NM_014946.4(SPAST):c.1253_1255del (p.Glu418del) AND Hereditary spastic paraplegia 4

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Oct 17, 2022
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:: RCV000755019.5

Allele description [Variation Report for NM_014946.4(SPAST):c.1253_1255del (p.Glu418del)]

NM_014946.4(SPAST):c.1253_1255del (p.Glu418del)

Gene:

SPAST:spastin [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

2p22.3

Genomic location:

Preferred name:

NM_014946.4(SPAST):c.1253_1255del (p.Glu418del)

HGVS:

NC_000002.12:g.32136570_32136572del
NG_008730.1:g.77960_77962del
NM_001363823.2:c.1250_1252del
NM_001363875.2:c.1154_1156del
NM_001377959.1:c.1157_1159del
NM_014946.4:c.1253_1255delMANE SELECT
NM_199436.2:c.1157_1159del
NP_001350752.1:p.Glu417del
NP_001350804.1:p.Glu385del
NP_001364888.1:p.Glu386del
NP_055761.2:p.Glu418del
NP_055761.2:p.Glu418del
NP_955468.1:p.Glu386del
LRG_714t1:c.1253_1255del
LRG_714:g.77960_77962del
LRG_714p1:p.Glu418del
NC_000002.11:g.32361637_32361639del
NC_000002.11:g.32361639_32361641del
NM_014946.3:c.1253_1255del

Protein change:

E385del

Links:

dbSNP: rs1558336544

NCBI 1000 Genomes Browser:

rs1558336544

Molecular consequence:

NM_001363823.2:c.1250_1252del - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001363875.2:c.1154_1156del - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001377959.1:c.1157_1159del - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_014946.4:c.1253_1255del - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_199436.2:c.1157_1159del - inframe_deletion - [Sequence Ontology: SO:0001822]

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
SCV000882761	Department of Rehabilitation Medicine, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea	no assertion criteria provided	Pathogenic (Feb 11, 2019)	de novo	research
SCV003524182	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 17, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 31594988, 23238845, 33446253, 34114234, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000882761

Department of Rehabilitation Medicine, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea

no assertion criteria provided

Pathogenic
(Feb 11, 2019)

de novo

research

SCV003524182

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 17, 2022)

germline

clinical testing

PubMed (5)
[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	de novo	yes	1	not provided	not provided	not provided	not provided	research
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutational Spectrum of Spast (Spg4) and Atl1 (Spg3a) Genes In Russian Patients With Hereditary Spastic Paraplegia.

Kadnikova VA, Rudenskaya GE, Stepanova AA, Sermyagina IG, Ryzhkova OP.

Sci Rep. 2019 Oct 8;9(1):14412. doi: 10.1038/s41598-019-50911-9.

PubMed [citation]

PMID:: 31594988
PMCID:: PMC6783457

The neurological and ophthalmological manifestations of SPG4-related hereditary spastic paraplegia.

Guthrie G, Pfeffer G, Bailie M, Bradshaw K, Browning AC, Horvath R, Chinnery PF, Yu-Wai-Man P.

J Neurol. 2013 Mar;260(3):906-9. doi: 10.1007/s00415-012-6780-3. Epub 2012 Dec 13. No abstract available. Erratum in: J Neurol. 2016 Feb;263(2):419-420. doi: 10.1007/s00415-015-8008-9.

PubMed [citation]

PMID:: 23238845
PMCID:: PMC3590400

See all PubMed Citations (5)

Details of each submission

From Department of Rehabilitation Medicine, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, SCV000882761.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1		1	not provided	not provided	research	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	de novo	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Invitae, SCV003524182.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the SPAST protein in which other variant(s) (p.Glu418Lys) have been determined to be pathogenic (PMID: 31594988; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 617765). This variant has been observed in individual(s) with SPAST-related conditions (PMID: 23238845, 33446253, 34114234). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This variant, c.1253_1255del, results in the deletion of 1 amino acid(s) of the SPAST protein (p.Glu418del), but otherwise preserves the integrity of the reading frame.

#	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: Aug 4, 2024

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