NM_014946.4(SPAST):c.1170G>A (p.Met390Ile) AND Hereditary spastic paraplegia 4

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Apr 2, 2021
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:: RCV001364718.7

Allele description [Variation Report for NM_014946.4(SPAST):c.1170G>A (p.Met390Ile)]

NM_014946.4(SPAST):c.1170G>A (p.Met390Ile)

Gene:

SPAST:spastin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2p22.3

Genomic location:

Preferred name:

NM_014946.4(SPAST):c.1170G>A (p.Met390Ile)

HGVS:

NC_000002.12:g.32127019G>A
NG_008730.1:g.68409G>A
NM_001363823.2:c.1167G>A
NM_001363875.2:c.1071G>A
NM_001377959.1:c.1074G>A
NM_014946.4:c.1170G>AMANE SELECT
NM_199436.2:c.1074G>A
NP_001350752.1:p.Met389Ile
NP_001350804.1:p.Met357Ile
NP_001364888.1:p.Met358Ile
NP_055761.2:p.Met390Ile
NP_055761.2:p.Met390Ile
NP_955468.1:p.Met358Ile
LRG_714t1:c.1170G>A
LRG_714:g.68409G>A
LRG_714p1:p.Met390Ile
NC_000002.11:g.32352088G>A
NM_014946.3:c.1170G>A

Protein change:

M357I

Links:

dbSNP: rs1131691971

NCBI 1000 Genomes Browser:

rs1131691971

Molecular consequence:

NM_001363823.2:c.1167G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001363875.2:c.1071G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001377959.1:c.1074G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_014946.4:c.1170G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_199436.2:c.1074G>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
SCV001560881	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Apr 2, 2021)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 14732620, 20932283, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001560881

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Apr 2, 2021)

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

Three novel mutations of the spastin gene in Chinese patients with hereditary spastic paraplegia.

Tang B, Zhao G, Xia K, Pan Q, Luo W, Shen L, Long Z, Dai H, Zi X, Jiang H.

Arch Neurol. 2004 Jan;61(1):49-55.

PubMed [citation]

PMID:: 14732620

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, SCV001560881.4

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

Description

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. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Met390 amino acid residue in SPAST. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14732620, 20932283). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This variant has been observed in individual(s) with clinical features of hereditary spastic paraplegia (PMID: Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 430448). This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with isoleucine at codon 390 of the SPAST protein (p.Met390Ile). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and isoleucine.

#	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: Oct 8, 2024

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