VCV000014762.4 - ClinVar

NM_000454.5(SOD1):c.338T>C (p.Ile113Thr)

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.

(2)

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.338T>C (p.Ile113Thr)

Variation ID: 14762 Accession: VCV000014762.4

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 21q22.11 21: 31667356 (GRCh38) [ NCBI UCSC ] 21: 33039669 (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	Feb 14, 2024	Sep 17, 2021

HGVS

Nucleotide	Protein	Molecular consequence
NM_000454.5:c.338T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000445.1:p.Ile113Thr	missense
NC_000021.9:g.31667356T>C
NC_000021.8:g.33039669T>C
NG_008689.1:g.12735T>C
LRG_652:g.12735T>C
	P00441:p.Ile113Thr

... more HGVS ... less HGVS

Protein change

I113T

Other names

Canonical SPDI

NC_000021.9:31667355:T: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: CA257331 UniProtKB: P00441#VAR_007154 OMIM: 147450.0011 dbSNP: rs74315452 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	Sep 17, 2021	RCV000015884.30

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 (Sep 17, 2021)	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: SCV002233629.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024	Publications: PubMed (7) PubMed: 7951252‚ 10321246‚ 24439480‚ 7673954‚ 8572658‚ 10540008‚ 10732812 Comment: For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SOD1 function (PMID: 7951252, 10321246, 24439480). … (more) For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SOD1 function (PMID: 7951252, 10321246, 24439480). 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: 14762). This variant is also known as p.Ile112Thr. This missense change has been observed in individuals with autosomal dominant amyotrophic lateral sclerosis (PMID: 7673954, 8572658, 10540008, 10732812). This variant is not present in population databases (ExAC no frequency). This sequence change replaces isoleucine with threonine at codon 113 of the SOD1 protein (p.Ile113Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. (less)
Pathogenic (Sep 01, 1997)	no assertion criteria provided Method: literature only	AMYOTROPHIC LATERAL SCLEROSIS 1 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000036151.2 First in ClinVar: Apr 04, 2013 Last updated: Apr 30, 2016	Publications: PubMed (5) PubMed: 8446170‚ 8105280‚ 7643359‚ 8900247‚ 10732812 Brock, D. J. H. Personal (more...) Brock, D. J. H. Personal Communication. 1998. Edinburgh, England Comment on evidence: In affected members of a family with amyotrophic lateral sclerosis (105400), Rosen et al. (1993) identified a T-to-C transition in exon 4 of the SOD1 … (more) In affected members of a family with amyotrophic lateral sclerosis (105400), Rosen et al. (1993) identified a T-to-C transition in exon 4 of the SOD1 gene, resulting in an ile113-to-thr (I113T) substitution. Jones et al. (1993) identified the I113T substitution in 3 of 56 patients with sporadic ALS drawn from a population-based study in Scotland. Jones et al. (1995) found the I113T mutation in 3 sporadic ALS cases and 3 unrelated familial cases of ALS in Scotland. Because of early death of parents of probands, together with illegitimacy in families, some of the apparently sporadic cases may have been familial. The average age at onset in patients with the I113T mutation was cited as 61.2 years, with mean survival of 1.6 years. Hayward et al. (1996) reported 6 additional cases in Scotland with the I113T mutation and a common haplotype despite no evidence of relatedness. Brock (1998) reported that he and his coworkers had found another 3 cases in the north of England with the I113T mutation and the identical genetic background, one that is rare in the general population. Kikugawa et al. (1997) performed mutation analyses of the SOD1 gene in 23 ALS patients (3 familial and 20 sporadic) from the Kii Peninsula of Japan and its vicinity, where a relatively high incidence of familial ALS had been observed. In 2 of the 23 patients, they identified heterozygosity for the I113T mutation. The mutation had been reported to be associated with the formation of neurofibrillary tangles, which was a characteristic feature of ALS in the Kii Peninsula. (less)

Comment:

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SOD1 function (PMID: 7951252, 10321246, 24439480). 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: 14762). This variant is also known as p.Ile112Thr. This missense change has been observed in individuals with autosomal dominant amyotrophic lateral sclerosis (PMID: 7673954, 8572658, 10540008, 10732812). This variant is not present in population databases (ExAC no frequency). This sequence change replaces isoleucine with threonine at codon 113 of the SOD1 protein (p.Ile113Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine.

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
Superoxide dismutase 1 mutation in a cellular model of amyotrophic lateral sclerosis shifts energy generation from oxidative phosphorylation to glycolysis.	Allen SP	Neurobiology of aging	2014	PMID: 24439480
Clinical characteristics of SOD1 gene mutations in UK families with ALS.	Orrell RW	Journal of the neurological sciences	1999	PMID: 10540008
SOD1 mutants linked to amyotrophic lateral sclerosis selectively inactivate a glial glutamate transporter.	Trotti D	Nature neuroscience	1999	PMID: 10321246
A missense mutation in the SOD1 gene in patients with amyotrophic lateral sclerosis from the Kii Peninsula and its vicinity, Japan.	Kikugawa K	Neurogenetics	1997	PMID: 10732812
A specific superoxide dismutase mutation is on the same genetic background in sporadic and familial cases of amyotrophic lateral sclerosis.	Hayward C	American journal of human genetics	1996	PMID: 8900247
SOD1 mutation is associated with accumulation of neurofilaments in amyotrophic lateral sclerosis.	Rouleau GA	Annals of neurology	1996	PMID: 8572658
Familial amyotrophic lateral sclerosis with a point mutation of SOD-1: intrafamilial heterogeneity of disease duration associated with neurofibrillary tangles.	Orrell RW	Journal of neurology, neurosurgery, and psychiatry	1995	PMID: 7673954
Superoxide dismutase mutations in an unselected cohort of Scottish amyotrophic lateral sclerosis patients.	Jones CT	Journal of medical genetics	1995	PMID: 7643359
Identification of two novel mutations and a new polymorphism in the gene for Cu/Zn superoxide dismutase in patients with amyotrophic lateral sclerosis.	Esteban J	Human molecular genetics	1994	PMID: 7951252
Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis.	Rosen DR	Nature	1993	PMID: 8446170
Cu/Zn superoxide dismutase (SOD1) mutations and sporadic amyotrophic lateral sclerosis.	Jones CT	Lancet (London, England)	1993	PMID: 8105280
Brock, D. J. H. Personal Communication. 1998. Edinburgh, England	-	-	-	-
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Text-mined citations for rs74315452 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000454.5(SOD1):c.338T>C (p.Ile113Thr)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs74315452 ...