VCV000448449.49 - ClinVar

NM_014946.4(SPAST):c.1684C>T (p.Arg562Ter)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(10)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_014946.4(SPAST):c.1684C>T (p.Arg562Ter)

Variation ID: 448449 Accession: VCV000448449.49

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2p22.3 2: 32145004 (GRCh38) [ NCBI UCSC ] 2: 32370073 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Dec 19, 2017	Nov 24, 2024	Sep 12, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_014946.4:c.1684C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_055761.2:p.Arg562Ter	nonsense
NM_001363823.2:c.1681C>T	NP_001350752.1:p.Arg561Ter	nonsense
NM_001363875.2:c.1585C>T	NP_001350804.1:p.Arg529Ter	nonsense
NM_001377959.1:c.1520+1589C>T		intron variant
NM_199436.2:c.1588C>T	NP_955468.1:p.Arg530Ter	nonsense
NC_000002.12:g.32145004C>T
NC_000002.11:g.32370073C>T
NG_008730.1:g.86394C>T
LRG_714:g.86394C>T
LRG_714t1:c.1684C>T	LRG_714p1:p.Arg562Ter

... more HGVS ... less HGVS

Protein change

R562*, R530*, R529*, R561*

Other names

Canonical SPDI

NC_000002.12:32145003:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Trans-Omics for Precision Medicine (TOPMed) 0.00000

Links

ClinGen: CA346504288 dbSNP: rs121908518 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
SPAST		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	1335	1402

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not provided	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	Sep 12, 2024	RCV000517099.33
Hereditary spastic paraplegia 4	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Dec 21, 2023	RCV000644889.17
Hereditary spastic paraplegia	Pathogenic (1)	criteria provided, single submitter	May 21, 2021	RCV001848905.4

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Feb 28, 2019)	criteria provided, single submitter (Classification criteria August 2017) Method: clinical testing	Hereditary spastic paraplegia 4 (Autosomal dominant inheritance) Affected status: yes Allele origin: de novo	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München Accession: SCV001150272.1 First in ClinVar: Feb 03, 2020 Last updated: Feb 03, 2020	Sex: male Tissue: blood
Pathogenic (Oct 23, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001446407.1 First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020	Clinical Features: Spasticity (present) , Paraplegia/paraparesis (present) , Urinary urgency (present) , Lower limb spasticity (present) , Somatic sensory dysfunction (present) , Hyperactive deep tendon reflexes (present) Sex: female
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary spastic paraplegia 4 Affected status: yes Allele origin: unknown	Paris Brain Institute, Inserm - ICM Accession: SCV001451012.1 First in ClinVar: May 16, 2021 Last updated: May 16, 2021	Number of individuals with the variant: 2
Pathogenic (Aug 25, 2020)	criteria provided, single submitter (Athena Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Athena Diagnostics Accession: SCV000615391.3 First in ClinVar: Dec 19, 2017 Last updated: Sep 19, 2021	Publications: PubMed (6) PubMed: 17597328‚ 27084228‚ 24381312‚ 20718791‚ 18701882‚ 10699187 Comment: This variant is expected to result in the loss of a functional protein. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). … (more) This variant is expected to result in the loss of a functional protein. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. The variant is located in a region that is considered important for protein function and/or structure (less)
Pathogenic (May 21, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary spastic paraplegia Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, The Hospital for Sick Children Accession: SCV002105621.1 First in ClinVar: Mar 19, 2022 Last updated: Mar 19, 2022
Pathogenic (Dec 21, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Hereditary spastic paraplegia 4 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000766607.6 First in ClinVar: May 28, 2018 Last updated: Feb 14, 2024	Publications: PubMed (6) PubMed: 10699187‚ 17597328‚ 18701882‚ 20718791‚ 24381312‚ 27084228 Comment: This sequence change creates a premature translational stop signal (p.Arg562) in the SPAST gene. While this is not anticipated to result in nonsense mediated decay, … (more) This sequence change creates a premature translational stop signal (p.Arg562) in the SPAST gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 55 amino acid(s) of the SPAST protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with hereditary spastic paraplegia (PMID: 10699187, 17597328, 18701882, 20718791, 24381312, 27084228). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 448449). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects SPAST function (PMID: 24381312). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Sep 12, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001873867.3 First in ClinVar: Sep 19, 2021 Last updated: Sep 29, 2024	Comment: Published functional studies demonstrate that the R562X variant results in reduced levels of SPAST protein, decreased neurite length and complexity, and severely disrupted microtubule structures … (more) Published functional studies demonstrate that the R562X variant results in reduced levels of SPAST protein, decreased neurite length and complexity, and severely disrupted microtubule structures (PMID: 24381312); Nonsense variant predicted to result in protein truncation, as the last 55 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 17597328, 12124993, 28389476, 30489674, 24731568, 27084228, 24381312, 18701882, 22960362, 10699187, 31157359, 32457567, 32501971, 25421405, 20932283, 29934652, 22552817, 20718791, 26671083, 31594988, 26208798, 27535533, 37251230, 34983064, 35472722, 21139634, 26094131) (less)
Pathogenic (Jun 01, 2021)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001247363.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Number of individuals with the variant: 3
Pathogenic (Oct 30, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV005413236.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Publications: PubMed (5) PubMed: 10699187‚ 17597328‚ 24381312‚ 27084228‚ 37251230 Comment: PP1, PM2_moderate, PM6, PS3, PS4, PVS1 Number of individuals with the variant: 1
Likely pathogenic (Jun 01, 2022)	no assertion criteria provided Method: provider interpretation	Hereditary spastic paraplegia 4 Affected status: yes Allele origin: inherited	Solve-RD Consortium Accession: SCV005091383.1 First in ClinVar: Oct 26, 2024 Last updated: Oct 26, 2024 Comment: Variant identified during reanalysis of unsolved cases by the Solve-RD project. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and … (more) Variant identified during reanalysis of unsolved cases by the Solve-RD project. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 779257. (less)	Comment: Variant confirmed as disease-causing by referring clinical team

Comment:

This variant is expected to result in the loss of a functional protein. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. The variant is located in a region that is considered important for protein function and/or structure

Comment:

This sequence change creates a premature translational stop signal (p.Arg562*) in the SPAST gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 55 amino acid(s) of the SPAST protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with hereditary spastic paraplegia (PMID: 10699187, 17597328, 18701882, 20718791, 24381312, 27084228). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 448449). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects SPAST function (PMID: 24381312). For these reasons, this variant has been classified as Pathogenic.

Comment:

Published functional studies demonstrate that the R562X variant results in reduced levels of SPAST protein, decreased neurite length and complexity, and severely disrupted microtubule structures (PMID: 24381312); Nonsense variant predicted to result in protein truncation, as the last 55 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 17597328, 12124993, 28389476, 30489674, 24731568, 27084228, 24381312, 18701882, 22960362, 10699187, 31157359, 32457567, 32501971, 25421405, 20932283, 29934652, 22552817, 20718791, 26671083, 31594988, 26208798, 27535533, 37251230, 34983064, 35472722, 21139634, 26094131)

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Genetic and clinical features of pediatric-onset hereditary spastic paraplegia: a single-center study in Japan.	Ikeda A	Frontiers in neurology	2023	PMID: 37251230
Genetic background of the hereditary spastic paraplegia phenotypes in Hungary - An analysis of 58 probands.	Balicza P	Journal of the neurological sciences	2016	PMID: 27084228
Gene dosage-dependent rescue of HSP neurite defects in SPG4 patients' neurons.	Havlicek S	Human molecular genetics	2014	PMID: 24381312
Mutation screening of spastin, atlastin, and REEP1 in hereditary spastic paraplegia.	McCorquodale DS 3rd	Clinical genetics	2011	PMID: 20718791
Expansion of mutation spectrum, determination of mutation cluster regions and predictive structural classification of SPAST mutations in hereditary spastic paraplegia.	Shoukier M	European journal of human genetics : EJHG	2009	PMID: 18701882
A de novo SPAST mutation leading to somatic mosaicism is associated with a later age at onset in HSP.	Depienne C	Neurogenetics	2007	PMID: 17597328
Spectrum of SPG4 mutations in autosomal dominant spastic paraplegia.	Fonknechten N	Human molecular genetics	2000	PMID: 10699187

Text-mined citations for rs121908518 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_014946.4(SPAST):c.1684C>T (p.Arg562Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121908518 ...