NM_014946.4(SPAST):c.1840dup (p.Thr614fs) AND Hereditary spastic paraplegia 4

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Sep 21, 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:: RCV003525275.1

Allele description [Variation Report for NM_014946.4(SPAST):c.1840dup (p.Thr614fs)]

NM_014946.4(SPAST):c.1840dup (p.Thr614fs)

Gene:

SPAST:spastin [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

2p22.3

Genomic location:

Preferred name:

NM_014946.4(SPAST):c.1840dup (p.Thr614fs)

HGVS:

NC_000002.12:g.32154485dup
NG_008730.1:g.95875dup
NM_001363823.2:c.1837dup
NM_001363875.2:c.1741dup
NM_001377959.1:c.*113dup
NM_014946.4:c.1840dupMANE SELECT
NM_199436.2:c.1744dup
NP_001350752.1:p.Thr613fs
NP_001350804.1:p.Thr581fs
NP_055761.2:p.Thr614Asnfs
NP_055761.2:p.Thr614fs
NP_955468.1:p.Thr582fs
LRG_714t1:c.1840dup
LRG_714:g.95875dup
LRG_714p1:p.Thr614Asnfs
NC_000002.11:g.32379553_32379554insA
NC_000002.11:g.32379554dup
NM_014946.3:c.1840dup

Protein change:

T581fs

Molecular consequence:

NM_001377959.1:c.*113dup - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001363823.2:c.1837dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001363875.2:c.1741dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_014946.4:c.1840dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_199436.2:c.1744dup - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV004292436	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 21, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 27084228, 27334366, 12124993, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004292436

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Sep 21, 2023)

germline

clinical testing

PubMed (4)
[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

Genetic background of the hereditary spastic paraplegia phenotypes in Hungary - An analysis of 58 probands.

Balicza P, Grosz Z, Gonzalez MA, Bencsik R, Pentelenyi K, Gal A, Varga E, Klivenyi P, Koller J, Züchner S, Molnar JM.

J Neurol Sci. 2016 May 15;364:116-21. doi: 10.1016/j.jns.2016.03.018. Epub 2016 Mar 12.

PubMed [citation]

PMID:: 27084228

SPAST mutation spectrum and familial occurrence among Czech patients with pure hereditary spastic paraplegia.

Mészárosová AU, Putzová M, Čermáková M, Vávrová D, Doležalová K, Smetanová I, Stejskal D, Beetz C, Seeman P.

J Hum Genet. 2016 Oct;61(10):845-850. doi: 10.1038/jhg.2016.73. Epub 2016 Jun 23.

PubMed [citation]

PMID:: 27334366

See all PubMed Citations (4)

Details of each submission

From Invitae, SCV004292436.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change results in a frameshift in the SPAST gene (p.Thr614Asnfs*17). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 3 amino acid(s) of the SPAST protein and extend the protein by 13 additional amino acid residues. This variant is not present in population databases (gnomAD no frequency). This frameshift has been observed in individuals with hereditary spastic paraplegia (PMID: 27084228, 27334366). This variant disrupts a region of the SPAST protein in which other variant(s) (p.Thr615Ile) have been determined to be pathogenic (PMID: 12124993; 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. 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

Last Updated: Feb 20, 2024

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