ClinVar Genomic variation as it relates to human health
NM_015915.5(ATL1):c.1243C>T (p.Arg415Trp)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_015915.5(ATL1):c.1243C>T (p.Arg415Trp)
Variation ID: 4352 Accession: VCV000004352.44
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 14q22.1 14: 50628154 (GRCh38) [ NCBI UCSC ] 14: 51094872 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Oct 1, 2013 Apr 20, 2024 Feb 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_015915.5:c.1243C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_056999.2:p.Arg415Trp missense NM_001127713.1:c.1243C>T NP_001121185.1:p.Arg415Trp missense NM_181598.4:c.1243C>T NP_853629.2:p.Arg415Trp missense NC_000014.9:g.50628154C>T NC_000014.8:g.51094872C>T NG_009028.1:g.100073C>T LRG_360:g.100073C>T LRG_360t1:c.1243C>T LRG_360p1:p.Arg415Trp LRG_360t2:c.1243C>T LRG_360p2:p.Arg415Trp Q8WXF7:p.Arg415Trp - Protein change
- R415W
- Other names
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- Canonical SPDI
- NC_000014.9:50628153:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
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 | ||
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HI score
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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. |
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ATL1 | - | - |
GRCh38 GRCh37 |
545 | 580 |
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. |
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Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Dec 11, 2023 | RCV000004600.21 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jul 17, 2014 | RCV000190652.5 | |
Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Feb 1, 2024 | RCV001090532.24 |
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. |
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Pathogenic
(Oct 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
(Unknown mechanism)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001446483.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Spastic paraplegia (present)
Sex: male
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Hereditary spastic paraplegia 3A
Affected status: yes
Allele origin:
unknown
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Paris Brain Institute, Inserm - ICM
Accession: SCV001451215.1
First in ClinVar: May 16, 2021 Last updated: May 16, 2021 |
Number of individuals with the variant: 3
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Pathogenic
(Aug 29, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hereditary spastic paraplegia 3A
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
paternal,
maternal,
germline
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Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV004045868.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
Observation 1:
Number of individuals with the variant: 1
Clinical Features:
Dystonic disorder (present)
Observation 2:
Number of individuals with the variant: 1
Clinical Features:
Dystonic disorder (present) , Spasticity (present)
Observation 3:
Number of individuals with the variant: 1
Clinical Features:
Dystonic disorder (present)
Observation 4:
Number of individuals with the variant: 1
Clinical Features:
Dystonic disorder (present)
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Pathogenic
(Feb 01, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001246136.20
First in ClinVar: May 12, 2020 Last updated: Apr 15, 2024 |
Comment:
ATL1: PP1:Strong, PM1, PM2, PM5, PS4:Moderate, PP3
Number of individuals with the variant: 6
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Likely pathogenic
(Jul 17, 2014)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000244092.8
First in ClinVar: Sep 14, 2015 Last updated: Apr 20, 2024 |
Comment:
The c.1243C>T (p.R415W) alteration is located in exon 12 (coding exon 12) of the ATL1 gene. This alteration results from a C to T substitution … (more)
The c.1243C>T (p.R415W) alteration is located in exon 12 (coding exon 12) of the ATL1 gene. This alteration results from a C to T substitution at nucleotide position 1243, causing the arginine (R) at amino acid position 415 to be replaced by a tryptophan (W). Based on data from the NHLBI Exome Sequencing Project (ESP), the c.1243C>T alteration was not observed among 6,503 individuals tested (0.0%). Allele frequency data for this nucleotide position are not currently available from the 1000 Genomes Project. This alteration is currently listed in the Database of Single Nucleotide Polymorphisms (dbSNP) under rs119476050. Though some variants may appear to be rare due to database-specific ethnic underrepresentation, rare missense alleles commonly exhibit a deleterious effect on protein function (Kryukov, 2007; Tennessen, 2012). The R415W missense alteration has been reported in several HSP families. The first report is an Italian family with pure autosomal dominant HSP (D'Amico, 2004). The proband was a 22-year old woman with slowly progressive HSP starting at age 3. Her brother and a maternal second cousin had a similar phenotype, while a maternal uncle and maternal great-uncle had infantile onset spastic paraparesis. The alteration was present in all affected individuals but was also present in nine unaffected relatives, who had normal neurological evaluations and motor evoked potentials (age range was 13-70 years). It was absent in 400 control chromosomes. This alteration was concluded to be a likely low penetrance mutation affected by modulator genes or strong epigenetic factors, although a neutral polymorphism could not be ruled out. This alteration was subsequently identified in second large family with apparently X-linked pure HSP. The alteration was present in three affected males and three unaffected family members, consistent with incomplete penetrance. Two of the unaffected carriers were women, and family history indicated that most unaffected women were obligate carriers. These findings were consistent with sex-associated reduced penetrance of this mutation. Varga et al. (2013) identified the same mutation in 1 of 83 Spanish patients with apparent sporadic HSP and in 2 of 28 Russian patients with dominant HSP. Evidence again suggested incomplete penetrance in these families._x000D_ _x000D_ A missense alteration affecting the same amino acid, R415Q, was reported in a consanguinous Moroccan family with childhood onset HSP (Varga, 2013). All four affected individuals were in the same generation, raising suspicion for an autosomal recessive etiology. Three of the affected individuals were found to be homozygous for the R415Q alteration and the fourth was heterozygous (three unaffected siblings and the parents were also heterozygous). The alteration showed complete penetrance in the homozygous state and incomplete penetrance in the heterozygous state. The authors discuss that c.1243C>T occurs at a CpG nucleotide and thus may represent a mutation hotspot. This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be possibly damaging and deleterious by PolyPhen and SIFT in silico analyses, respectively. Based on the available evidence, this alteration is classified as likely pathogenic. (less)
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Likely pathogenic
(Nov 10, 2020)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: unknown
Allele origin:
germline
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001716182.1
First in ClinVar: Jun 15, 2021 Last updated: Jun 15, 2021 |
Comment:
PS4_moderate, PM1, PM2, PP3
Number of individuals with the variant: 1
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Likely pathogenic
(Sep 13, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV003837298.1
First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023 |
Comment:
Reported previously in a large multi-generation family with early onset progressive spastic paraplegia in affected and unaffected individuals suggesting of autosomal dominant inheritance with reduced … (more)
Reported previously in a large multi-generation family with early onset progressive spastic paraplegia in affected and unaffected individuals suggesting of autosomal dominant inheritance with reduced penetrance (D'Amico et al., 2004); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23334294, 31594988, 24417445, 30780198, 26671083, 20862796, 21220294, 34808209, 20932283, 25341883, 31236401, 15184642, 23483706) (less)
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Likely pathogenic
(Jun 07, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Athena Diagnostics Inc
Accession: SCV004229184.1
First in ClinVar: Jan 26, 2024 Last updated: Jan 26, 2024 |
Comment:
The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical … (more)
The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with autosomal dominant spastic paraplegia. Computational tools predict that this variant is damaging. (less)
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Pathogenic
(Dec 11, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hereditary spastic paraplegia 3A
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000551414.8
First in ClinVar: Oct 11, 2015 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 415 of the ATL1 protein … (more)
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 415 of the ATL1 protein (p.Arg415Trp). This variant is present in population databases (rs119476050, gnomAD 0.0009%). This missense change has been observed in individuals with autosomal dominant hereditary spastic paraplegia (PMID: 15184642, 16401858, 19459885, 20932283, 23483706, 24417445, 24451228). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4352). 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) performed at Invitae indicates that this missense variant is not expected to disrupt ATL1 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jun 01, 2013)
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no assertion criteria provided
Method: literature only
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SPASTIC PARAPLEGIA 3, AUTOSOMAL DOMINANT
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000024774.3
First in ClinVar: Apr 04, 2013 Last updated: Dec 19, 2013 |
Comment on evidence:
In all 3 affected members tested from an Italian family with SPG3A (182600), D'Amico et al. (2004) identified a heterozygous mutation in exon 12 of … (more)
In all 3 affected members tested from an Italian family with SPG3A (182600), D'Amico et al. (2004) identified a heterozygous mutation in exon 12 of the atlastin gene, resulting in an arg415-to-trp (R415W) substitution. The mutation was not identified in 400 control chromosomes. The 3 patients had onset before 5 years of age, and 2 additional family members were reportedly affected by infantile-onset spastic paraparesis. However, 9 asymptomatic relatives ranging in age from 13 to 70 years also had the mutation. D'Amico et al. (2004) concluded that the reduced penetrance of this mutation indicated that modulator genes or epigenetic factors are involved in the development of the disease, and they noted the implications for genetic counseling. Varga et al. (2013) identified a heterozygous c.1243C-T transition in the ATL1 gene resulting in an R415W substitution in affected members of a family with SPG3A originally reported by Raggio et al. (1973) as having a pure spastic paraplegia transmitted in an X-linked pattern of inheritance. Whole-exome sequencing of 1 of the affected males identified the heterozygous R415W substitution. This mutation was then identified in 3 affected family members and in 3 unaffected family members, consistent with incomplete penetrance. Two of the unaffected carriers were women, and family history indicated that most unaffected women were obligate carriers. These findings were consistent with sex-associated reduced penetrance of this mutation. Varga et al. (2013) identified the same mutation in 1 of 83 Spanish patients with apparent sporadic HSP and in 2 of 28 Russian patients with dominant HSP. Evidence again suggested incomplete penetrance in these families. Varga et al. (2013) also identified a heterozygous c.1244A-G transition, resulting in an arg415-to-gln (R415Q; 606439.0014) substitution, in a Moroccan family with SPG3A and incomplete penetrance. Varga et al. (2013) noted that both the c.1243C-T and c.1244A-G transitions occur at a CpG nucleotide (on the plus and minus strands, respectively) and thus may represent a mutation hotspot due to spontaneous deamination of methylated cytosines. R415 affects a highly conserved residue that does not localize to a known protein domain. (less)
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Uncertain significance
(Jan 06, 2016)
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no assertion criteria provided
Method: literature only
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Hereditary spastic paraplegia 3A
Affected status: yes
Allele origin:
germline
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Inherited Neuropathy Consortium Ii, University Of Miami
Accession: SCV004011938.1
First in ClinVar: Jul 16, 2023 Last updated: Jul 16, 2023 |
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not provided
(-)
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no classification provided
Method: literature only
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Hereditary spastic paraplegia 3A
Affected status: not provided
Allele origin:
unknown
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GeneReviews
Accession: SCV000041287.3
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Spastic Paraplegia 3A. | Adam MP | - | 2020 | PMID: 20862796 |
Mutational Spectrum of Spast (Spg4) and Atl1 (Spg3a) Genes In Russian Patients With Hereditary Spastic Paraplegia. | Kadnikova VA | Scientific reports | 2019 | PMID: 31594988 |
Clinical and genetic characterization of a cohort of Chinese patients with hereditary spastic paraplegia. | Yan YT | Clinical genetics | 2019 | PMID: 30780198 |
Genetic and phenotypic characterization of complex hereditary spastic paraplegia. | Kara E | Brain : a journal of neurology | 2016 | PMID: 27217339 |
Molecular epidemiology and clinical spectrum of hereditary spastic paraplegia in the Japanese population based on comprehensive mutational analyses. | Ishiura H | Journal of human genetics | 2016 | PMID: 27108959 |
Molecular spectrum of the SPAST, ATL1 and REEP1 gene mutations associated with the most common hereditary spastic paraplegias in a group of Polish patients. | Elert-Dobkowska E | Journal of the neurological sciences | 2015 | PMID: 26671083 |
Molecular epidemiology and clinical spectrum of hereditary spastic paraplegia in the Japanese population based on comprehensive mutational analyses. | Ishiura H | Journal of human genetics | 2014 | PMID: 24451228 |
'When atlastin meets spastin'. | Di Fabio R | Clinical genetics | 2014 | PMID: 24417445 |
Do not trust the pedigree: reduced and sex-dependent penetrance at a novel mutation hotspot in ATL1 blurs autosomal dominant inheritance of spastic paraplegia. | Varga RE | Human mutation | 2013 | PMID: 23483706 |
Splice site mutations in the ATP7A gene. | Skjørringe T | PloS one | 2011 | PMID: 21494555 |
Mutational spectrum of the SPG4 (SPAST) and SPG3A (ATL1) genes in Spanish patients with hereditary spastic paraplegia. | Alvarez V | BMC neurology | 2010 | PMID: 20932283 |
Four novel SPG3A/atlastin mutations identified in autosomal dominant hereditary spastic paraplegia kindreds with intra-familial variability in age of onset and complex phenotype. | Smith BN | Clinical genetics | 2009 | PMID: 19459885 |
SPG3A is the most frequent cause of hereditary spastic paraplegia with onset before age 10 years. | Namekawa M | Neurology | 2006 | PMID: 16401858 |
Incomplete penetrance in an SPG3A-linked family with a new mutation in the atlastin gene. | D'Amico A | Neurology | 2004 | PMID: 15184642 |
X-linked hereditary spastic paraplegia. | Raggio JF | The Journal of the Louisiana State Medical Society : official organ of the Louisiana State Medical Society | 1973 | PMID: 4684346 |
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Text-mined citations for rs119476050 ...
HelpRecord last updated Apr 20, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.