NM_014946.4(SPAST):c.1141T>G (p.Phe381Val) AND Hereditary spastic paraplegia 4

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Oct 3, 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:: RCV001889536.4

Allele description [Variation Report for NM_014946.4(SPAST):c.1141T>G (p.Phe381Val)]

NM_014946.4(SPAST):c.1141T>G (p.Phe381Val)

Gene:

SPAST:spastin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2p22.3

Genomic location:

Preferred name:

NM_014946.4(SPAST):c.1141T>G (p.Phe381Val)

HGVS:

NC_000002.12:g.32126990T>G
NG_008730.1:g.68380T>G
NM_001363823.2:c.1138T>G
NM_001363875.2:c.1042T>G
NM_001377959.1:c.1045T>G
NM_014946.4:c.1141T>GMANE SELECT
NM_199436.2:c.1045T>G
NP_001350752.1:p.Phe380Val
NP_001350804.1:p.Phe348Val
NP_001364888.1:p.Phe349Val
NP_055761.2:p.Phe381Val
NP_955468.1:p.Phe349Val
LRG_714:g.68380T>G
NC_000002.11:g.32352059T>G

Protein change:

F348V

Links:

dbSNP: rs1553316821

NCBI 1000 Genomes Browser:

rs1553316821

Molecular consequence:

NM_001363823.2:c.1138T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001363875.2:c.1042T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001377959.1:c.1045T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_014946.4:c.1141T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_199436.2:c.1045T>G - 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

Recent activity

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plectin-like isoform X1 [Acanthopagrus latus]
plectin-like isoform X1 [Acanthopagrus latus]
gi|1927222966|ref|XP_036931790.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002161274	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 3, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 33480217, 10699187, 16832076, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002161274

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 3, 2023)

germline

clinical testing

PubMed (4)
[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 SPG4 Mutation in a Patient with Sporadic Hereditary Spastic Paraplegia and Elevated Cerebrospinal Fluid Protein.

She H, Zheng X, Xiao Y, Mastaglia F, Akkari A, Wu J.

J Clin Neurol. 2021 Jan;17(1):152-153. doi: 10.3988/jcn.2021.17.1.152. No abstract available.

PubMed [citation]

PMID:: 33480217
PMCID:: PMC7840324

Spectrum of SPG4 mutations in autosomal dominant spastic paraplegia.

Fonknechten N, Mavel D, Byrne P, Davoine CS, Cruaud C, Bönsch D, Samson D, Coutinho P, Hutchinson M, McMonagle P, Burgunder JM, Tartaglione A, Heinzlef O, Feki I, Deufel T, Parfrey N, Brice A, Fontaine B, Prud'homme JF, Weissenbach J, Dürr A, Hazan J.

Hum Mol Genet. 2000 Mar 1;9(4):637-44. Erratum in: Hum Mol Genet. 2005 Feb 1;14(3):461. Boentsch, D [corrected to Bönsch, D].

PubMed [citation]

PMID:: 10699187

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002161274.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces phenylalanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 381 of the SPAST protein (p.Phe381Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hereditary spastic paraplegia (PMID: 33480217). ClinVar contains an entry for this variant (Variation ID: 1390387). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SPAST protein function. This variant disrupts the p.Phe381 amino acid residue in SPAST. Other variant(s) that disrupt this residue have been observed in individuals with SPAST-related conditions (PMID: 10699187, 16832076), which suggests that this may be a clinically significant amino acid residue. 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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