NM_014946.4(SPAST):c.1173+185_1245del AND Hereditary spastic paraplegia 4

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Apr 8, 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:: RCV001223514.2

Allele description [Variation Report for NM_014946.4(SPAST):c.1173+185_1245del]

NM_014946.4(SPAST):c.1173+185_1245del

Gene:

SPAST:spastin [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

2p22.3

Genomic location:

Preferred name:

NM_014946.4(SPAST):c.1173+185_1245del

HGVS:

NC_000002.12:g.32127206_32128478del
NC_000002.12:g.32127207_32128479del
NG_008730.1:g.68597_69869del
NM_001363823.2:c.1170+185_1242del
NM_001363875.2:c.1074+185_1146del
NM_001377959.1:c.1077+185_1149del
NM_014946.4:c.1173+185_1245delMANE SELECT
NM_199436.2:c.1077+185_1149del
LRG_714t1:c.1173+184_1244del
LRG_714:g.68597_69869del
NC_000002.11:g.32352276_32353548del
NM_014946.3:c.1173+184_1244del

Molecular consequence:

NM_001363823.2:c.1170+185_1242del - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001363875.2:c.1074+185_1146del - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001377959.1:c.1077+185_1149del - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_014946.4:c.1173+185_1245del - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_199436.2:c.1077+185_1149del - splice acceptor variant - [Sequence Ontology: SO:0001574]

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
SCV001395670	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Apr 8, 2019)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 20550563, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001395670

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Apr 8, 2019)

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

Clinical and genetic findings in a series of Italian children with pure hereditary spastic paraplegia.

Battini R, Fogli A, Borghetti D, Michelucci A, Perazza S, Baldinotti F, Conidi ME, Ferreri MI, Simi P, Cioni G.

Eur J Neurol. 2011 Jan;18(1):150-7. doi: 10.1111/j.1468-1331.2010.03102.x.

PubMed [citation]

PMID:: 20550563

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

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001395670.1

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

Description

This variant is a deletion of the genomic region encompassing part of exon 9 (c.1173+184_1244del) of the SPAST gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant has not been reported in the literature in individuals with SPAST-related conditions. This copy number variant disrupts the p.Ser413 amino acid residue in SPAST. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20550563, Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: Sep 29, 2024

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