ClinVar Genomic variation as it relates to human health
NM_000454.5(SOD1):c.14C>T (p.Ala5Val)
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_000454.5(SOD1):c.14C>T (p.Ala5Val)
Variation ID: 14763 Accession: VCV000014763.23
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 21q22.11 21: 31659783 (GRCh38) [ NCBI UCSC ] 21: 33032096 (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 Aug 22, 2016 Feb 20, 2024 Jan 29, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000454.5:c.14C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000445.1:p.Ala5Val missense NC_000021.9:g.31659783C>T NC_000021.8:g.33032096C>T NG_008689.1:g.5162C>T LRG_652:g.5162C>T LRG_652t1:c.14C>T LRG_652p1:p.Ala5Val P00441:p.Ala5Val - Protein change
- A5V
- Other names
- A4V
- Canonical SPDI
- NC_000021.9:31659782: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
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00004
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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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SOD1 | - | - |
GRCh38 GRCh37 |
199 | 311 | |
SOD1-DT | - | - | - | GRCh38 | - | 85 |
Conditions - Germline
Condition
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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 (5) |
criteria provided, multiple submitters, no conflicts
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Jan 29, 2024 | RCV000015885.42 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Jun 29, 2023 | RCV000518025.14 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 12, 2023 | RCV003390686.4 |
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
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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
(Feb 23, 2021)
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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: SCV001715588.1
First in ClinVar: Jun 15, 2021 Last updated: Jun 15, 2021 |
Comment:
PS3, PS4, PM2, PP3
Number of individuals with the variant: 1
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Pathogenic
(Feb 18, 2020)
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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: SCV001767218.1
First in ClinVar: Aug 05, 2021 Last updated: Aug 05, 2021 |
Comment:
Functional studies demonstrate a 50% reduction in activity of cytosolic SOD1 in patients with A5V compared to unaffected individuals (Rosen et al., 1994; Lindberg et … (more)
Functional studies demonstrate a 50% reduction in activity of cytosolic SOD1 in patients with A5V compared to unaffected individuals (Rosen et al., 1994; Lindberg et al., 2002); Additional published functional studies demonstrate that the variant alters protein stability and activity, results in reduced nuclear localization, and leads to formation of inclusions (Brasil et al., 2018); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 28884318, 8351519, 19618436, 31781168, 29564924, 31134679, 19176896, 26362407, 26298469, 26084641, 12482932, 21257910, 16945901, 20404910, 23118898, 23784844, 21930207, 22094223, 18319614, 24793051, 20184893, 21549128, 20399791, 23291526, 25096579, 23760509, 20404329, 19635794, 19196430, 24134191, 7951249, 19483195, 22589106, 19259395, 19751676, 23280792, 19800308, 26413785) (less)
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Pathogenic
(Sep 12, 2023)
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criteria provided, single submitter
Method: clinical testing
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SOD1-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004112622.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The SOD1 c.14C>T variant is predicted to result in the amino acid substitution p.Ala5Val. This variant, previously described as p.Ala4Val using legacy nomenclature, has been … (more)
The SOD1 c.14C>T variant is predicted to result in the amino acid substitution p.Ala5Val. This variant, previously described as p.Ala4Val using legacy nomenclature, has been repeatedly reported to be causative for amyotrophic lateral sclerosis (Deng et al. 1993. PubMed ID: 8351519; Saeed et al. 2009. PubMed ID: 19176896). The c.14C>T variant has also been interpreted as pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/14763/). We interpret this variant as pathogenic. (less)
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Pathogenic
(Jun 29, 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: SCV000615369.5
First in ClinVar: Dec 19, 2017 Last updated: Jan 26, 2024 |
Comment:
A5V is the most common ALS-associated variant in North America (PMID: 19176896, 18055113, 9029070), therefore, the frequency of this variant in the general population is … (more)
A5V is the most common ALS-associated variant in North America (PMID: 19176896, 18055113, 9029070), therefore, the frequency of this variant in the general population is consistent with pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. This variant is also referred to as A4V in published literature. This variant occurs as the most likely explanation for disease in a significant number of cases, suggesting this variant is associated with disease. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 20184893, 19635794, 16945901, 23291526) (less)
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Pathogenic
(Jan 29, 2024)
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criteria provided, single submitter
Method: clinical testing
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Amyotrophic lateral sclerosis type 1
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000644790.9
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 5 of the SOD1 protein (p.Ala5Val). … (more)
This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 5 of the SOD1 protein (p.Ala5Val). This variant is present in population databases (rs121912442, gnomAD 0.008%). This missense change has been observed in individuals with autosomal dominant amyotrophic lateral sclerosis (PMID: 7951249, 8351519, 19176896, 19618436). This variant is also known as p.Ala4Val. ClinVar contains an entry for this variant (Variation ID: 14763). 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 expected to disrupt SOD1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SOD1 function (PMID: 12482932, 19259395, 19483195, 19800308, 20404329, 21549128, 22094223). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jul 28, 2014)
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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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Eurofins Ntd Llc (ga)
Accession: SCV000224225.5
First in ClinVar: Jun 28, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 2
Sex: mixed
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Pathogenic
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Amyotrophic lateral sclerosis type 1
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000893547.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Amyotrophic lateral sclerosis type 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004048541.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
Comment:
The missense variant c.14C>T (p.Ala5Val) has been reported in many individuals affected with familial amyotrophic lateral sclerosis (FALS) (Deng et al. 1993, Salameh et al. … (more)
The missense variant c.14C>T (p.Ala5Val) has been reported in many individuals affected with familial amyotrophic lateral sclerosis (FALS) (Deng et al. 1993, Salameh et al. 2009) and has been reported to segregate with disease in multiple families (Deng et al. 1993). Experimental studies have shown that this missense change impacts SOD1 protein structure and leads to mis-folding and aggregation (Prudencio et al. 2011). It has also been shown to impact cell survival in human embryonic stem cell-derived motor neurons (Karumbayaram et al. 2009). The p.Ala5Val variant is novel (not in any individuals) in 1000 Genomes and is present in the gnomAD exomes database with a frequency of 0.004%. This variant has been reported to the ClinVar database as Pathogenic. The amino acid Ala at position 5 is changed to a Val changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Ala5Val in SOD1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. (less)
Clinical Features:
Abnormal lower motor neuron morphology (present) , Tongue fasciculations (present)
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Pathogenic
(May 12, 2009)
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no assertion criteria provided
Method: literature only
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AMYOTROPHIC LATERAL SCLEROSIS 1
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000036152.3
First in ClinVar: Apr 04, 2013 Last updated: Aug 22, 2016 |
Comment on evidence:
Deng et al. (1993) found that the ala4-to-val (A4V) mutation in exon 1 of the SOD1 gene is the most frequent basis for familial amyotrophic … (more)
Deng et al. (1993) found that the ala4-to-val (A4V) mutation in exon 1 of the SOD1 gene is the most frequent basis for familial amyotrophic lateral sclerosis (105400). This mutation was found in affected members of 8 unrelated families. One of the families with the A4V mutation was the Farr family reported by Brown (1951, 1960). Rosen et al. (1994) confirmed that the A4V mutation is the most commonly detected of all SOD1 mutations in familial ALS, and that it is among the most clinically severe. In comparison with other ALS families, the exon 1 mutation is associated with reduced survival time after onset: 1.2 years as compared to 2.5 years for all other familial ALS patients. Wiedau-Pazos et al. (1996) showed that the A4V mutant SOD1 enzyme catalyzed the oxidation of a model substrate (spin trap 5,5-prime-dimethyl-1-pyrroline N-oxide) by hydrogen peroxide at a higher rate than that seen with the wildtype enzyme. Catalysis of this reaction by the mutant enzyme was more sensitive to inhibition by the copper chelators diethyldithiocarbamate and penicillamine than was catalysis by wildtype SOD1. The same 2 chelators reversed the apoptosis-inducing effect of the mutant enzyme expressed in a neural cell line. The findings were interpreted to mean that oxidative reactions catalyzed by mutant SOD1 enzymes initiate the neuropathologic changes in familial ALS. Rakhit et al. (2007) used a specific SOD1 antibody to identify misfolded SOD1 within degenerating motor neurons in the spinal cord from an individual with ALS due to the A4V mutation. The findings provided evidence that misfolded SOD1 plays a toxic or pathogenic role in ALS. Saeed et al. (2009) identified a single 5.86-cM haplotype encompassing the A4V variant in 54 white North American ALS patients that was not found in 96 controls (p = 3 x 10(-11)), indicating a founder effect. To determine the origin, several additional cohorts were genotyped, including 54 North American, 3 Swedish, and 6 Italian patients with the A4V mutation, 66 ALS patients with non-A4V SOD1 mutations, 96 patients with sporadic ALS, and 96 white, 17 African American, 53 Chinese, 11 Amerindian, and 12 Hispanic healthy controls. The strength of association of the white founder haplotype progressively decreased when other ethnicities were used as controls, and almost disappeared when compared to Amerindians, indicating that the A4V mutation was introduced from Amerindians who migrated from Asia into North America. The associated European haplotype was different from the North American haplotype, indicating an Amerindian founder effect (accounting for 82%) and a European founder effect (accounting for 18%) for A4V in North America. Amerindians were both homozygous and heterozygous, whereas Europeans were only homozygous, for nearby SNPs. The age of the A4V mutation was estimated to be 458 +/- 59 years (range, 398 to 569 years). Saeed et al. (2009) postulated that A4V was introduced into the white population by Amerindians about 400 to 500 years ago at the time of the Jamestown and Plymouth landings. Furthermore, there were no Amerindians with ALS in their database, suggesting either that the mutation became extinct in Amerindians or that they have an additional protective effect. (less)
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not provided
(-)
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no classification provided
Method: phenotyping only
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Amyotrophic lateral sclerosis type 1
Affected status: yes
Allele origin:
unknown
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GenomeConnect, ClinGen
Accession: SCV001423357.1
First in ClinVar: Jul 19, 2020 Last updated: Jul 19, 2020 |
Comment:
Variant interpretted as Pathogenic and reported on 08-15-2019 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided … (more)
Variant interpretted as Pathogenic and reported on 08-15-2019 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less)
Clinical Features:
Abnormality of muscle physiology (present) , Abnormality of the somatic nervous system (present) , Abnormality of the musculature of the limbs (present)
Indication for testing: Diagnostic
Age: 60-69 years
Sex: male
Method: Sanger Sequencing
Testing laboratory: GeneDx
Date variant was reported to submitter: 2019-08-15
Testing laboratory interpretation: Pathogenic
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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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Genetic Spectrum and Variability in Chinese Patients with Amyotrophic Lateral Sclerosis. | Liu ZJ | Aging and disease | 2019 | PMID: 31788332 |
Haplotype Analysis of the First A4V-SOD1 Spanish Family: Two Separate Founders or a Single Common Founder? | Garcia C | Frontiers in genetics | 2019 | PMID: 31781168 |
SOD1 in amyotrophic lateral sclerosis development - in silico analysis and molecular dynamics of A4F and A4V variants. | Da Silva ANR | Journal of cellular biochemistry | 2019 | PMID: 31134679 |
Identification of an A4V SOD1 mutation in a Chinese patient with amyotrophic lateral sclerosis without the A4V founder effect common in North America. | Tang L | Amyotrophic lateral sclerosis & frontotemporal degeneration | 2018 | PMID: 29564924 |
Mutation analysis of patients with neurodegenerative disorders using NeuroX array. | Ghani M | Neurobiology of aging | 2015 | PMID: 25174650 |
Mechanical probes of SOD1 predict systematic trends in metal and dimer affinity of ALS-associated mutants. | Das A | Journal of molecular biology | 2013 | PMID: 23291526 |
Superoxide dismutase 1 encoding mutations linked to ALS adopts a spectrum of misfolded states. | Prudencio M | Molecular neurodegeneration | 2011 | PMID: 22094223 |
ALS-causing SOD1 mutations promote production of copper-deficient misfolded species. | Ip P | Journal of molecular biology | 2011 | PMID: 21549128 |
Mutation-dependent polymorphism of Cu,Zn-superoxide dismutase aggregates in the familial form of amyotrophic lateral sclerosis. | Furukawa Y | The Journal of biological chemistry | 2010 | PMID: 20404329 |
Disulfide-reduced ALS variants of Cu, Zn superoxide dismutase exhibit increased populations of unfolded species. | Kayatekin C | Journal of molecular biology | 2010 | PMID: 20184893 |
Structural and biophysical properties of metal-free pathogenic SOD1 mutants A4V and G93A. | Galaleldeen A | Archives of biochemistry and biophysics | 2009 | PMID: 19800308 |
A common property of amyotrophic lateral sclerosis-associated variants: destabilization of the copper/zinc superoxide dismutase electrostatic loop. | Molnar KS | The Journal of biological chemistry | 2009 | PMID: 19635794 |
SOD1 (A4V)-mediated ALS presenting with lower motor neuron facial diplegia and unilateral vocal cord paralysis. | Salameh JS | Muscle & nerve | 2009 | PMID: 19618436 |
Variation in aggregation propensities among ALS-associated variants of SOD1: correlation to human disease. | Prudencio M | Human molecular genetics | 2009 | PMID: 19483195 |
Human embryonic stem cell-derived motor neurons expressing SOD1 mutants exhibit typical signs of motor neuron degeneration linked to ALS. | Karumbayaram S | Disease models & mechanisms | 2009 | PMID: 19259395 |
Age and founder effect of SOD1 A4V mutation causing ALS. | Saeed M | Neurology | 2009 | PMID: 19176896 |
SOD1 gene mutations in ALS patients from British Columbia, Canada: clinical features, neurophysiology and ethical issues in management. | Eisen A | Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases | 2008 | PMID: 18428003 |
Transduction of familial amyotrophic lateral sclerosis-related mutant PEP-1-SOD proteins into neuronal cells. | An JJ | Molecules and cells | 2008 | PMID: 18319614 |
SOD1A4V-mediated ALS: absence of a closely linked modifier gene and origination in Asia. | Broom WJ | Neuroscience letters | 2008 | PMID: 18055113 |
An immunological epitope selective for pathological monomer-misfolded SOD1 in ALS. | Rakhit R | Nature medicine | 2007 | PMID: 17486090 |
Familial ALS-superoxide dismutases associate with mitochondria and shift their redox potentials. | Ferri A | Proceedings of the National Academy of Sciences of the United States of America | 2006 | PMID: 16945901 |
Common denominator of Cu/Zn superoxide dismutase mutants associated with amyotrophic lateral sclerosis: decreased stability of the apo state. | Lindberg MJ | Proceedings of the National Academy of Sciences of the United States of America | 2002 | PMID: 12482932 |
Superoxide dismutase gene mutations in Italian patients with familial and sporadic amyotrophic lateral sclerosis: identification of three novel missense mutations. | Gellera C | Neuromuscular disorders : NMD | 2001 | PMID: 11369193 |
Phenotypic heterogeneity in motor neuron disease patients with CuZn-superoxide dismutase mutations in Scandinavia. | Andersen PM | Brain : a journal of neurology | 1997 | PMID: 9365366 |
Epidemiology of mutations in superoxide dismutase in amyotrophic lateral sclerosis. | Cudkowicz ME | Annals of neurology | 1997 | PMID: 9029070 |
Altered reactivity of superoxide dismutase in familial amyotrophic lateral sclerosis. | Wiedau-Pazos M | Science (New York, N.Y.) | 1996 | PMID: 8560268 |
Identification of new mutations in the Cu/Zn superoxide dismutase gene of patients with familial amyotrophic lateral sclerosis. | Pramatarova A | American journal of human genetics | 1995 | PMID: 7887412 |
A frequent ala 4 to val superoxide dismutase-1 mutation is associated with a rapidly progressive familial amyotrophic lateral sclerosis. | Rosen DR | Human molecular genetics | 1994 | PMID: 7951249 |
Amyotrophic lateral sclerosis and structural defects in Cu,Zn superoxide dismutase. | Deng HX | Science (New York, N.Y.) | 1993 | PMID: 8351519 |
Homologous radioimmunoassay for human prolactin. | Reuter AM | International journal of nuclear medicine and biology | 1976 | PMID: 1248932 |
The inheritance of progressive muscular atrophy as a dominant trait in two New England families. | BROWN MR | The New England journal of medicine | 1960 | PMID: 13804989 |
"Wetherbee Ail"; the inheritance of progressive muscular atrophy as a dominant trait in two New England families. | BROWN MR | The New England journal of medicine | 1951 | PMID: 14875225 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SOD1 | - | - | - | - |
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Text-mined citations for rs121912442 ...
HelpRecord last updated Apr 06, 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.