NM_014946.4(SPAST):c.1115G>T (p.Arg372Ile) AND Hereditary spastic paraplegia 4

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Feb 12, 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:: RCV000203812.7

Allele description [Variation Report for NM_014946.4(SPAST):c.1115G>T (p.Arg372Ile)]

NM_014946.4(SPAST):c.1115G>T (p.Arg372Ile)

Gene:

SPAST:spastin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2p22.3

Genomic location:

Preferred name:

NM_014946.4(SPAST):c.1115G>T (p.Arg372Ile)

HGVS:

NC_000002.12:g.32126964G>T
NG_008730.1:g.68354G>T
NM_001363823.2:c.1112G>T
NM_001363875.2:c.1016G>T
NM_001377959.1:c.1019G>T
NM_014946.4:c.1115G>TMANE SELECT
NM_199436.2:c.1019G>T
NP_001350752.1:p.Arg371Ile
NP_001350804.1:p.Arg339Ile
NP_001364888.1:p.Arg340Ile
NP_055761.2:p.Arg372Ile
NP_055761.2:p.Arg372Ile
NP_955468.1:p.Arg340Ile
LRG_714t1:c.1115G>T
LRG_714:g.68354G>T
LRG_714p1:p.Arg372Ile
NC_000002.11:g.32352033G>T
NM_014946.3:c.1115G>T

Protein change:

R339I

Links:

dbSNP: rs864622327

NCBI 1000 Genomes Browser:

rs864622327

Molecular consequence:

NM_001363823.2:c.1112G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001363875.2:c.1016G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001377959.1:c.1019G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_014946.4:c.1115G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_199436.2:c.1019G>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
SCV000260168	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Feb 12, 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

SCV000260168

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Feb 12, 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):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Invitae, SCV000260168.5

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

Description

This variant disrupts the p.Arg372 amino acid residue in SPAST. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C65"). This variant has not been reported in the literature in individuals with SPAST-related disease. ClinVar contains an entry for this variant (Variation ID: 219966). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with isoleucine at codon 372 of the SPAST protein (p.Arg372Ile). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and isoleucine.

#	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: Mar 5, 2024

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