NM_014946.4(SPAST):c.1215_1219del (p.Asn405fs) AND Hereditary spastic paraplegia 4

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jan 20, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000548535.9

Allele description [Variation Report for NM_014946.4(SPAST):c.1215_1219del (p.Asn405fs)]

NM_014946.4(SPAST):c.1215_1219del (p.Asn405fs)

Gene:

SPAST:spastin [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

2p22.3

Genomic location:

Preferred name:

NM_014946.4(SPAST):c.1215_1219del (p.Asn405fs)

HGVS:

NC_000002.12:g.32128449_32128453del
NG_008730.1:g.69839_69843del
NM_001363823.2:c.1212_1216del
NM_001363875.2:c.1116_1120del
NM_001377959.1:c.1119_1123del
NM_014946.4:c.1215_1219delMANE SELECT
NM_199436.2:c.1119_1123del
NP_001350752.1:p.Asn404fs
NP_001350804.1:p.Asn372fs
NP_001364888.1:p.Asn373fs
NP_055761.2:p.Asn405fs
NP_055761.2:p.Asn405fs
NP_955468.1:p.Asn373fs
LRG_714t1:c.1215_1219del
LRG_714:g.69839_69843del
LRG_714p1:p.Asn405fs
NC_000002.11:g.32353515_32353519del
NC_000002.11:g.32353518_32353522del
NM_014946.3:c.1215_1219del
NM_014946.3:c.1215_1219del
NM_014946.3:c.1215_1219delTATAA

Protein change:

N372fs

Links:

dbSNP: rs1553317032

NCBI 1000 Genomes Browser:

rs1553317032

Molecular consequence:

NM_001363823.2:c.1212_1216del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001363875.2:c.1116_1120del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001377959.1:c.1119_1123del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_014946.4:c.1215_1219del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_199436.2:c.1119_1123del - frameshift variant - [Sequence Ontology: SO:0001589]

Observations:

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
SCV000645342	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 20, 2024)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 20932283, 10699187, 15841487, 17594340, 17598599, 18701882, 19289482, 26671083, 28492532
SCV001450958	Paris Brain Institute, Inserm - ICM	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000645342

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 20, 2024)

germline

clinical testing

PubMed (9)
[See all records that cite these PMIDs]

SCV001450958

Paris Brain Institute, Inserm - ICM

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	yes	1	not provided	not provided	not provided	not provided	clinical testing
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

Spectrum of SPG4 mutations in autosomal dominant spastic paraplegia.

Fonknechten N, Mavel D, Byrne P, Davoine CS, Cruaud C, Bönsch D, Samson D, Coutinho P, Hutchinson M, McMonagle P, Burgunder JM, Tartaglione A, Heinzlef O, Feki I, Deufel T, Parfrey N, Brice A, Fontaine B, Prud'homme JF, Weissenbach J, Dürr A, Hazan J.

Hum Mol Genet. 2000 Mar 1;9(4):637-44. Erratum in: Hum Mol Genet. 2005 Feb 1;14(3):461. Boentsch, D [corrected to Bönsch, D].

PubMed [citation]

PMID:: 10699187

See all PubMed Citations (10)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000645342.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

This sequence change creates a premature translational stop signal (p.Asn405Lysfs*36) in the SPAST gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SPAST are known to be pathogenic (PMID: 20932283). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with hereditary spastic paraplegia (PMID: 10699187, 15841487, 17594340, 17598599, 18701882, 19289482, 26671083). It has also been observed to segregate with disease in related individuals. This variant is also known as c.1340_1344delTATAA or 1340del5. ClinVar contains an entry for this variant (Variation ID: 468562). 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

From Paris Brain Institute, Inserm - ICM, SCV001450958.1

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

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

Last Updated: Oct 20, 2024

ClinVar

Relating variation to medicine