NM_014946.4(SPAST):c.1225G>A (p.Ala409Thr) AND Hereditary spastic paraplegia 4

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Aug 29, 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:: RCV002525773.3

Allele description [Variation Report for NM_014946.4(SPAST):c.1225G>A (p.Ala409Thr)]

NM_014946.4(SPAST):c.1225G>A (p.Ala409Thr)

Gene:

SPAST:spastin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2p22.3

Genomic location:

Preferred name:

NM_014946.4(SPAST):c.1225G>A (p.Ala409Thr)

HGVS:

NC_000002.12:g.32128459G>A
NG_008730.1:g.69849G>A
NM_001363823.2:c.1222G>A
NM_001363875.2:c.1126G>A
NM_001377959.1:c.1129G>A
NM_014946.4:c.1225G>AMANE SELECT
NM_199436.2:c.1129G>A
NP_001350752.1:p.Ala408Thr
NP_001350804.1:p.Ala376Thr
NP_001364888.1:p.Ala377Thr
NP_055761.2:p.Ala409Thr
NP_055761.2:p.Ala409Thr
NP_955468.1:p.Ala377Thr
LRG_714t1:c.1225G>A
LRG_714:g.69849G>A
LRG_714p1:p.Ala409Thr
NC_000002.11:g.32353528G>A
NM_014946.3:c.1225G>A

Protein change:

A376T

Links:

dbSNP: rs1064793273

NCBI 1000 Genomes Browser:

rs1064793273

Molecular consequence:

NM_001363823.2:c.1222G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001363875.2:c.1126G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001377959.1:c.1129G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_014946.4:c.1225G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_199436.2:c.1129G>A - 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
SCV003523974	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Aug 29, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 31157359, 20932283, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003523974

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Aug 29, 2022)

germline

clinical testing

PubMed (3)
[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

De novo SPAST mutations may cause a complex SPG4 phenotype.

Schieving JH, de Bot ST, van de Pol LA, Wolf NI, Brilstra EH, Frints SG, van Gaalen J, Misra-Isrie M, Pennings M, Verschuuren-Bemelmans CC, Kamsteeg EJ, van de Warrenburg BP, Willemsen MA.

Brain. 2019 Jul 1;142(7):e31. doi: 10.1093/brain/awz140. No abstract available.

PubMed [citation]

PMID:: 31157359

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 (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003523974.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Ala409 amino acid residue in SPAST. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20932283, 31157359). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SPAST protein function. ClinVar contains an entry for this variant (Variation ID: 418502). This missense change has been observed in individual(s) with hereditary spastic paraplegia (PMID: 20932283). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 409 of the SPAST protein (p.Ala409Thr).

#	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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