VCV000014758.5 - ClinVar

NM_000454.5(SOD1):c.256G>C (p.Gly86Arg)

Germline

Classification

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.

(3)

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.

Pathogenic

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000454.5(SOD1):c.256G>C (p.Gly86Arg)

Variation ID: 14758 Accession: VCV000014758.5

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 21q22.11 21: 31667274 (GRCh38) [ NCBI UCSC ] 21: 33039587 (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	Oct 8, 2024	Aug 23, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_000454.5:c.256G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000445.1:p.Gly86Arg	missense
NM_000454.4:c.256G>C
NC_000021.9:g.31667274G>C
NC_000021.8:g.33039587G>C
NG_008689.1:g.12653G>C
LRG_652:g.12653G>C
LRG_652t1:c.256G>C
	P00441:p.Gly86Arg

... more HGVS ... less HGVS

Protein change

G86R

Other names

G85R

Canonical SPDI

NC_000021.9:31667273:G:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Links

ClinGen: CA257323 UniProtKB: P00441#VAR_007144 OMIM: 147450.0006 dbSNP: rs121912436 VarSome

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
Gene	OMIM	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	206	321

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.
Amyotrophic lateral sclerosis type 1	Pathogenic (2)	criteria provided, single submitter	Aug 23, 2022	RCV000015880.30
SOD1-related disorder	Pathogenic (1)	no assertion criteria provided	Mar 25, 2024	RCV004745157.1

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 (Aug 23, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Amyotrophic lateral sclerosis type 1 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002289726.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024	Publications: PubMed (12) PubMed: 20075587‚ 15050437‚ 15208263‚ 16945901‚ 19165329‚ 20399791‚ 23280792‚ 24134191‚ 8446170‚ 20472325‚ 24908169‚ 32166880 Comment: This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 86 of the SOD1 protein (p.Gly86Arg). … (more) This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 86 of the SOD1 protein (p.Gly86Arg). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly86 amino acid residue in SOD1. Other variant(s) that disrupt this residue have been observed in individuals with SOD1-related conditions (PMID: 20075587), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects SOD1 function (PMID: 15050437, 15208263, 16945901, 19165329, 20399791, 23280792, 24134191). 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. ClinVar contains an entry for this variant (Variation ID: 14758). This variant is also known as G85R. This missense change has been observed in individuals with autosomal dominant amyotrophic lateral sclerosis (PMID: 8446170, 20472325, 24908169, 32166880; Invitae). This variant is not present in population databases (gnomAD no frequency). (less)
Pathogenic (Sep 18, 1998)	no assertion criteria provided Method: literature only	AMYOTROPHIC LATERAL SCLEROSIS 1 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000036147.2 First in ClinVar: Apr 04, 2013 Last updated: Apr 30, 2016	Publications: PubMed (5) PubMed: 8446170‚ 8058797‚ 7891072‚ 9052802‚ 9743498 Comment on evidence: 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 … (more) 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 gly85-to-arg (G85R) substitution. By transient expression in COS cells, Borchelt et al. (1994) found that the G85R mutant protein was enzymatically inactive. However, Fujii et al. (1995) found that the G85R enzyme exhibited 99% of wildtype SOD activity in a baculovirus expression system in insect cells. Bruijn et al. (1997) found that the G85R mutant protein retained SOD1 activity in studies of transgenic mice with the G85R mutation. However, even low levels of the mutant protein caused motor neuron disease characterized by extremely rapid clinical progression. Initial indicators of disease were astrocytic inclusions that stained intensely with SOD1 antibodies and ubiquitin and SOD1-containing aggregates in motor neurons. Astrocytic inclusions escalated markedly as disease progressed, concomitant with a decrease in the glial glutamate transporter (GLT1; 600300). The authors concluded that G85R mediates direct damage to astrocytes, which may promote the nearly synchronous degeneration of motor neurons. Using the G85R mutation in transgenic mouse experiments, Bruijn et al. (1998) demonstrated that neither elimination nor elevation of wildtype SOD1 had any effect on mutant-mediated disease. The fact that aggregates containing SOD1 were common to disease caused by different mutants implied that coaggregation of an unidentified essential component or aberrant catalysis by misfolded mutants underlies, in part, mutant-mediated toxicity. (less)
Pathogenic (Mar 25, 2024)	no assertion criteria provided Method: clinical testing	SOD1-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005342067.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The SOD1 c.256G>C variant is predicted to result in the amino acid substitution p.Gly86Arg. This variant, which is also referred to as p.Gly85Arg in past … (more) The SOD1 c.256G>C variant is predicted to result in the amino acid substitution p.Gly86Arg. This variant, which is also referred to as p.Gly85Arg in past reports using older genome reference builds, has been well-documented to be a cause of amyotrophic lateral sclerosis (Rosen et al. 1993. PubMed ID: 8446170; Prudencio et al. 2009. PubMed ID: 19483195; Chen et al. 2020. PubMed ID: 32166880). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. (less)

Comment:

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 86 of the SOD1 protein (p.Gly86Arg). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly86 amino acid residue in SOD1. Other variant(s) that disrupt this residue have been observed in individuals with SOD1-related conditions (PMID: 20075587), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects SOD1 function (PMID: 15050437, 15208263, 16945901, 19165329, 20399791, 23280792, 24134191). 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. ClinVar contains an entry for this variant (Variation ID: 14758). This variant is also known as G85R. This missense change has been observed in individuals with autosomal dominant amyotrophic lateral sclerosis (PMID: 8446170, 20472325, 24908169, 32166880; Invitae). This variant is not present in population databases (gnomAD no frequency).

Comment:

The SOD1 c.256G>C variant is predicted to result in the amino acid substitution p.Gly86Arg. This variant, which is also referred to as p.Gly85Arg in past reports using older genome reference builds, has been well-documented to be a cause of amyotrophic lateral sclerosis (Rosen et al. 1993. PubMed ID: 8446170; Prudencio et al. 2009. PubMed ID: 19483195; Chen et al. 2020. PubMed ID: 32166880). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic.

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.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Clinical and genetic features of patients with amyotrophic lateral sclerosis in southern China.	Chen W	European journal of neurology	2020	PMID: 32166880
Extensive molecular genetic survey of Taiwanese patients with amyotrophic lateral sclerosis.	Soong BW	Neurobiology of aging	2014	PMID: 24908169
Mutant SOD1 inhibits ER-Golgi transport in amyotrophic lateral sclerosis.	Atkin JD	Journal of neurochemistry	2014	PMID: 24134191
A novel monoclonal antibody reveals a conformational alteration shared by amyotrophic lateral sclerosis-linked SOD1 mutants.	Fujisawa T	Annals of neurology	2012	PMID: 23280792
FUS, TARDBP, and SOD1 mutations in a Taiwanese cohort with familial ALS.	Tsai CP	Neurobiology of aging	2011	PMID: 20472325
Exposure of hydrophobic surfaces initiates aggregation of diverse ALS-causing superoxide dismutase-1 mutants.	Münch C	Journal of molecular biology	2010	PMID: 20399791
Familial amyotrophic lateral sclerosis with a novel G85S mutation of superoxide dismutase 1 gene: clinical features of lower motor neuron disease.	Takazawa T	Internal medicine (Tokyo, Japan)	2010	PMID: 20075587
An ALS-linked mutant SOD1 produces a locomotor defect associated with aggregation and synaptic dysfunction when expressed in neurons of Caenorhabditis elegans.	Wang J	PLoS genetics	2009	PMID: 19165329
Familial ALS-superoxide dismutases associate with mitochondria and shift their redox potentials.	Ferri A	Proceedings of the National Academy of Sciences of the United States of America	2006	PMID: 16945901
Cell death in amyotrophic lateral sclerosis: interplay between neuronal and glial cells.	Ferri A	FASEB journal : official publication of the Federation of American Societies for Experimental Biology	2004	PMID: 15208263
Disruption of the structure of the Golgi apparatus and the function of the secretory pathway by mutants G93A and G85R of Cu, Zn superoxide dismutase (SOD1) of familial amyotrophic lateral sclerosis.	Stieber A	Journal of the neurological sciences	2004	PMID: 15050437
Aggregation and motor neuron toxicity of an ALS-linked SOD1 mutant independent from wild-type SOD1.	Bruijn LI	Science (New York, N.Y.)	1998	PMID: 9743498
ALS-linked SOD1 mutant G85R mediates damage to astrocytes and promotes rapidly progressive disease with SOD1-containing inclusions.	Bruijn LI	Neuron	1997	PMID: 9052802
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
Superoxide dismutase 1 with mutations linked to familial amyotrophic lateral sclerosis possesses significant activity.	Borchelt DR	Proceedings of the National Academy of Sciences of the United States of America	1994	PMID: 8058797
Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis.	Rosen DR	Nature	1993	PMID: 8446170
click to load more click to collapse

Text-mined citations for rs121912436 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 13, 2024

ClinVar Genomic variation as it relates to human health

NM_000454.5(SOD1):c.256G>C (p.Gly86Arg)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121912436 ...