c.1394+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001377959.1:c.1397+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_014946.4:c.1493+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_199436.2:c.1397+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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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001391332Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Jul 26, 2019) 		germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Splicing in action: assessing disease causing sequence changes.

Baralle D, Baralle M.

J Med Genet. 2005 Oct;42(10):737-48. Review.

PubMed [citation]
PMID:
16199547
PMCID:
PMC1735933

Mutational spectrum of the SPG4 (SPAST) and SPG3A (ATL1) genes in Spanish patients with hereditary spastic paraplegia.

Alvarez V, Sánchez-Ferrero E, Beetz C, Díaz M, Alonso B, Corao AI, Gámez J, Esteban J, Gonzalo JF, Pascual-Pascual SI, López de Munain A, Moris G, Ribacoba R, Márquez C, Rosell J, Marín R, García-Barcina MJ, Del Castillo E, Benito C, Coto E; Group for the Study of the Genetics of Spastic Paraplegia..

BMC Neurol. 2010 Oct 8;10:89. doi: 10.1186/1471-2377-10-89.

PubMed [citation]
PMID:
20932283
PMCID:
PMC2964648
See all PubMed Citations (4)

Details of each submission

From Invitae, SCV001391332.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

For these reasons, this variant has been classified as Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SPAST are known to be pathogenic (PMID: 20932283). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 20491894). This variant has been observed to segregate with hereditary spastic paraplegia in a family (PMID: 20491894). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 12 of the SPAST gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: May 7, 2024