NM_014946.4(SPAST):c.1495C>T (p.Arg499Cys) AND Hereditary spastic paraplegia 4

Germline classification:: Pathogenic (7 submissions)
Last evaluated:: Apr 4, 2024
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:: RCV000006014.20

Allele description [Variation Report for NM_014946.4(SPAST):c.1495C>T (p.Arg499Cys)]

NM_014946.4(SPAST):c.1495C>T (p.Arg499Cys)

Gene:

SPAST:spastin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2p22.3

Genomic location:

Preferred name:

NM_014946.4(SPAST):c.1495C>T (p.Arg499Cys)

HGVS:

NC_000002.12:g.32141905C>T
NG_008730.1:g.83295C>T
NM_001363823.2:c.1492C>T
NM_001363875.2:c.1396C>T
NM_001377959.1:c.1399C>T
NM_014946.4:c.1495C>TMANE SELECT
NM_199436.2:c.1399C>T
NP_001350752.1:p.Arg498Cys
NP_001350804.1:p.Arg466Cys
NP_001364888.1:p.Arg467Cys
NP_055761.2:p.Arg499Cys
NP_055761.2:p.Arg499Cys
NP_955468.1:p.Arg467Cys
LRG_714t1:c.1495C>T
LRG_714:g.83295C>T
LRG_714p1:p.Arg499Cys
NC_000002.11:g.32366974C>T
NM_014946.3:c.1495C>T
Q9UBP0:p.Arg499Cys

Protein change:

R466C; ARG499CYS

Links:

UniProtKB: Q9UBP0#VAR_010198; OMIM: 604277.0004; dbSNP: rs121908511

NCBI 1000 Genomes Browser:

rs121908511

Molecular consequence:

NM_001363823.2:c.1492C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001363875.2:c.1396C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001377959.1:c.1399C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_014946.4:c.1495C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_199436.2:c.1399C>T - 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
SCV000026196	OMIM	no assertion criteria provided	Pathogenic (May 1, 2001)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 10610178, 11309678
SCV000645351	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Apr 19, 2023)	germline	clinical testing	PubMed (17) [See all records that cite these PMIDs] 16009769, 16682546, 18701882, 20562464, 15716377, 10610178, 11309678, 12161613, 16055926, 17594340, 17957230, 19438933, 20718791, 25658484, 26208798, 27334366, 28492532
SCV001450998	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]
SCV002556973	Genetics and Molecular Pathology, SA Pathology See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 21, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002760024	GenomeConnect - Brain Gene Registry	no classification provided	not provided	unknown	phenotyping only
SCV004809673	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 4, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005086594	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 17, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 29421991, 30006150, 30476002, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	phenotyping only
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutation analysis of SPG4 and SPG3A genes and its implication in molecular diagnosis of Korean patients with hereditary spastic paraplegia.

Park SY, Ki CS, Kim HJ, Kim JW, Sung DH, Kim BJ, Lee WY.

Arch Neurol. 2005 Jul;62(7):1118-21.

PubMed [citation]

PMID:: 16009769

Eight novel mutations in SPG4 in a large sample of patients with hereditary spastic paraplegia.

Crippa F, Panzeri C, Martinuzzi A, Arnoldi A, Redaelli F, Tonelli A, Baschirotto C, Vazza G, Mostacciuolo ML, Daga A, Orso G, Profice P, Trabacca A, D'Angelo MG, Comi GP, Galbiati S, Lamperti C, Bonato S, Pandolfo M, Meola G, Musumeci O, Toscano A, et al.

Arch Neurol. 2006 May;63(5):750-5.

PubMed [citation]

PMID:: 16682546

See all PubMed Citations (21)

Details of each submission

From OMIM, SCV000026196.2

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

Description

In a member of a family with spastic paraplegia-4 (SPG4; 182601), Hazan et al. (1999) identified a heterozygous 1620C-T transition in exon 13 of the SPAST gene, resulting in an arg499-to-cys(R499C) substitution. This mutation was identified in family 618.

Svenson et al. (2001) identified heterozygosity for the R499C mutation in another family segregating SPG4.

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000645351.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (17)

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg499 amino acid residue in SPAST. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16009769, 16682546, 18701882, 20562464). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects SPAST function (PMID: 15716377). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 5660). This variant is also known as 1620C>T. This missense change has been observed in individuals with hereditary spastic paraplegia (HSP) (PMID: 10610178, 11309678, 12161613, 16055926, 17594340, 17957230, 19438933, 20718791, 25658484, 26208798, 27334366). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 499 of the SPAST protein (p.Arg499Cys).

#	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, SCV001450998.1

#	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

From Genetics and Molecular Pathology, SA Pathology, SCV002556973.2

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

Description

The SPAST c.1495C>T variant is classified as Pathogenic (PS4_Moderate, PS3, PM2, PM5)

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

From GenomeConnect - Brain Gene Registry, SCV002760024.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	phenotyping only	not provided

Description

Variant interpreted as Pathogenic and reported on 07-18-2019 by Lab or GTR ID 26957. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator John Constantino MD PhD from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/.

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

From Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, SCV004809673.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	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	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV005086594.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease for this gene and are associated with spastic paraplegia 4 (MIM#182601). Multiple loss of function variants have been reported, while a dominant negative mechanism has been stipulated for a small number of missense variants (ClinVar; PMID: 30006150). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance, but this is age-dependent and only a small proportion of individuals remain asymptomatic (PMID: 30476002). (I) 0115 - Variants in this gene are known to have variable expressivity, with variable age of onset and disease severity (PMID: 30476002). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as pathogenic, and observed in individuals with hereditary spastic paraplegia, with an elevated risk of cognitive impairment (ClinVar, PMID: 29421991). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

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

Last Updated: Oct 20, 2024

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