ClinVar Genomic variation as it relates to human health
NM_000454.5(SOD1):c.131A>G (p.His44Arg)
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
-
NM_000454.5(SOD1):c.131A>G (p.His44Arg)
Variation ID: 14756 Accession: VCV000014756.35
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 21q22.11 21: 31663848 (GRCh38) [ NCBI UCSC ] 21: 33036161 (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 30, 2016 Jul 15, 2024 Dec 5, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000454.5:c.131A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000445.1:p.His44Arg missense NC_000021.9:g.31663848A>G NC_000021.8:g.33036161A>G NG_008689.1:g.9227A>G LRG_652:g.9227A>G LRG_652t1:c.131A>G LRG_652p1:p.His44Arg P00441:p.His44Arg - Protein change
- H44R
- Other names
- H43R
- Canonical SPDI
- NC_000021.9:31663847:A:G
-
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
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 |
200 | 313 |
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 (2) |
criteria provided, single submitter
|
Dec 5, 2023 | RCV000015878.33 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Oct 18, 2021 | RCV000713397.26 | |
Pathogenic (1) |
criteria provided, single submitter
|
Aug 5, 2022 | RCV002463588.2 | |
SOD1-related disorder
|
Pathogenic (1) |
criteria provided, single submitter
|
Jul 28, 2023 | RCV003398522.4 |
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
(Jul 28, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
SOD1-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004119968.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The SOD1 c.131A>G variant is predicted to result in the amino acid substitution p.His44Arg. This variant has been reported to be causative for amyotrophic lateral … (more)
The SOD1 c.131A>G variant is predicted to result in the amino acid substitution p.His44Arg. This variant has been reported to be causative for amyotrophic lateral sclerosis (Deng et al. 1993. PubMed ID: 8351519; Rosen et al. 1993. PubMed ID: 8446170; Wei et al. 2017. PubMed ID: 28291249). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/21-33036161-A-G). This variant is interpreted as pathogenic. (less)
|
|
Pathogenic
(Apr 12, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Athena Diagnostics
Accession: SCV000843998.1
First in ClinVar: Oct 20, 2018 Last updated: Oct 20, 2018 |
|
|
Pathogenic
(Aug 05, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Amyotrophic lateral sclerosis type 10
Affected status: yes
Allele origin:
germline
|
Human Genetics Bochum, Ruhr University Bochum
Accession: SCV002758554.1
First in ClinVar: Dec 11, 2022 Last updated: Dec 11, 2022 |
Comment:
ACMG criteria used to clasify this variant: PS3, PM2, PS4, PP3
|
|
Pathogenic
(Oct 18, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002020771.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
Pathogenic
(Dec 05, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Amyotrophic lateral sclerosis type 1
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000815824.6
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 44 of the SOD1 protein (p.His44Arg). … (more)
This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 44 of the SOD1 protein (p.His44Arg). This variant is present in population databases (rs121912435, gnomAD 0.0009%). This missense change has been observed in individuals with autosomal dominant amyotrophic lateral sclerosis (PMID: 8351519, 8446170, 9008494, 9029070, 14506936, 14658402, 22292843, 28105640, 28291249). This variant is also known as p.His43Arg. ClinVar contains an entry for this variant (Variation ID: 14756). 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: 7891072, 8351519, 19483195, 21257910, 23280792). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
Pathogenic
(Aug 01, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001250465.23
First in ClinVar: May 12, 2020 Last updated: Jul 15, 2024 |
Number of individuals with the variant: 1
|
|
Pathogenic
(Apr 01, 1995)
|
no assertion criteria provided
Method: literature only
|
AMYOTROPHIC LATERAL SCLEROSIS 1
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000036145.2
First in ClinVar: Apr 04, 2013 Last updated: Apr 30, 2016 |
Comment on evidence:
In affected members of a family with autosomal dominant amyotrophic lateral sclerosis (105400), Rosen et al. (1993) identified a heterozygous A-to-G transition in exon 2 … (more)
In affected members of a family with autosomal dominant amyotrophic lateral sclerosis (105400), Rosen et al. (1993) identified a heterozygous A-to-G transition in exon 2 of the SOD1 gene, resulting in a his43-to-arg (H43R) substitution. In a baculovirus expression system in insect cells, Fujii et al. (1995) found that the H43R enzyme exhibited 66% of wildtype SOD1 activity. (less)
|
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 |
---|---|---|---|---|
Analysis of SOD1 mutations in a Chinese population with amyotrophic lateral sclerosis: a case-control study and literature review. | Wei Q | Scientific reports | 2017 | PMID: 28291249 |
The genotype-phenotype landscape of familial amyotrophic lateral sclerosis in Australia. | McCann EP | Clinical genetics | 2017 | PMID: 28105640 |
The structural analysis of the pro-oxidant copper-binding site of denatured apo-H43R SOD1 and the elucidation of the origin of the acquisition of the pro-oxidant activity. | Fujimaki N | Physical chemistry chemical physics : PCCP | 2016 | PMID: 26791423 |
Next-generation sequencing of 28 ALS-related genes in a Japanese ALS cohort. | Nakamura R | Neurobiology of aging | 2016 | PMID: 26742954 |
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 |
Interaction between dimer interface residues of native and mutated SOD1 protein: a theoretical study. | Keerthana SP | Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry | 2015 | PMID: 25578810 |
Computing stability effects of mutations in human superoxide dismutase 1. | Kepp KP | The journal of physical chemistry. B | 2014 | PMID: 24472010 |
Comparative structural and conformational studies on H43R and W32F mutants of copper-zinc superoxide dismutase by molecular dynamics simulation. | Muneeswaran G | Biophysical chemistry | 2014 | PMID: 24369116 |
Pro-oxidant copper-binding mode of the Apo form of ALS-linked SOD1 mutant H43R denatured at physiological temperature. | Fujimaki N | Biochemistry | 2013 | PMID: 23837654 |
Using reference databases of genetic variation to evaluate the potential pathogenicity of candidate disease variants. | Kenna KP | Human mutation | 2013 | PMID: 23447461 |
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 |
A novel monoclonal antibody reveals a conformational alteration shared by amyotrophic lateral sclerosis-linked SOD1 mutants. | Fujisawa T | Annals of neurology | 2012 | PMID: 23280792 |
Distinctive clinicopathological features of 2 large families with amyotrophic lateral sclerosis having L106V mutation in SOD1 gene. | Hineno A | Journal of the neurological sciences | 2012 | PMID: 22647583 |
A novel variant of human superoxide dismutase 1 harboring amyotrophic lateral sclerosis-associated and experimental mutations in metal-binding residues and free cysteines lacks toxicity in vivo. | Prudencio M | Journal of neurochemistry | 2012 | PMID: 22332887 |
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 |
Making connections: pathology and genetics link amyotrophic lateral sclerosis with frontotemporal lobe dementia. | Fecto F | Journal of molecular neuroscience : MN | 2011 | PMID: 21901496 |
Cutting off functional loops from homodimeric enzyme superoxide dismutase 1 (SOD1) leaves monomeric β-barrels. | Danielsson J | The Journal of biological chemistry | 2011 | PMID: 21700707 |
Structural instability and Cu-dependent pro-oxidant activity acquired by the apo form of mutant SOD1 associated with amyotrophic lateral sclerosis. | Kitamura F | Biochemistry | 2011 | PMID: 21506602 |
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 |
Monomerized Cu, Zn-superoxide dismutase induces oxidative stress through aberrant Cu binding. | Kishigami H | Free radical biology & medicine | 2010 | PMID: 20079423 |
Variation in aggregation propensities among ALS-associated variants of SOD1: correlation to human disease. | Prudencio M | Human molecular genetics | 2009 | PMID: 19483195 |
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 |
Impaired extracellular secretion of mutant superoxide dismutase 1 associates with neurotoxicity in familial amyotrophic lateral sclerosis. | Turner BJ | The Journal of neuroscience : the official journal of the Society for Neuroscience | 2005 | PMID: 15634772 |
[Clinical features and neuropathological findings of familial amyotrophic lateral sclerosis with an H43R mutation in Cu/Zn superoxide dismutase]. | Mochizuki Y | Rinsho shinkeigaku = Clinical neurology | 2003 | PMID: 14658402 |
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 |
ALS mutants of human superoxide dismutase form fibrous aggregates via framework destabilization. | DiDonato M | Journal of molecular biology | 2003 | PMID: 12963370 |
A study to survey susceptible genetic factors responsible for troglitazone-associated hepatotoxicity in Japanese patients with type 2 diabetes mellitus. | Watanabe I | Clinical pharmacology and therapeutics | 2003 | PMID: 12732844 |
The structure of holo and metal-deficient wild-type human Cu, Zn superoxide dismutase and its relevance to familial amyotrophic lateral sclerosis. | Strange RW | Journal of molecular biology | 2003 | PMID: 12729761 |
Current status of SOD1 mutations in familial amyotrophic lateral sclerosis. | Gaudette M | Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases | 2000 | PMID: 11467054 |
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 |
Epidemiology of mutations in superoxide dismutase in amyotrophic lateral sclerosis. | Cudkowicz ME | Annals of neurology | 1997 | PMID: 9029070 |
Prognosis in familial amyotrophic lateral sclerosis: progression and survival in patients with glu100gly and ala4val mutations in Cu,Zn superoxide dismutase. | Juneja T | Neurology | 1997 | PMID: 9008494 |
Characterization of wild-type and amyotrophic lateral sclerosis-related mutant Cu,Zn-superoxide dismutases overproduced in baculovirus-infected insect cells. | Fujii J | Journal of neurochemistry | 1995 | PMID: 7891072 |
Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. | Rosen DR | Nature | 1993 | PMID: 8446170 |
Amyotrophic lateral sclerosis and structural defects in Cu,Zn superoxide dismutase. | Deng HX | Science (New York, N.Y.) | 1993 | PMID: 8351519 |
click to load more click to collapse |
Text-mined citations for rs121912435 ...
HelpRecord last updated Jul 15, 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.