NM_000454.4(SOD1):c.281G>C (p.Gly94Ala) AND Amyotrophic lateral sclerosis type 1

Clinical significance:Pathogenic (Last evaluated: Jul 25, 1997)

Review status:(0/4) 0 stars out of maximum of 4 stars

no assertion criteria provided

Based on:
1 submission [Details]
Record status:

Allele description

NM_000454.4(SOD1):c.281G>C (p.Gly94Ala)

SOD1:superoxide dismutase 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
NM_000454.4(SOD1):c.281G>C (p.Gly94Ala)
  • NC_000021.9:g.31667299G>C
  • NG_008689.1:g.12678G>C
  • NM_000454.4:c.281G>C
  • NP_000445.1:p.Gly94Ala
  • LRG_652t1:c.281G>C
  • LRG_652:g.12678G>C
  • LRG_652p1:p.Gly94Ala
  • NC_000021.8:g.33039612G>C
  • P00441:p.Gly94Ala
Protein change:
UniProtKB: P00441#VAR_007146; OMIM: 147450.0008; dbSNP: rs121912438
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_000454.4:c.281G>C - missense variant - [Sequence Ontology: SO:0001583]


Amyotrophic lateral sclerosis type 1 (ALS1)
MedGen: C1862939; Orphanet: 803; OMIM: 105400

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
SCV000036149OMIMno assertion criteria providedPathogenic
(Jul 25, 1997)
germlineliterature only

PubMed (4)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only



Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis.

Rosen DR, Siddique T, Patterson D, Figlewicz DA, Sapp P, Hentati A, Donaldson D, Goto J, O'Regan JP, Deng HX, et al.

Nature. 1993 Mar 4;362(6415):59-62. Erratum in: Nature. 1993 Jul 22;364(6435):362.

PubMed [citation]

A gain-of-function of an amyotrophic lateral sclerosis-associated Cu,Zn-superoxide dismutase mutant: An enhancement of free radical formation due to a decrease in Km for hydrogen peroxide.

Yim MB, Kang JH, Yim HS, Kwak HS, Chock PB, Stadtman ER.

Proc Natl Acad Sci U S A. 1996 Jun 11;93(12):5709-14.

PubMed [citation]
See all PubMed Citations (4)

Details of each submission

From OMIM, SCV000036149.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (4)


In affected members of a family with amyotrophic lateral sclerosis (105400), Rosen et al. (1993) identified a G-to-C transversion in exon 4 of the SOD1 gene, resulting in a gly93-to-ala (G93A) substitution.

Yim et al. (1996) observed that overexpression of mutant human H93A SOD1 in Sf9 insect cells resulted in enhanced generation of free radicals compared to wildtype SOD1, as measured by the spin trapping method. The effect was more intense at lower peroxide concentrations due to a small, but reproducible, decrease in the value of K(m) for peroxide for the G93A mutant, while the k(cat) was identical for the mutant and wildtype. The G93A mutant and wildtype enzymes had identical dismutation activity. Yim et al. (1996) concluded that ALS symptoms observed in G93A transgenic mice were not caused by the reduction of SOD1 activity, but rather were induced by a gain-of-function enhancement of the free radical-generating function. The findings were consistent with x-ray crystallographic studies showing that the active channel of the G93A mutant is slightly larger than that of the wildtype enzyme, rendering it more accessible to peroxide. See also Kostic et al. (1997).

Wiedau-Pazos et al. (1996) showed that the G93A 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.

OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

Last Updated: Mar 7, 2018