NM_014946.4(SPAST):c.1228A>C (p.Ser410Arg) AND Hereditary spastic paraplegia 4

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Aug 12, 2019
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:: RCV001237635.8

Allele description [Variation Report for NM_014946.4(SPAST):c.1228A>C (p.Ser410Arg)]

NM_014946.4(SPAST):c.1228A>C (p.Ser410Arg)

Gene:

SPAST:spastin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2p22.3

Genomic location:

Preferred name:

NM_014946.4(SPAST):c.1228A>C (p.Ser410Arg)

HGVS:

NC_000002.12:g.32128462A>C
NG_008730.1:g.69852A>C
NM_001363823.2:c.1225A>C
NM_001363875.2:c.1129A>C
NM_001377959.1:c.1132A>C
NM_014946.4:c.1228A>CMANE SELECT
NM_199436.2:c.1132A>C
NP_001350752.1:p.Ser409Arg
NP_001350804.1:p.Ser377Arg
NP_001364888.1:p.Ser378Arg
NP_055761.2:p.Ser410Arg
NP_955468.1:p.Ser378Arg
LRG_714t1:c.1228A>C
LRG_714:g.69852A>C
NC_000002.11:g.32353531A>C
NM_014946.3:c.1228A>C

Protein change:

S377R

Links:

dbSNP: rs1679266894

NCBI 1000 Genomes Browser:

rs1679266894

Molecular consequence:

NM_001363823.2:c.1225A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001363875.2:c.1129A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001377959.1:c.1132A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_014946.4:c.1228A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_199436.2:c.1132A>C - 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
SCV001410402	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 12, 2019)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 20932283, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001410402

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Aug 12, 2019)

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

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

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, SCV001410402.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This variant has been observed in an individual affected with hereditary spastic paraplegia (PMID: 20932283). This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with arginine at codon 410 of the SPAST protein (p.Ser410Arg). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and arginine. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). 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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