NM_014946.4(SPAST):c.1164G>C (p.Lys388Asn) AND Hereditary spastic paraplegia 4

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Nov 28, 2022
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:: RCV001960564.6

Allele description [Variation Report for NM_014946.4(SPAST):c.1164G>C (p.Lys388Asn)]

NM_014946.4(SPAST):c.1164G>C (p.Lys388Asn)

Gene:

SPAST:spastin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2p22.3

Genomic location:

Preferred name:

NM_014946.4(SPAST):c.1164G>C (p.Lys388Asn)

HGVS:

NC_000002.12:g.32127013G>C
NG_008730.1:g.68403G>C
NM_001363823.2:c.1161G>C
NM_001363875.2:c.1065G>C
NM_001377959.1:c.1068G>C
NM_014946.4:c.1164G>CMANE SELECT
NM_199436.2:c.1068G>C
NP_001350752.1:p.Lys387Asn
NP_001350804.1:p.Lys355Asn
NP_001364888.1:p.Lys356Asn
NP_055761.2:p.Lys388Asn
NP_955468.1:p.Lys356Asn
LRG_714:g.68403G>C
NC_000002.11:g.32352082G>C

Protein change:

K355N

Links:

dbSNP: rs1553316838

NCBI 1000 Genomes Browser:

rs1553316838

Molecular consequence:

NM_001363823.2:c.1161G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001363875.2:c.1065G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001377959.1:c.1068G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_014946.4:c.1164G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_199436.2:c.1068G>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
SCV002227817	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 28, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 30476002, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002227817

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 28, 2022)

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

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

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, SCV002227817.3

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

Description

For these reasons, this variant has been classified as Pathogenic. 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: 1454039). This missense change has been observed in individual(s) with clinical features of hereditary spastic paraplegia (PMID: 30476002). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 388 of the SPAST protein (p.Lys388Asn).

#	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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