NM_014946.4(SPAST):c.1250G>A (p.Gly417Glu) AND Hereditary spastic paraplegia 4

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Oct 4, 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:: RCV001213726.9

Allele description [Variation Report for NM_014946.4(SPAST):c.1250G>A (p.Gly417Glu)]

NM_014946.4(SPAST):c.1250G>A (p.Gly417Glu)

Gene:

SPAST:spastin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2p22.3

Genomic location:

Preferred name:

NM_014946.4(SPAST):c.1250G>A (p.Gly417Glu)

HGVS:

NC_000002.12:g.32136567G>A
NG_008730.1:g.77957G>A
NM_001363823.2:c.1247G>A
NM_001363875.2:c.1151G>A
NM_001377959.1:c.1154G>A
NM_014946.4:c.1250G>AMANE SELECT
NM_199436.2:c.1154G>A
NP_001350752.1:p.Gly416Glu
NP_001350804.1:p.Gly384Glu
NP_001364888.1:p.Gly385Glu
NP_055761.2:p.Gly417Glu
NP_955468.1:p.Gly385Glu
LRG_714t1:c.1250G>A
LRG_714:g.77957G>A
NC_000002.11:g.32361636G>A
NM_014946.3:c.1250G>A

Protein change:

G384E

Links:

dbSNP: rs1553318161

NCBI 1000 Genomes Browser:

rs1553318161

Molecular consequence:

NM_001363823.2:c.1247G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001363875.2:c.1151G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001377959.1:c.1154G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_014946.4:c.1250G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_199436.2:c.1154G>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
SCV001385375	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Oct 4, 2019)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 18701882, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001385375

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Oct 4, 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

Expansion of mutation spectrum, determination of mutation cluster regions and predictive structural classification of SPAST mutations in hereditary spastic paraplegia.

Shoukier M, Neesen J, Sauter SM, Argyriou L, Doerwald N, Pantakani DV, Mannan AU.

Eur J Hum Genet. 2009 Feb;17(2):187-94. doi: 10.1038/ejhg.2008.147. Epub 2008 Aug 13. Erratum in: Eur J Hum Genet. 2009 Mar;17(3):401-2.

PubMed [citation]

PMID:: 18701882
PMCID:: PMC2986068

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, SCV001385375.5

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

Description

This sequence change replaces glycine with glutamic acid at codon 417 of the SPAST protein (p.Gly417Glu). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of hereditary spastic paraplegia (PMID: 18701882, Invitae). In at least one individual the variant was observed to be de novo. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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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