NM_014946.4(SPAST):c.98C>T (p.Pro33Leu) AND Hereditary spastic paraplegia 4

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Dec 30, 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:: RCV003522977.2

Allele description [Variation Report for NM_014946.4(SPAST):c.98C>T (p.Pro33Leu)]

NM_014946.4(SPAST):c.98C>T (p.Pro33Leu)

Gene:

SPAST:spastin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2p22.3

Genomic location:

Preferred name:

NM_014946.4(SPAST):c.98C>T (p.Pro33Leu)

HGVS:

NC_000002.12:g.32063929C>T
NG_008730.1:g.5319C>T
NM_001363823.2:c.98C>T
NM_001363875.2:c.98C>T
NM_001377959.1:c.98C>T
NM_014946.4:c.98C>TMANE SELECT
NM_199436.2:c.98C>T
NP_001350752.1:p.Pro33Leu
NP_001350804.1:p.Pro33Leu
NP_001364888.1:p.Pro33Leu
NP_055761.2:p.Pro33Leu
NP_055761.2:p.Pro33Leu
NP_955468.1:p.Pro33Leu
LRG_714t1:c.98C>T
LRG_714:g.5319C>T
LRG_714p1:p.Pro33Leu
NC_000002.11:g.32288998C>T
NM_014946.3:c.98C>T

Protein change:

P33L

Links:

dbSNP: rs777721232

NCBI 1000 Genomes Browser:

rs777721232

Molecular consequence:

NM_001363823.2:c.98C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001363875.2:c.98C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001377959.1:c.98C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_014946.4:c.98C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_199436.2:c.98C>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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004274147	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 30, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 33770234, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004274147

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 30, 2023)

germline

clinical testing

PubMed (2)
[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

Targeted sequencing panels in Italian ALS patients support different etiologies in the ALS/FTD continuum.

Bartoletti-Stella A, Vacchiano V, De Pasqua S, Mengozzi G, De Biase D, Bartolomei I, Avoni P, Rizzo G, Parchi P, Donadio V, Chiò A, Pession A, Oppi F, Salvi F, Liguori R, Capellari S; BoReALS..

J Neurol. 2021 Oct;268(10):3766-3776. doi: 10.1007/s00415-021-10521-w. Epub 2021 Mar 26.

PubMed [citation]

PMID:: 33770234
PMCID:: PMC8463338

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004274147.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 33 of the SPAST protein (p.Pro33Leu). This variant is present in population databases (rs777721232, gnomAD 0.006%). This missense change has been observed in individual(s) with amyotrophic lateral sclerosis (PMID: 33770234). ClinVar contains an entry for this variant (Variation ID: 391244). 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 not expected to disrupt SPAST protein function with a negative predictive value of 95%. 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.

#	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: Oct 20, 2024

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