NM_014946.4(SPAST):c.1304C>T (p.Pro435Leu) AND Hereditary spastic paraplegia 4

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Aug 21, 2021
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:: RCV001905076.4

Allele description [Variation Report for NM_014946.4(SPAST):c.1304C>T (p.Pro435Leu)]

NM_014946.4(SPAST):c.1304C>T (p.Pro435Leu)

Gene:

SPAST:spastin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2p22.3

Genomic location:

Preferred name:

NM_014946.4(SPAST):c.1304C>T (p.Pro435Leu)

HGVS:

NC_000002.12:g.32136621C>T
NG_008730.1:g.78011C>T
NM_001363823.2:c.1301C>T
NM_001363875.2:c.1205C>T
NM_001377959.1:c.1208C>T
NM_014946.4:c.1304C>TMANE SELECT
NM_199436.2:c.1208C>T
NP_001350752.1:p.Pro434Leu
NP_001350804.1:p.Pro402Leu
NP_001364888.1:p.Pro403Leu
NP_055761.2:p.Pro435Leu
NP_955468.1:p.Pro403Leu
LRG_714:g.78011C>T
NC_000002.11:g.32361690C>T

Protein change:

P402L

Links:

dbSNP: rs1553318182

NCBI 1000 Genomes Browser:

rs1553318182

Molecular consequence:

NM_001363823.2:c.1301C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001363875.2:c.1205C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001377959.1:c.1208C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_014946.4:c.1304C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_199436.2:c.1208C>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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EYA3 EYA transcriptional coactivator and phosphatase 3 [Homo sapiens]
EYA3 EYA transcriptional coactivator and phosphatase 3 [Homo sapiens]
Gene ID:2140

Gene
2140[uid] AND (alive[prop]) (1)
Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002129574	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 21, 2021)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 16684598, 27084228, 27334366, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002129574

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Aug 21, 2021)

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

Novel spastin (SPG4) mutations in Italian patients with hereditary spastic paraplegia.

Magariello A, Muglia M, Patitucci A, Mazzei R, Conforti FL, Gabriele AL, Sprovieri T, Ungaro C, Gambardella A, Mancuso M, Siciliano G, Branca D, Aguglia U, de Angelis MV, Longo K, Quattrone A.

Neuromuscul Disord. 2006 Jun;16(6):387-90. Epub 2006 May 8.

PubMed [citation]

PMID:: 16684598

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

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002129574.3

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

Description

For these reasons, this variant has been classified as Pathogenic. This sequence change replaces proline with leucine at codon 435 of the SPAST protein (p.Pro435Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individuals with hereditary spastic paraplegia (PMID: 16684598, 27084228; Invitae). 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. This variant disrupts the p.Pro435 amino acid residue in SPAST. Other variant(s) that disrupt this residue have been observed in individuals with SPAST-related conditions (PMID: 27334366), which suggests that this may be a clinically significant amino acid residue.

#	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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