NM_014946.4(SPAST):c.1260G>T (p.Glu420Asp) AND Hereditary spastic paraplegia 4

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Aug 28, 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:: RCV002050789.6

Allele description [Variation Report for NM_014946.4(SPAST):c.1260G>T (p.Glu420Asp)]

NM_014946.4(SPAST):c.1260G>T (p.Glu420Asp)

Gene:

SPAST:spastin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2p22.3

Genomic location:

Preferred name:

NM_014946.4(SPAST):c.1260G>T (p.Glu420Asp)

HGVS:

NC_000002.12:g.32136577G>T
NG_008730.1:g.77967G>T
NM_001363823.2:c.1257G>T
NM_001363875.2:c.1161G>T
NM_001377959.1:c.1164G>T
NM_014946.4:c.1260G>TMANE SELECT
NM_199436.2:c.1164G>T
NP_001350752.1:p.Glu419Asp
NP_001350804.1:p.Glu387Asp
NP_001364888.1:p.Glu388Asp
NP_055761.2:p.Glu420Asp
NP_955468.1:p.Glu388Asp
LRG_714:g.77967G>T
NC_000002.11:g.32361646G>T

Protein change:

E387D

Links:

dbSNP: rs1679543195

NCBI 1000 Genomes Browser:

rs1679543195

Molecular consequence:

NM_001363823.2:c.1257G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001363875.2:c.1161G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001377959.1:c.1164G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_014946.4:c.1260G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_199436.2:c.1164G>T - 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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Tssr2529 AND (alive[prop]) (0)
Gene
Gm39526 predicted gene, 39526 [Mus musculus]
Gm39526 predicted gene, 39526 [Mus musculus]
Gene ID:105243704

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002112124	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Aug 28, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 35020098, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002112124

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Aug 28, 2023)

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

A p.Glu420Gln mutation in SPAST is associated with infantile onset spastic paraplegia complicated by cerebella ataxia, epilepsy, peripheral neuropathy, and hypoplasia of the corpus callosum.

Nan H, Mizuno T, Arisaka A, Sei K, Takiyama Y.

Neurol Sci. 2022 Mar;43(3):2123-2126. doi: 10.1007/s10072-022-05879-2. Epub 2022 Jan 12. No abstract available.

PubMed [citation]

PMID:: 35020098

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, SCV002112124.3

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

Description

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. This variant disrupts the p.Glu420 amino acid residue in SPAST. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 35020098; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 1348218). This missense change has been observed in individuals with clinical features of hereditary spastic paraplegia (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 420 of the SPAST protein (p.Glu420Asp).

#	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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