NM_014946.4(SPAST):c.1458_1459dup (p.Asn487fs) AND Hereditary spastic paraplegia 4

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Apr 10, 2018
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:: RCV000707183.5

Allele description [Variation Report for NM_014946.4(SPAST):c.1458_1459dup (p.Asn487fs)]

NM_014946.4(SPAST):c.1458_1459dup (p.Asn487fs)

Gene:

SPAST:spastin [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

2p22.3

Genomic location:

Preferred name:

NM_014946.4(SPAST):c.1458_1459dup (p.Asn487fs)

HGVS:

NC_000002.12:g.32137153_32137154dup
NG_008730.1:g.78543_78544dup
NM_001363823.2:c.1455_1456dup
NM_001363875.2:c.1359_1360dup
NM_001377959.1:c.1362_1363dup
NM_014946.4:c.1458_1459dupMANE SELECT
NM_199436.2:c.1362_1363dup
NP_001350752.1:p.Asn486fs
NP_001350804.1:p.Asn454fs
NP_001364888.1:p.Asn455fs
NP_055761.2:p.Asn487fs
NP_955468.1:p.Asn455fs
LRG_714:g.78543_78544dup
NC_000002.11:g.32362221_32362222insTA
NC_000002.11:g.32362222_32362223dup
NM_014946.3:c.1458_1459dupTA

Protein change:

N454fs

Links:

dbSNP: rs1558337136

NCBI 1000 Genomes Browser:

rs1558337136

Molecular consequence:

NM_001363823.2:c.1455_1456dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001363875.2:c.1359_1360dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001377959.1:c.1362_1363dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_014946.4:c.1458_1459dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_199436.2:c.1362_1363dup - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV000836268	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Apr 10, 2018)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 20932283, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000836268

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Apr 10, 2018)

germline

clinical testing

PubMed (2)
[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

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

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):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Invitae, SCV000836268.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change creates a premature translational stop signal (p.Asn487Ilefs*44) in the SPAST gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with SPAST-related disease. Loss-of-function variants in SPAST are known to be pathogenic (PMID: 20932283). 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

Last Updated: Feb 20, 2024

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