NM_014946.4(SPAST):c.3G>C (p.Met1Ile) AND Hereditary spastic paraplegia 4

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jul 7, 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:: RCV002598340.3

Allele description [Variation Report for NM_014946.4(SPAST):c.3G>C (p.Met1Ile)]

NM_014946.4(SPAST):c.3G>C (p.Met1Ile)

Gene:

SPAST:spastin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2p22.3

Genomic location:

Preferred name:

NM_014946.4(SPAST):c.3G>C (p.Met1Ile)

HGVS:

NC_000002.12:g.32063834G>C
NG_008730.1:g.5224G>C
NG_094904.1:g.467G>C
NM_001363823.2:c.3G>C
NM_001363875.2:c.3G>C
NM_001377959.1:c.3G>C
NM_014946.4:c.3G>CMANE SELECT
NM_199436.2:c.3G>C
NP_001350752.1:p.Met1Ile
NP_001350804.1:p.Met1Ile
NP_001364888.1:p.Met1Ile
NP_055761.2:p.Met1Ile
NP_055761.2:p.Met1Ile
NP_955468.1:p.Met1Ile
LRG_714t1:c.3G>C
LRG_714:g.5224G>C
LRG_714p1:p.Met1Ile
NC_000002.11:g.32288903G>C
NM_014946.3:c.3G>C

Protein change:

M1I

Molecular consequence:

NM_001363823.2:c.3G>C - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_001363875.2:c.3G>C - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_001377959.1:c.3G>C - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_014946.4:c.3G>C - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_199436.2:c.3G>C - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_001363823.2:c.3G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001363875.2:c.3G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001377959.1:c.3G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_014946.4:c.3G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_199436.2:c.3G>C - 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
SCV002953370	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jul 7, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 30476002, 16055926, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002953370

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jul 7, 2023)

germline

clinical testing

PubMed (3)
[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

Spastic paraplegia due to SPAST mutations is modified by the underlying mutation and sex.

Parodi L, Fenu S, Barbier M, Banneau G, Duyckaerts C, Tezenas du Montcel S, Monin ML, Ait Said S, Guegan J, Tallaksen CME, Sablonniere B, Brice A, Stevanin G, Depienne C, Durr A; SPATAX network..

Brain. 2018 Dec 1;141(12):3331-3342. doi: 10.1093/brain/awy285.

PubMed [citation]

PMID:: 30476002

Spastin mutations are frequent in sporadic spastic paraparesis and their spectrum is different from that observed in familial cases.

Depienne C, Tallaksen C, Lephay JY, Bricka B, Poea-Guyon S, Fontaine B, Labauge P, Brice A, Durr A.

J Med Genet. 2006 Mar;43(3):259-65. Epub 2005 Jul 31.

PubMed [citation]

PMID:: 16055926
PMCID:: PMC2563242

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002953370.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the SPAST mRNA. The next in-frame methionine is located at codon 87. Disruption of the initiator codon has been observed in individual(s) with clinical features of SPAST-related conditions (PMID: 30476002). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts a region of the SPAST protein in which other variant(s) (p.Glu43Gln) have been observed in individuals with SPAST-related conditions (PMID: 16055926). 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: 1917540).

#	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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