For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ala5 amino acid residue in SOD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7951249, 8351519, 19176896, 19618436). 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 SOD1 function (PMID: 8179602, 17543992, 21257910, 23280792, 26362407). 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. ClinVar contains an entry for this variant (Variation ID: 14765). This variant is also known as p.Ala4Thr. This missense change has been observed in individuals with autosomal dominant amyotrophic lateral sclerosis (PMID: 8179602, 12792143, 17543992, 22292843). It has also been observed to segregate with disease in related individuals. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 5 of the SOD1 protein (p.Ala5Thr).
ClinVar Genomic variation as it relates to human health
NM_000454.5(SOD1):c.13G>A (p.Ala5Thr)
Germline
Classification
Help
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.
(4)
Help
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
4
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000454.5(SOD1):c.13G>A (p.Ala5Thr)
Variation ID: 14765 Accession: VCV000014765.7
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 21q22.11 21: 31659782 (GRCh38) [ NCBI UCSC ] 21: 33032095 (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 Apr 4, 2013 Feb 14, 2024 Nov 23, 2022 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000454.5:c.13G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000445.1:p.Ala5Thr missense NC_000021.9:g.31659782G>A NC_000021.8:g.33032095G>A NG_008689.1:g.5161G>A LRG_652:g.5161G>A LRG_652t1:c.13G>A LRG_652p1:p.Ala5Thr P00441:p.Ala5Thr - Protein change
- A5T
- Other names
-
A4T
- Canonical SPDI
- NC_000021.9:31659781:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD), exomes 0.00000
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|||
| SOD1 | - | - |
GRCh38 GRCh37 |
206 | 321 | |
| SOD1-DT | - | - | - | GRCh38 | - | 87 |
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. |
|---|---|---|---|---|
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Nov 23, 2022 | RCV000015887.31 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Mar 9, 2017 | RCV000518527.2 |
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
(Nov 23, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Amyotrophic lateral sclerosis type 1
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000962776.4
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ala5 amino acid residue in SOD1. Other variant(s) that disrupt this … (more)
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ala5 amino acid residue in SOD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7951249, 8351519, 19176896, 19618436). 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 SOD1 function (PMID: 8179602, 17543992, 21257910, 23280792, 26362407). 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. ClinVar contains an entry for this variant (Variation ID: 14765). This variant is also known as p.Ala4Thr. This missense change has been observed in individuals with autosomal dominant amyotrophic lateral sclerosis (PMID: 8179602, 12792143, 17543992, 22292843). It has also been observed to segregate with disease in related individuals. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 5 of the SOD1 protein (p.Ala5Thr). (less)
|
|
|
Pathogenic
(Mar 09, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Athena Diagnostics
Accession: SCV000615367.1
First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017 |
|
|
|
Pathogenic
(Mar 31, 2020)
|
criteria provided, single submitter
Method: research
|
Amyotrophic lateral sclerosis type 1
Affected status: yes
Allele origin:
germline
|
Suna and Inan Kirac Foundation Neurodegeneration Research Laboratory, Koc University
Accession: SCV001251043.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Number of individuals with the variant: 1
Geographic origin: Anatolian Peninsula
|
|
|
Pathogenic
(Jun 11, 1994)
|
no assertion criteria provided
Method: literature only
|
AMYOTROPHIC LATERAL SCLEROSIS 1
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000036154.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
Kawamata et al. (1994) made reference to a Japanese family with ALS (105400) associated with a G-to-A transition in the SOD1 gene, resulting in an … (more)
Kawamata et al. (1994) made reference to a Japanese family with ALS (105400) associated with a G-to-A transition in the SOD1 gene, resulting in an ala4-to-thr (A4T) substitution. Nakano et al. (1994) reported this family in full. See A4V (147450.0012) for a mutation involving the same codon. (less)
|
Comment:
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:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ala5 amino acid residue in SOD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7951249, 8351519, 19176896, 19618436). 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 SOD1 function (PMID: 8179602, 17543992, 21257910, 23280792, 26362407). 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. ClinVar contains an entry for this variant (Variation ID: 14765). This variant is also known as p.Ala4Thr. This missense change has been observed in individuals with autosomal dominant amyotrophic lateral sclerosis (PMID: 8179602, 12792143, 17543992, 22292843). It has also been observed to segregate with disease in related individuals. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 5 of the SOD1 protein (p.Ala5Thr).
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Defining SOD1 ALS natural history to guide therapeutic clinical trial design. | Bali T | Journal of neurology, neurosurgery, and psychiatry | 2017 | PMID: 27261500 |
| Increased cytoplasmic TARDBP mRNA in affected spinal motor neurons in ALS caused by abnormal autoregulation of TDP-43. | Koyama A | Nucleic acids research | 2016 | PMID: 27257061 |
| Genotype-phenotype correlations of amyotrophic lateral sclerosis. | Li HF | Translational neurodegeneration | 2016 | PMID: 26843957 |
| Destabilization of the dimer interface is a common consequence of diverse ALS-associated mutations in metal free SOD1. | Broom HR | Protein science : a publication of the Protein Society | 2015 | PMID: 26362407 |
| SUMO3 modification accelerates the aggregation of ALS-linked SOD1 mutants. | Niikura T | PloS one | 2014 | PMID: 24971881 |
| An antisense oligonucleotide against SOD1 delivered intrathecally for patients with SOD1 familial amyotrophic lateral sclerosis: a phase 1, randomised, first-in-man study. | Miller TM | The Lancet. Neurology | 2013 | PMID: 23541756 |
| Using reference databases of genetic variation to evaluate the potential pathogenicity of candidate disease variants. | Kenna KP | Human mutation | 2013 | PMID: 23447461 |
| A novel monoclonal antibody reveals a conformational alteration shared by amyotrophic lateral sclerosis-linked SOD1 mutants. | Fujisawa T | Annals of neurology | 2012 | PMID: 23280792 |
| Co-aggregation of RNA binding proteins in ALS spinal motor neurons: evidence of a common pathogenic mechanism. | Keller BA | Acta neuropathologica | 2012 | PMID: 22941224 |
| SOD1, ANG, TARDBP and FUS mutations in amyotrophic lateral sclerosis: a United States clinical testing lab experience. | Brown JA | Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases | 2012 | PMID: 22292843 |
| Decreased stability and increased formation of soluble aggregates by immature superoxide dismutase do not account for disease severity in ALS. | Vassall KA | Proceedings of the National Academy of Sciences of the United States of America | 2011 | PMID: 21257910 |
| DHPLC can be used to detect low-level mutations in amyotrophic lateral sclerosis. | Luquin N | Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases | 2010 | PMID: 20184515 |
| Tar DNA binding protein of 43 kDa (TDP-43), 14-3-3 proteins and copper/zinc superoxide dismutase (SOD1) interact to modulate NFL mRNA stability. Implications for altered RNA processing in amyotrophic lateral sclerosis (ALS). | Volkening K | Brain research | 2009 | PMID: 19815002 |
| 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 |
| Age and founder effect of SOD1 A4V mutation causing ALS. | Saeed M | Neurology | 2009 | PMID: 19176896 |
| Protein aggregation and protein instability govern familial amyotrophic lateral sclerosis patient survival. | Wang Q | PLoS biology | 2008 | PMID: 18666828 |
| SOD1A4V-mediated ALS: absence of a closely linked modifier gene and origination in Asia. | Broom WJ | Neuroscience letters | 2008 | PMID: 18055113 |
| Lack of TDP-43 abnormalities in mutant SOD1 transgenic mice shows disparity with ALS. | Robertson J | Neuroscience letters | 2007 | PMID: 17543992 |
| TDP-43 immunoreactivity in neuronal inclusions in familial amyotrophic lateral sclerosis with or without SOD1 gene mutation. | Tan CF | Acta neuropathologica | 2007 | PMID: 17333220 |
| Protein-bound crotonaldehyde accumulates in the spinal cord of superoxide dismutase-1 mutation-associated familial amyotrophic lateral sclerosis and its transgenic mouse model. | Shibata N | Neuropathology : official journal of the Japanese Society of Neuropathology | 2007 | PMID: 17319283 |
| Rapid disease progression correlates with instability of mutant SOD1 in familial ALS. | Sato T | Neurology | 2005 | PMID: 16291929 |
| The role of trace metallic elements in neurodegenerative disorders: quantitative analysis using XRF and XANES spectroscopy. | Ide-Ektessabi A | Analytical sciences : the international journal of the Japan Society for Analytical Chemistry | 2005 | PMID: 16038516 |
| A Rac1/phosphatidylinositol 3-kinase/Akt3 anti-apoptotic pathway, triggered by AlsinLF, the product of the ALS2 gene, antagonizes Cu/Zn-superoxide dismutase (SOD1) mutant-induced motoneuronal cell death. | Kanekura K | The Journal of biological chemistry | 2005 | PMID: 15579468 |
| Alsin, the product of ALS2 gene, suppresses SOD1 mutant neurotoxicity through RhoGEF domain by interacting with SOD1 mutants. | Kanekura K | The Journal of biological chemistry | 2004 | PMID: 14970233 |
| Sixteen novel mutations in the Cu/Zn superoxide dismutase gene in amyotrophic lateral sclerosis: a decade of discoveries, defects and disputes. | Andersen PM | Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases | 2003 | PMID: 14506936 |
| A4T mutation in the SOD1 gene causing familial amyotrophic lateral sclerosis. | Aksoy H | Neuroepidemiology | 2003 | PMID: 12792143 |
| New consensus research on neuropathological aspects of familial amyotrophic lateral sclerosis with superoxide dismutase 1 (SOD1) gene mutations: inclusions containing SOD1 in neurons and astrocytes. | Kato S | Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases | 2000 | PMID: 11464950 |
| Formation of granular cytoplasmic aggregates in COS7 cells expressing mutant Cu/Zn superoxide dismutase associated with familial amyotrophic lateral sclerosis. | Koide T | Neuroscience letters | 1998 | PMID: 9857958 |
| Instability of mutant Cu/Zn superoxide dismutase (Ala4Thr) associated with familial amyotrophic lateral sclerosis. | Nakano R | Neuroscience letters | 1996 | PMID: 8830861 |
| Two novel SOD1 mutations in patients with familial amyotrophic lateral sclerosis. | Deng HX | Human molecular genetics | 1995 | PMID: 7655471 |
| A novel mutation in Cu/Zn superoxide dismutase gene in Japanese familial amyotrophic lateral sclerosis. | Nakano R | Biochemical and biophysical research communications | 1994 | PMID: 8179602 |
| Familial amyotrophic lateral sclerosis with a mutation in the Cu/Zn superoxide dismutase gene. | Takahashi H | Acta neuropathologica | 1994 | PMID: 7985500 |
| 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 |
| Leu106-->Val (CTC-->GTC) mutation of superoxide dismutase-1 gene in patient with familial amyotrophic lateral sclerosis in Japan. | Kawamata J | Lancet (London, England) | 1994 | PMID: 7911198 |
| Amyotrophic lateral sclerosis and structural defects in Cu,Zn superoxide dismutase. | Deng HX | Science (New York, N.Y.) | 1993 | PMID: 8351519 |
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Text-mined citations for rs121912444 ...
HelpThese 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 Sep 29, 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.