NM_014946.4(SPAST):c.1196C>G (p.Ser399Trp) AND Hereditary spastic paraplegia 4

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 24, 2024
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:: RCV000536355.7

Allele description [Variation Report for NM_014946.4(SPAST):c.1196C>G (p.Ser399Trp)]

NM_014946.4(SPAST):c.1196C>G (p.Ser399Trp)

Gene:

SPAST:spastin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2p22.3

Genomic location:

Preferred name:

NM_014946.4(SPAST):c.1196C>G (p.Ser399Trp)

HGVS:

NC_000002.12:g.32128430C>G
NG_008730.1:g.69820C>G
NM_001363823.2:c.1193C>G
NM_001363875.2:c.1097C>G
NM_001377959.1:c.1100C>G
NM_014946.4:c.1196C>GMANE SELECT
NM_199436.2:c.1100C>G
NP_001350752.1:p.Ser398Trp
NP_001350804.1:p.Ser366Trp
NP_001364888.1:p.Ser367Trp
NP_055761.2:p.Ser399Trp
NP_055761.2:p.Ser399Trp
NP_955468.1:p.Ser367Trp
LRG_714t1:c.1196C>G
LRG_714:g.69820C>G
LRG_714p1:p.Ser399Trp
NC_000002.11:g.32353499C>G
NM_014946.3:c.1196C>G

Protein change:

S366W

Links:

dbSNP: rs1553317025

NCBI 1000 Genomes Browser:

rs1553317025

Molecular consequence:

NM_001363823.2:c.1193C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001363875.2:c.1097C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001377959.1:c.1100C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_014946.4:c.1196C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_199436.2:c.1100C>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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SRX7691910 (1)
SRA
Homo sapiens nebulin (NEB), transcript variant 3, mRNA
Homo sapiens nebulin (NEB), transcript variant 3, mRNA
gi|257743030|ref|NM_004543.4|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000645341	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 24, 2024)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 33179235, 11843700, 16832076, 19875132, 22960362, 29980238, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000645341

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 24, 2024)

germline

clinical testing

PubMed (7)
[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

[Identification of SPAST gene variant in a pedigree affected with hereditary spastic paraplegia type 4].

Qi N, Ma M, Yang K, Lou G, Qin L, Hou Q, Zhang Y, Liao S.

Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2020 Nov 10;37(11):1261-1264. doi: 10.3760/cma.j.cn511374-20191120-00592. Chinese.

PubMed [citation]

PMID:: 33179235

Spectrum of SPG4 mutations in a large collection of North American families with hereditary spastic paraplegia.

Meijer IA, Hand CK, Cossette P, Figlewicz DA, Rouleau GA.

Arch Neurol. 2002 Feb;59(2):281-6.

PubMed [citation]

PMID:: 11843700

See all PubMed Citations (7)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000645341.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This sequence change replaces serine, which is neutral and polar, with tryptophan, which is neutral and slightly polar, at codon 399 of the SPAST protein (p.Ser399Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hereditary spastic paraplegia (PMID: 33179235; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 468561). 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%. This variant disrupts the p.Ser399 amino acid residue in SPAST. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11843700, 16832076, 19875132, 22960362, 29980238). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

#	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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