ClinVar Genomic variation as it relates to human health
NM_000454.5(SOD1):c.280G>T (p.Gly94Cys)
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.280G>T (p.Gly94Cys)
Variation ID: 14759 Accession: VCV000014759.4
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 21q22.11 21: 31667298 (GRCh38) [ NCBI UCSC ] 21: 33039611 (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 Apr 30, 2016 Feb 14, 2024 Oct 22, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000454.5:c.280G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000445.1:p.Gly94Cys missense NC_000021.9:g.31667298G>T NC_000021.8:g.33039611G>T NG_008689.1:g.12677G>T LRG_652:g.12677G>T P00441:p.Gly94Cys - Protein change
- G94C
- Other names
- G93C
- Canonical SPDI
- NC_000021.9:31667297:G: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.
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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
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 (2) |
criteria provided, single submitter
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Oct 22, 2023 | RCV000015881.25 |
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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Pathogenic
(Oct 22, 2023)
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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: SCV002117782.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 94 of the SOD1 protein … (more)
This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 94 of the SOD1 protein (p.Gly94Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with amyotrophic lateral sclerosis (PMID: 8446170, 16476815, 20577002, 25585530). This variant is also known as Gly93->Cys, G93C. ClinVar contains an entry for this variant (Variation ID: 14759). 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. Experimental studies have shown that this missense change affects SOD1 function (PMID: 12482932, 19483195). This variant disrupts the p.Gly94 amino acid residue in SOD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8004110, 9029070, 18273717, 21120636, 24325798, 28089114). 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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Pathogenic
(Feb 01, 2006)
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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: SCV000036148.2
First in ClinVar: Apr 04, 2013 Last updated: Apr 30, 2016 |
Comment on evidence:
In affected members of a family with amyotrophic lateral sclerosis (105400), Rosen et al. (1993) identified a G-to-T transversion in exon 4 of the SOD1 … (more)
In affected members of a family with amyotrophic lateral sclerosis (105400), Rosen et al. (1993) identified a G-to-T transversion in exon 4 of the SOD1 gene, resulting in a gly93-to-cys (G93C) substitution. Regal et al. (2006) reported the clinical features of 20 ALS patients from 4 families with the G93C mutation. Mean age at onset was 45.9 years, and all patients had slowly progressive weakness and atrophy starting in the distal lower limbs. Although symptoms gradually spread proximally and to the upper extremities, bulbar function was preserved. None of the patients developed upper motor neuron signs. Postmortem findings of 1 patient showed severe loss of anterior horn cells and loss of myelinated fibers in the posterior column and spinocerebellar tracts, but only mild changes in the lateral corticospinal tracts. Lipofuscin and hyaline inclusions were observed in many neurons. Patients with the G93C mutation had significantly longer survival compared to patients with other SOD1 mutations. (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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Genetic epidemiology of motor neuron disease-associated variants in the Scottish population. | Black HA | Neurobiology of aging | 2017 | PMID: 28089114 |
Genetic analysis of amyotrophic lateral sclerosis in the Slovenian population. | Vrabec K | Neurobiology of aging | 2015 | PMID: 25585530 |
Improving the knowledge of amyotrophic lateral sclerosis genetics: novel SOD1 and FUS variants. | Bertolin C | Neurobiology of aging | 2014 | PMID: 24325798 |
Phenotypic heterogeneity in a SOD1 G93D Italian ALS family: an example of human model to study a complex disease. | Penco S | Journal of molecular neuroscience : MN | 2011 | PMID: 21120636 |
SOD1, ANG, VAPB, TARDBP, and FUS mutations in familial amyotrophic lateral sclerosis: genotype-phenotype correlations. | Millecamps S | Journal of medical genetics | 2010 | PMID: 20577002 |
Variation in aggregation propensities among ALS-associated variants of SOD1: correlation to human disease. | Prudencio M | Human molecular genetics | 2009 | PMID: 19483195 |
The rare G93D mutation causes a slowly progressing lower motor neuron disease. | Restagno G | Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases | 2008 | PMID: 18273717 |
The G93C mutation in superoxide dismutase 1: clinicopathologic phenotype and prognosis. | Régal L | Archives of neurology | 2006 | PMID: 16476815 |
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 |
Epidemiology of mutations in superoxide dismutase in amyotrophic lateral sclerosis. | Cudkowicz ME | Annals of neurology | 1997 | PMID: 9029070 |
Identification of a new missense point mutation in exon 4 of the Cu/Zn superoxide dismutase (SOD-1) gene in a family with amyotrophic lateral sclerosis. | Elshafey A | Human molecular genetics | 1994 | PMID: 8004110 |
Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. | Rosen DR | Nature | 1993 | PMID: 8446170 |
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Text-mined citations for rs121912437 ...
HelpRecord last updated Feb 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.