ClinVar Genomic variation as it relates to human health
NM_000454.5(SOD1):c.301G>A (p.Glu101Lys)
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.301G>A (p.Glu101Lys)
Variation ID: 574319 Accession: VCV000574319.7
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 21q22.11 21: 31667319 (GRCh38) [ NCBI UCSC ] 21: 33039632 (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 10, 2018 Feb 14, 2024 Jan 18, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000454.5:c.301G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000445.1:p.Glu101Lys missense NC_000021.9:g.31667319G>A NC_000021.8:g.33039632G>A NG_008689.1:g.12698G>A LRG_652:g.12698G>A LRG_652t1:c.301G>A LRG_652p1:p.Glu101Lys - Protein change
- E101K
- Other names
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- Canonical SPDI
- NC_000021.9:31667318:G:A
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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.
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- Links
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 |
200 | 313 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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 (1) |
criteria provided, single submitter
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Jan 18, 2024 | RCV000696225.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 7, 2021 | RCV000713400.4 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jan 1, 2022 | RCV001843542.1 |
Submissions - Germline
Classification
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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
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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
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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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Likely pathogenic
(Jan 01, 2022)
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criteria provided, single submitter
Method: research
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Amyotrophic Lateral Sclerosis
Affected status: yes
Allele origin:
germline
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Dept. of Medical Genetics, Telemark Hospital Trust, Telemark Hospital Trust
Accession: SCV002103179.1
First in ClinVar: Mar 12, 2022 Last updated: Mar 12, 2022 |
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Pathogenic
(Jun 07, 2021)
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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
Accession: SCV000844001.3
First in ClinVar: Oct 20, 2018 Last updated: Dec 31, 2022 |
Comment:
This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated … (more)
This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. In some published literature, this variant is referred to as E100K. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant increased propensity of the protein to form aggregates (PMID: 19483195, 25600987). (less)
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Pathogenic
(Jan 18, 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: SCV000824777.4
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 101 of the SOD1 protein … (more)
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 101 of the SOD1 protein (p.Glu101Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant amyotrophic lateral sclerosis (PMID: 15258228, 20460594, 20540686, 29411640; Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as 382G>A (E100K). ClinVar contains an entry for this variant (Variation ID: 574319). 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 SOD1 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change affects SOD1 function (PMID: 19483195, 23280792, 25600987). This variant disrupts the p.Glu101 amino acid residue in SOD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19483195, 20399791, 23280792, 26362407, 28105640). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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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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Screening for possible oligogenic pathogenesis in Chinese sporadic ALS patients. | Zhang H | Amyotrophic lateral sclerosis & frontotemporal degeneration | 2018 | PMID: 29411640 |
The genotype-phenotype landscape of familial amyotrophic lateral sclerosis in Australia. | McCann EP | Clinical genetics | 2017 | PMID: 28105640 |
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 |
Mitochondrial membrane disruption by aggregation products of ALS-causing superoxide dismutase-1 mutants. | Salehi M | International journal of biological macromolecules | 2015 | PMID: 25600987 |
Protein charge ladders reveal that the net charge of ALS-linked superoxide dismutase can be different in sign and magnitude from predicted values. | Shi Y | Protein science : a publication of the Protein Society | 2014 | PMID: 25052939 |
A novel monoclonal antibody reveals a conformational alteration shared by amyotrophic lateral sclerosis-linked SOD1 mutants. | Fujisawa T | Annals of neurology | 2012 | PMID: 23280792 |
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 |
An unusual case of familial ALS and cerebellar ataxia. | Yasser S | Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases | 2010 | PMID: 20540686 |
Four familial ALS pedigrees discordant for two SOD1 mutations: are all SOD1 mutations pathogenic? | Felbecker A | Journal of neurology, neurosurgery, and psychiatry | 2010 | PMID: 20460594 |
Exposure of hydrophobic surfaces initiates aggregation of diverse ALS-causing superoxide dismutase-1 mutants. | Münch C | Journal of molecular biology | 2010 | PMID: 20399791 |
Variation in aggregation propensities among ALS-associated variants of SOD1: correlation to human disease. | Prudencio M | Human molecular genetics | 2009 | PMID: 19483195 |
Impaired post-translational folding of familial ALS-linked Cu, Zn superoxide dismutase mutants. | Bruns CK | The EMBO journal | 2007 | PMID: 17255946 |
Destabilization of apoprotein is insufficient to explain Cu,Zn-superoxide dismutase-linked ALS pathogenesis. | Rodriguez JA | Proceedings of the National Academy of Sciences of the United States of America | 2005 | PMID: 16020530 |
Copper-zinc superoxide dismutase and amyotrophic lateral sclerosis. | Valentine JS | Annual review of biochemistry | 2005 | PMID: 15952898 |
Familial ALS in Germany: origin of the R115G SOD1 mutation by a founder effect. | Niemann S | Journal of neurology, neurosurgery, and psychiatry | 2004 | PMID: 15258228 |
Mechanisms for activating Cu- and Zn-containing superoxide dismutase in the absence of the CCS Cu chaperone. | Carroll MC | Proceedings of the National Academy of Sciences of the United States of America | 2004 | PMID: 15069187 |
Folding of Cu, Zn superoxide dismutase and familial amyotrophic lateral sclerosis. | Khare SD | Journal of molecular biology | 2003 | PMID: 14623191 |
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 |
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 |
Genetics of amyotrophic lateral sclerosis. | Siddique T | Human molecular genetics | 1996 | PMID: 8875253 |
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Text-mined citations for rs76731700 ...
HelpRecord last updated May 08, 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.