NM_014946.4(SPAST):c.1196C>T (p.Ser399Leu) AND Hereditary spastic paraplegia 4

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Jul 16, 2023
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:: RCV000686298.13

Allele description [Variation Report for NM_014946.4(SPAST):c.1196C>T (p.Ser399Leu)]

NM_014946.4(SPAST):c.1196C>T (p.Ser399Leu)

Gene:

SPAST:spastin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2p22.3

Genomic location:

Preferred name:

NM_014946.4(SPAST):c.1196C>T (p.Ser399Leu)

HGVS:

NC_000002.12:g.32128430C>T
NG_008730.1:g.69820C>T
NM_001363823.2:c.1193C>T
NM_001363875.2:c.1097C>T
NM_001377959.1:c.1100C>T
NM_014946.4:c.1196C>TMANE SELECT
NM_199436.2:c.1100C>T
NP_001350752.1:p.Ser398Leu
NP_001350804.1:p.Ser366Leu
NP_001364888.1:p.Ser367Leu
NP_055761.2:p.Ser399Leu
NP_055761.2:p.Ser399Leu
NP_955468.1:p.Ser367Leu
LRG_714t1:c.1196C>T
LRG_714:g.69820C>T
LRG_714p1:p.Ser399Leu
NC_000002.11:g.32353499C>T
NM_014946.3:c.1196C>T

Protein change:

S366L

Links:

dbSNP: rs1553317025

NCBI 1000 Genomes Browser:

rs1553317025

Molecular consequence:

NM_001363823.2:c.1193C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001363875.2:c.1097C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001377959.1:c.1100C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_014946.4:c.1196C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_199436.2:c.1100C>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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MaoC family dehydratase [Sulfitobacter albidus]
MaoC family dehydratase [Sulfitobacter albidus]
gi|2030480929|gnl|PRJNA723136|KDD17 5|gb|QUJ76880.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000813810	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jul 16, 2023)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 11843700, 16832076, 18701882, 19875132, 22960362, 24824479, 25045380, 27334366, 29934652, 29980238, 28492532
SCV001450956	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]
SCV002768024	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 6, 2021)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 24824479, 25045380, 29980238, 30006150, 30476002, 31594988, 25741868
SCV002811662	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 21, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	2	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	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

Spectrum of SPG4 mutations in a large collection of North American families with hereditary spastic paraplegia.

Meijer IA, Hand CK, Cossette P, Figlewicz DA, Rouleau GA.

Arch Neurol. 2002 Feb;59(2):281-6.

PubMed [citation]

PMID:: 11843700

Clinical features of hereditary spastic paraplegia due to spastin mutation.

McDermott CJ, Burness CE, Kirby J, Cox LE, Rao DG, Hewamadduma C, Sharrack B, Hadjivassiliou M, Chinnery PF, Dalton A, Shaw PJ; UK and Irish HSP Consortium..

Neurology. 2006 Jul 11;67(1):45-51. Erratum in: Neurology. 2009 Apr 28;72(17):1534.

PubMed [citation]

PMID:: 16832076

See all PubMed Citations (15)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000813810.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (11)

Description

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 399 of the SPAST protein (p.Ser399Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hereditary spastic paraplegia (PMID: 11843700, 16832076, 18701882, 19875132, 22960362, 24824479, 25045380, 27334366, 29934652, 29980238). ClinVar contains an entry for this variant (Variation ID: 448442). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SPAST protein function. For these reasons, this variant has been classified as Pathogenic.

#	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, SCV001450956.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	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		2	not provided	not provided	not provided

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002768024.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

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 serine to leucine. (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) (AAA cassette, PMID: 29980238). (SP) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. This alternative change (p.Ser399Trp) has been reported as a VUS (ClinVar). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic and likely pathogenic, in multiple patients with hereditary spastic paraplegia (ClinVar, LOVD, PMID: 29980238, PMID: 31594988, PMID: 25045380; PMID: 24824479). (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

From Fulgent Genetics, Fulgent Genetics, SCV002811662.1

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 8, 2024

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