NM_000454.5(SOD1):c.280G>T (p.Gly94Cys) AND Amyotrophic lateral sclerosis type 1

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Oct 22, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000015881.26

Allele description [Variation Report for NM_000454.5(SOD1):c.280G>T (p.Gly94Cys)]

NM_000454.5(SOD1):c.280G>T (p.Gly94Cys)

Gene:

SOD1:superoxide dismutase 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

21q22.11

Genomic location:

Preferred name:

NM_000454.5(SOD1):c.280G>T (p.Gly94Cys)

Other names:

G93C

HGVS:

NC_000021.9:g.31667298G>T
NG_008689.1:g.12677G>T
NM_000454.5:c.280G>TMANE SELECT
NP_000445.1:p.Gly94Cys
LRG_652:g.12677G>T
NC_000021.8:g.33039611G>T
P00441:p.Gly94Cys

Protein change:

G94C; GLY93CYS

Links:

UniProtKB: P00441#VAR_007147; OMIM: 147450.0007; dbSNP: rs121912437

NCBI 1000 Genomes Browser:

rs121912437

Molecular consequence:

NM_000454.5:c.280G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Amyotrophic lateral sclerosis type 1 (ALS1)
Synonyms:: AMYOTROPHIC LATERAL SCLEROSIS 1, FAMILIAL
Identifiers:: MONDO: MONDO:0007103; MedGen: C1862939; Orphanet: 803; OMIM: 105400

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000036148	OMIM	no assertion criteria provided	Pathogenic (Feb 1, 2006)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 8446170, 16476815
SCV002117782	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 22, 2023)	germline	clinical testing	PubMed (13) [See all records that cite these PMIDs] 8446170, 16476815, 20577002, 25585530, 12482932, 19483195, 8004110, 9029070, 18273717, 21120636, 24325798, 28089114, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000036148

OMIM

no assertion criteria provided

Pathogenic
(Feb 1, 2006)

germline

literature only

PubMed (2)
[See all records that cite these PMIDs]

SCV002117782

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 22, 2023)

germline

clinical testing

PubMed (13)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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. doi: 10.1038/364362c0.

PubMed [citation]

PMID:: 8446170

The G93C mutation in superoxide dismutase 1: clinicopathologic phenotype and prognosis.

Régal L, Vanopdenbosch L, Tilkin P, Van den Bosch L, Thijs V, Sciot R, Robberecht W.

Arch Neurol. 2006 Feb;63(2):262-7. Erratum in: Arch Neurol. 2006 Jul;63(7):963.

PubMed [citation]

PMID:: 16476815

See all PubMed Citations (13)

Details of each submission

From OMIM, SCV000036148.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002117782.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (13)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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