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NM_014946.4(SPAST):c.1151C>T (p.Pro384Leu) AND Hereditary spastic paraplegia 4

Germline classification:
Pathogenic (1 submission)
Last evaluated:
May 28, 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:
RCV000817235.7

Allele description [Variation Report for NM_014946.4(SPAST):c.1151C>T (p.Pro384Leu)]

NM_014946.4(SPAST):c.1151C>T (p.Pro384Leu)

Gene:
SPAST:spastin [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
2p22.3
Genomic location:
Preferred name:
NM_014946.4(SPAST):c.1151C>T (p.Pro384Leu)
HGVS:
  • NC_000002.12:g.32127000C>T
  • NG_008730.1:g.68390C>T
  • NM_001363823.2:c.1148C>T
  • NM_001363875.2:c.1052C>T
  • NM_001377959.1:c.1055C>T
  • NM_014946.4:c.1151C>TMANE SELECT
  • NM_199436.2:c.1055C>T
  • NP_001350752.1:p.Pro383Leu
  • NP_001350804.1:p.Pro351Leu
  • NP_001364888.1:p.Pro352Leu
  • NP_055761.2:p.Pro384Leu
  • NP_055761.2:p.Pro384Leu
  • NP_955468.1:p.Pro352Leu
  • LRG_714t1:c.1151C>T
  • LRG_714:g.68390C>T
  • LRG_714p1:p.Pro384Leu
  • NC_000002.11:g.32352069C>T
  • NM_014946.3:c.1151C>T
Protein change:
P351L
Links:
dbSNP: rs1573139616
NCBI 1000 Genomes Browser:
rs1573139616
Molecular consequence:
  • NM_001363823.2:c.1148C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001363875.2:c.1052C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001377959.1:c.1055C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_014946.4:c.1151C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_199436.2:c.1055C>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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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000957785Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(May 28, 2023) 		germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

The impact of next-generation sequencing on the diagnosis of pediatric-onset hereditary spastic paraplegias: new genotype-phenotype correlations for rare HSP-related genes.

Travaglini L, Aiello C, Stregapede F, D'Amico A, Alesi V, Ciolfi A, Bruselles A, Catteruccia M, Pizzi S, Zanni G, Loddo S, Barresi S, Vasco G, Tartaglia M, Bertini E, Nicita F.

Neurogenetics. 2018 May;19(2):111-121. doi: 10.1007/s10048-018-0545-9. Epub 2018 Apr 24.

PubMed [citation]
PMID:
29691679

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, SCV000957785.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro384 amino acid residue in SPAST. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 29691679). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 660105). This missense change has been observed in individual(s) with hereditary spastic paraplegia (Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 384 of the SPAST protein (p.Pro384Leu).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024