NM_014946.4(SPAST):c.1117G>C (p.Ala373Pro) AND Hereditary spastic paraplegia 4

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Dec 9, 2020
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:: RCV002020175.6

Allele description [Variation Report for NM_014946.4(SPAST):c.1117G>C (p.Ala373Pro)]

NM_014946.4(SPAST):c.1117G>C (p.Ala373Pro)

Gene:

SPAST:spastin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2p22.3

Genomic location:

Preferred name:

NM_014946.4(SPAST):c.1117G>C (p.Ala373Pro)

HGVS:

NC_000002.12:g.32126966G>C
NG_008730.1:g.68356G>C
NM_001363823.2:c.1114G>C
NM_001363875.2:c.1018G>C
NM_001377959.1:c.1021G>C
NM_014946.4:c.1117G>CMANE SELECT
NM_199436.2:c.1021G>C
NP_001350752.1:p.Ala372Pro
NP_001350804.1:p.Ala340Pro
NP_001364888.1:p.Ala341Pro
NP_055761.2:p.Ala373Pro
NP_955468.1:p.Ala341Pro
LRG_714:g.68356G>C
NC_000002.11:g.32352035G>C

Protein change:

A340P

Links:

dbSNP: rs1679214464

NCBI 1000 Genomes Browser:

rs1679214464

Molecular consequence:

NM_001363823.2:c.1114G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001363875.2:c.1018G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001377959.1:c.1021G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_014946.4:c.1117G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_199436.2:c.1021G>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
SCV002289506	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 9, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002289506

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 9, 2020)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

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

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, SCV002289506.3

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

Description

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. 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 has not been reported in the literature in individuals with SPAST-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with proline at codon 373 of the SPAST protein (p.Ala373Pro). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and proline.

#	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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