NM_014946.4(SPAST):c.1600C>A (p.Leu534Ile) AND Hereditary spastic paraplegia 4

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Oct 4, 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:: RCV003816079.1

Allele description [Variation Report for NM_014946.4(SPAST):c.1600C>A (p.Leu534Ile)]

NM_014946.4(SPAST):c.1600C>A (p.Leu534Ile)

Gene:

SPAST:spastin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2p22.3

Genomic location:

Preferred name:

NM_014946.4(SPAST):c.1600C>A (p.Leu534Ile)

HGVS:

NC_000002.12:g.32143399C>A
NG_008730.1:g.84789C>A
NM_001363823.2:c.1597C>A
NM_001363875.2:c.1501C>A
NM_001377959.1:c.1504C>A
NM_014946.4:c.1600C>AMANE SELECT
NM_199436.2:c.1504C>A
NP_001350752.1:p.Leu533Ile
NP_001350804.1:p.Leu501Ile
NP_001364888.1:p.Leu502Ile
NP_055761.2:p.Leu534Ile
NP_055761.2:p.Leu534Ile
NP_955468.1:p.Leu502Ile
LRG_714t1:c.1600C>A
LRG_714:g.84789C>A
LRG_714p1:p.Leu534Ile
NC_000002.11:g.32368468C>A
NM_014946.3:c.1600C>A

Protein change:

L501I

Molecular consequence:

NM_001363823.2:c.1597C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001363875.2:c.1501C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001377959.1:c.1504C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_014946.4:c.1600C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_199436.2:c.1504C>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
SCV004612307	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 4, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 12939659, 19875132, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004612307

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 4, 2023)

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

Novel spastin mutations and their expression analysis in two Italian families.

Molon A, Montagna P, Angelini C, Pegoraro E.

Eur J Hum Genet. 2003 Sep;11(9):710-3.

PubMed [citation]

PMID:: 12939659

Mutation analysis of the SPG4 gene in Italian patients with pure and complicated forms of spastic paraplegia.

Magariello A, Muglia M, Patitucci A, Ungaro C, Mazzei R, Gabriele AL, Sprovieri T, Citrigno L, Conforti FL, Liguori M, Gambardella A, Bono F, Piccoli T, Patti F, Zappia M, Mancuso M, Iemolo F, Quattrone A.

J Neurol Sci. 2010 Jan 15;288(1-2):96-100. doi: 10.1016/j.jns.2009.09.025. Epub 2009 Oct 28.

PubMed [citation]

PMID:: 19875132

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV004612307.1

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

Description

This sequence change replaces leucine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 534 of the SPAST protein (p.Leu534Ile). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SPAST-related conditions. 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 not expected to disrupt SPAST protein function. This variant disrupts the p.Leu534 amino acid residue in SPAST. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12939659, 19875132; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: Mar 5, 2024

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