NM_014946.4(SPAST):c.1223C>T (p.Ala408Val) AND Hereditary spastic paraplegia 4

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Nov 24, 2023
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:: RCV001209308.8

Allele description [Variation Report for NM_014946.4(SPAST):c.1223C>T (p.Ala408Val)]

NM_014946.4(SPAST):c.1223C>T (p.Ala408Val)

Gene:

SPAST:spastin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2p22.3

Genomic location:

Preferred name:

NM_014946.4(SPAST):c.1223C>T (p.Ala408Val)

HGVS:

NC_000002.12:g.32128457C>T
NG_008730.1:g.69847C>T
NM_001363823.2:c.1220C>T
NM_001363875.2:c.1124C>T
NM_001377959.1:c.1127C>T
NM_014946.4:c.1223C>TMANE SELECT
NM_199436.2:c.1127C>T
NP_001350752.1:p.Ala407Val
NP_001350804.1:p.Ala375Val
NP_001364888.1:p.Ala376Val
NP_055761.2:p.Ala408Val
NP_055761.2:p.Ala408Val
NP_955468.1:p.Ala376Val
LRG_714t1:c.1223C>T
LRG_714:g.69847C>T
LRG_714p1:p.Ala408Val
NC_000002.11:g.32353526C>T
NM_014946.3:c.1223C>T

Protein change:

A375V

Links:

dbSNP: rs1553317043

NCBI 1000 Genomes Browser:

rs1553317043

Molecular consequence:

NM_001363823.2:c.1220C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001363875.2:c.1124C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001377959.1:c.1127C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_014946.4:c.1223C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_199436.2:c.1127C>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
SCV001380736	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Nov 24, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 23400676, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001380736

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Nov 24, 2023)

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

Autosomal dominant spastic paraplegias: a review of 89 families resulting from a portuguese survey.

Loureiro JL, Brandão E, Ruano L, Brandão AF, Lopes AM, Thieleke-Matos C, Miller-Fleming L, Cruz VT, Barbosa M, Silveira I, Stevanin G, Pinto-Basto J, Sequeiros J, Alonso I, Coutinho P.

JAMA Neurol. 2013 Apr;70(4):481-7. doi: 10.1001/jamaneurol.2013.1956. Review.

PubMed [citation]

PMID:: 23400676

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, SCV001380736.5

#	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 alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 408 of the SPAST protein (p.Ala408Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hereditary spastic paraplegia (PMID: 23400676). ClinVar contains an entry for this variant (Variation ID: 586656). 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 with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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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