NM_014946.4(SPAST):c.1238C>T (p.Ser413Leu) AND Hereditary spastic paraplegia 4

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Aug 1, 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:: RCV000799219.7

Allele description [Variation Report for NM_014946.4(SPAST):c.1238C>T (p.Ser413Leu)]

NM_014946.4(SPAST):c.1238C>T (p.Ser413Leu)

Gene:

SPAST:spastin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2p22.3

Genomic location:

Preferred name:

NM_014946.4(SPAST):c.1238C>T (p.Ser413Leu)

HGVS:

NC_000002.12:g.32128472C>T
NG_008730.1:g.69862C>T
NM_001363823.2:c.1235C>T
NM_001363875.2:c.1139C>T
NM_001377959.1:c.1142C>T
NM_014946.4:c.1238C>TMANE SELECT
NM_199436.2:c.1142C>T
NP_001350752.1:p.Ser412Leu
NP_001350804.1:p.Ser380Leu
NP_001364888.1:p.Ser381Leu
NP_055761.2:p.Ser413Leu
NP_055761.2:p.Ser413Leu
NP_955468.1:p.Ser381Leu
LRG_714t1:c.1238C>T
LRG_714:g.69862C>T
LRG_714p1:p.Ser413Leu
NC_000002.11:g.32353541C>T
NM_014946.3:c.1238C>T

Protein change:

S380L

Links:

dbSNP: rs1553317045

NCBI 1000 Genomes Browser:

rs1553317045

Molecular consequence:

NM_001363823.2:c.1235C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001363875.2:c.1139C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001377959.1:c.1142C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_014946.4:c.1238C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_199436.2:c.1142C>T - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000938873	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 1, 2018)	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

SCV000938873

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Aug 1, 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

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, SCV000938873.4

#	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 replaces serine with leucine at codon 413 of the SPAST protein (p.Ser413Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed to be de novo in individuals affected with hereditary spastic paraplegias (HSP) (PMID: 20550563, Invitae). This variant is not present in population databases (ExAC no frequency).

#	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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