NM_014946.4(SPAST):c.1168A>G (p.Met390Val) AND Hereditary spastic paraplegia 4

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Nov 23, 2020
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000206286.10

Allele description [Variation Report for NM_014946.4(SPAST):c.1168A>G (p.Met390Val)]

NM_014946.4(SPAST):c.1168A>G (p.Met390Val)

Gene:

SPAST:spastin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2p22.3

Genomic location:

Preferred name:

NM_014946.4(SPAST):c.1168A>G (p.Met390Val)

HGVS:

NC_000002.12:g.32127017A>G
NG_008730.1:g.68407A>G
NM_001363823.2:c.1165A>G
NM_001363875.2:c.1069A>G
NM_001377959.1:c.1072A>G
NM_014946.4:c.1168A>GMANE SELECT
NM_199436.2:c.1072A>G
NP_001350752.1:p.Met389Val
NP_001350804.1:p.Met357Val
NP_001364888.1:p.Met358Val
NP_055761.2:p.Met390Val
NP_055761.2:p.Met390Val
NP_955468.1:p.Met358Val
LRG_714t1:c.1168A>G
LRG_714:g.68407A>G
LRG_714p1:p.Met390Val
NC_000002.11:g.32352086A>G
NM_014946.3:c.1168A>G
Q9UBP0:p.Met390Val

Protein change:

M357V

Links:

UniProtKB: Q9UBP0#VAR_019441; dbSNP: rs797044850

NCBI 1000 Genomes Browser:

rs797044850

Molecular consequence:

NM_001363823.2:c.1165A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001363875.2:c.1069A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001377959.1:c.1072A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_014946.4:c.1168A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_199436.2:c.1072A>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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
SCV000260546	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 23, 2020)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 14732620, 20932283, 28492532
SCV001450952	Paris Brain Institute, Inserm - ICM	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	unknown	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

SCV000260546

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 23, 2020)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV001450952

Paris Brain Institute, Inserm - ICM

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic

unknown

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
not provided	unknown	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Three novel mutations of the spastin gene in Chinese patients with hereditary spastic paraplegia.

Tang B, Zhao G, Xia K, Pan Q, Luo W, Shen L, Long Z, Dai H, Zi X, Jiang H.

Arch Neurol. 2004 Jan;61(1):49-55.

PubMed [citation]

PMID:: 14732620

Mutational spectrum of the SPG4 (SPAST) and SPG3A (ATL1) genes in Spanish patients with hereditary spastic paraplegia.

Alvarez V, Sánchez-Ferrero E, Beetz C, Díaz M, Alonso B, Corao AI, Gámez J, Esteban J, Gonzalo JF, Pascual-Pascual SI, López de Munain A, Moris G, Ribacoba R, Márquez C, Rosell J, Marín R, García-Barcina MJ, Del Castillo E, Benito C, Coto E; Group for the Study of the Genetics of Spastic Paraplegia..

BMC Neurol. 2010 Oct 8;10:89. doi: 10.1186/1471-2377-10-89.

PubMed [citation]

PMID:: 20932283
PMCID:: PMC2964648

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000260546.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

In summary, this is a rare missense variant that is absent from the general population and reported to co-segregate with disease in two independent families. For these reasons, this variant has been classified as Pathogenic. 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: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant is not present in population databases and has been reported in patients with hereditary spastic paraplegia (HSP). In one family, this variant co-segregated with HSP in 4 individuals and was absent from 1 tested individual without disease (PMID: 14732620). In a second family, this variant was confirmed to be de novo in a young child with apparently sporadic HSP (PMID: 20932283). This sequence change replaces methionine with valine at codon 390 of the SPAST protein (p.Met390Val). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and valine.

#	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

From Paris Brain Institute, Inserm - ICM, SCV001450952.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Oct 8, 2024

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