This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls (http://gnomad.broadinstitute.org). This variant has been reported in multiple families with reduced penetrance and variable expressivity of disease. Assessment of experimental evidence suggests this variant results in abnormal protein function. Experiments demonstrate this variant increases protein aggregation (PMID 19483195), as well as accumulation of neurofilaments and mutant SOD1 protein in neuronal cells (PMID 12358759). Computational tools predict that this variant is damaging.
ClinVar Genomic variation as it relates to human health
NM_000454.5(SOD1):c.341T>C (p.Ile114Thr)
Germline
Classification
Help
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.
(12)
Help
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/Likely pathogenic
12
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000454.5(SOD1):c.341T>C (p.Ile114Thr)
Variation ID: 197145 Accession: VCV000197145.28
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 21q22.11 21: 31667359 (GRCh38) [ NCBI UCSC ] 21: 33039672 (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 Jul 1, 2017 Nov 24, 2024 Oct 9, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000454.5:c.341T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000445.1:p.Ile114Thr missense NC_000021.9:g.31667359T>C NC_000021.8:g.33039672T>C NG_008689.1:g.12738T>C LRG_652:g.12738T>C LRG_652t1:c.341T>C LRG_652p1:p.Ile114Thr P00441:p.Ile114Thr - Protein change
- I114T
- Other names
- -
- Canonical SPDI
- NC_000021.9:31667358:T:C
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00005
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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 |
207 | 322 | |
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. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Oct 9, 2024 | RCV000178103.15 | |
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Jun 24, 2021 | RCV000255754.17 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Aug 31, 2016 | RCV000492500.1 | |
|
SOD1-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
Sep 18, 2024 | RCV003398894.6 |
| Likely pathogenic (1) |
no assertion criteria provided
|
Jun 1, 2022 | RCV004767120.1 |
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
(Dec 02, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Athena Diagnostics
Accession: SCV000615370.4
First in ClinVar: Dec 19, 2017 Last updated: Sep 19, 2021 |
Comment:
This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls (http://gnomad.broadinstitute.org). This variant has been reported in multiple … (more)
This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls (http://gnomad.broadinstitute.org). This variant has been reported in multiple families with reduced penetrance and variable expressivity of disease. Assessment of experimental evidence suggests this variant results in abnormal protein function. Experiments demonstrate this variant increases protein aggregation (PMID 19483195), as well as accumulation of neurofilaments and mutant SOD1 protein in neuronal cells (PMID 12358759). Computational tools predict that this variant is damaging. (less)
|
|
|
Pathogenic
(Nov 17, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Amyotrophic lateral sclerosis type 1
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004222806.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
Variant summary: SOD1 c.341T>C (p.Ile114Thr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more)
Variant summary: SOD1 c.341T>C (p.Ile114Thr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 251478 control chromosomes. c.341T>C has been reported in the literature in multiple individuals affected with Amyotrophic Lateral Sclerosis (Pfister_2013). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence and showed that this mutation affects cell morphology and viability (Karumbayaram_2009). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(Oct 09, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Amyotrophic lateral sclerosis type 1
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV005399154.1
First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and toxic gain of … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and toxic gain of function are known mechanisms of disease in this gene and are associated with amyotrophic lateral sclerosis 1 (MIM#105400). Missense variants have been described with both a loss- and toxic gain of function effect, where protein expression and activity is reduced, but residual protein results in misfolded aggregates (OMIM, PMID: 34721532). (I) 0108 - This gene is known to be associated with both recessive and dominant disease (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from an isoleucine to a threonine. (I) 0251 - Variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (12 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in-silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. p.(Ile114Pro) has been previously reported in an individual with amyotrophic lateral sclerosis 1 (PMID: 16291929). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported eight times as pathogenic and once as likely pathogenic (ClinVar) and has been reported in many individuals with amyotrophic lateral sclerosis 1 (PMIDs: 28430856, 28105640). (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
|
|
|
Pathogenic
(Aug 31, 2016)
|
criteria provided, single submitter
(Submitter's publication)
Method: case-control
|
Motor neuron disease
Affected status: no, yes
Allele origin:
unknown
|
Centre for Genomic and Experimental Medicine, University of Edinburgh
Accession: SCV000323231.1
First in ClinVar: Jul 01, 2017 Last updated: Jul 01, 2017 |
Observation 1: Observation 2: Observation 3: Observation 4: Observation 5: Observation 6: Observation 7: Observation 8: Observation 9: Observation 10: Observation 11: Observation 12: Observation 13: Observation 14: Observation 15: Observation 16: Observation 17: Observation 18: Observation 19: |
|
|
Pathogenic
(Jul 28, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000230098.5
First in ClinVar: Jun 28, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 2
Sex: mixed
|
|
|
Pathogenic
(May 06, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000322193.8
First in ClinVar: Oct 09, 2016 Last updated: Dec 15, 2018 |
Comment:
Functional studies demonstrate that the I114T variant results in aberrant interaction between glial and neuronal cells, protein misfolding, as well as accumulation of neurofilaments and … (more)
Functional studies demonstrate that the I114T variant results in aberrant interaction between glial and neuronal cells, protein misfolding, as well as accumulation of neurofilaments and mutant SOD1 protein in neuronal cells (Kokubo et al., 1999; Ferri et al., 2004;Ip ei al., 2011 ).; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23736301, 10732812, 7643359, 30985904, 28430856, 23280792, 19259395, 15208263, 19483195, 23291526, 10593307, 28089114, 26707039, 25588603, 8446170, 23873540, 23773010, 16423367, 17543992, 30887850, 31579943, 30805795, 21549128, 26362407, 32789025) (less)
|
|
|
Likely pathogenic
(Jul 07, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Amyotrophic lateral sclerosis type 1
Affected status: yes
Allele origin:
germline
|
MGZ Medical Genetics Center
Accession: SCV002579987.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PS3_MOD, PS4_MOD, PP1, PP2, PP3
|
Number of individuals with the variant: 1
Sex: male
|
|
|
Pathogenic
(Jun 24, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001715590.2
First in ClinVar: Jun 15, 2021 Last updated: Jun 03, 2023 |
Comment:
PS3, PS4_moderate, PM2, PP3, PP5
|
|
|
Pathogenic
(Jan 21, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Amyotrophic lateral sclerosis type 1
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000830139.7
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 114 of the SOD1 protein (p.Ile114Thr). … (more)
This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 114 of the SOD1 protein (p.Ile114Thr). This variant is present in population databases (rs121912441, gnomAD 0.01%). This missense change has been observed in individuals with autosomal dominant amyotrophic lateral sclerosis (PMID: 2517465, 7673954, 7997024, 17543992). ClinVar contains an entry for this variant (Variation ID: 197145). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SOD1 function (PMID: 1259395, 19483195, 21549128, 23726301, 26362407). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Mar 30, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Amyotrophic lateral sclerosis type 1
Affected status: yes
Allele origin:
germline
|
Molecular Genetics, Royal Melbourne Hospital
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV004812518.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
Comment:
This sequence change in SOD1 is predicted to replace isoleucine with threonine at codon 114, p.(Ile114Thr) (also known as p.Ile113Thr). The isoleucine residue is highly … (more)
This sequence change in SOD1 is predicted to replace isoleucine with threonine at codon 114, p.(Ile114Thr) (also known as p.Ile113Thr). The isoleucine residue is highly conserved (100 vertebrates, UCSC), and is located in copper/zinc superoxide dismutase domain. There is a moderate physicochemical difference between isoleucine and threonine. The highest population minor allele frequency in gnomAD v2.1 is 0.01% (12/113,758 alleles) in the European (non-Finnish) population. The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (odds ratio 200, 95% CI: 23.3-1711; cases - PMID: 28430856; controls - non-neuro non-Finnish European cohort gnomAD v2.1). It is the most common pathogenic SOD1 variant and has been associated with incomplete penetrance. The variant has been reported to segregate with amyotrophic lateral sclerosis (ALS) in multiple families, with at least two founder events identified in the Australian population (PMID: 32789025). Expression of the variant in human embryonic stem cell-derived motor neurones resulted in motor neurones with characteristics of ALS-related degeneration (PMID: 19259395). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (6/6 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as PATHOGENIC. Following criteria are met: PS4, PP1_Strong, PS3_Supporting, PP3. (less)
|
|
|
Likely pathogenic
(Jun 01, 2022)
|
no assertion criteria provided
Method: provider interpretation
|
Spastic tetraplegia and axial hypotonia, progressive
Affected status: yes
Allele origin:
inherited
|
Solve-RD Consortium
Accession: SCV005091387.1
First in ClinVar: Oct 26, 2024 Last updated: Oct 26, 2024
Comment:
Variant identified during reanalysis of unsolved cases by the Solve-RD project. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and … (more)
Variant identified during reanalysis of unsolved cases by the Solve-RD project. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 779257. (less)
|
Comment:
Variant confirmed as disease-causing by referring clinical team
|
|
|
Pathogenic
(Sep 18, 2024)
|
no assertion criteria provided
Method: clinical testing
|
SOD1-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004105473.3
First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024 |
Comment:
The SOD1 c.341T>C variant is predicted to result in the amino acid substitution p.Ile114Thr. This variant, previously described as p.Ile113Thr using legacy nomenclature, has been … (more)
The SOD1 c.341T>C variant is predicted to result in the amino acid substitution p.Ile114Thr. This variant, previously described as p.Ile113Thr using legacy nomenclature, has been documented to be causative for amyotrophic lateral sclerosis (ALS, Rosen et al. 1993. PubMed ID: 8446170; Nakamura et al. 2014. PubMed ID: 23773010; Kikugawa et al. 1997. PubMed ID: 10732812; Morgan et al. 2017. PubMed ID: 28430856). This variant is reported in 0.011% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has been classified as pathogenic by multiple laboratories in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/197145/). This variant is interpreted as pathogenic. (less)
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Comment:
Comment:
Variant summary: SOD1 c.341T>C (p.Ile114Thr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 251478 control chromosomes. c.341T>C has been reported in the literature in multiple individuals affected with Amyotrophic Lateral Sclerosis (Pfister_2013). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence and showed that this mutation affects cell morphology and viability (Karumbayaram_2009). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and toxic gain of function are known mechanisms of disease in this gene and are associated with amyotrophic lateral sclerosis 1 (MIM#105400). Missense variants have been described with both a loss- and toxic gain of function effect, where protein expression and activity is reduced, but residual protein results in misfolded aggregates (OMIM, PMID: 34721532). (I) 0108 - This gene is known to be associated with both recessive and dominant disease (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from an isoleucine to a threonine. (I) 0251 - Variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (12 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in-silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. p.(Ile114Pro) has been previously reported in an individual with amyotrophic lateral sclerosis 1 (PMID: 16291929). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported eight times as pathogenic and once as likely pathogenic (ClinVar) and has been reported in many individuals with amyotrophic lateral sclerosis 1 (PMIDs: 28430856, 28105640). (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
Functional studies demonstrate that the I114T variant results in aberrant interaction between glial and neuronal cells, protein misfolding, as well as accumulation of neurofilaments and mutant SOD1 protein in neuronal cells (Kokubo et al., 1999; Ferri et al., 2004;Ip ei al., 2011 ).; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23736301, 10732812, 7643359, 30985904, 28430856, 23280792, 19259395, 15208263, 19483195, 23291526, 10593307, 28089114, 26707039, 25588603, 8446170, 23873540, 23773010, 16423367, 17543992, 30887850, 31579943, 30805795, 21549128, 26362407, 32789025)
Comment:
PS3, PS4_moderate, PM2, PP3, PP5
Comment:
This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 114 of the SOD1 protein (p.Ile114Thr). This variant is present in population databases (rs121912441, gnomAD 0.01%). This missense change has been observed in individuals with autosomal dominant amyotrophic lateral sclerosis (PMID: 2517465, 7673954, 7997024, 17543992). ClinVar contains an entry for this variant (Variation ID: 197145). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SOD1 function (PMID: 1259395, 19483195, 21549128, 23726301, 26362407). For these reasons, this variant has been classified as Pathogenic.
Comment:
This sequence change in SOD1 is predicted to replace isoleucine with threonine at codon 114, p.(Ile114Thr) (also known as p.Ile113Thr). The isoleucine residue is highly conserved (100 vertebrates, UCSC), and is located in copper/zinc superoxide dismutase domain. There is a moderate physicochemical difference between isoleucine and threonine. The highest population minor allele frequency in gnomAD v2.1 is 0.01% (12/113,758 alleles) in the European (non-Finnish) population. The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (odds ratio 200, 95% CI: 23.3-1711; cases - PMID: 28430856; controls - non-neuro non-Finnish European cohort gnomAD v2.1). It is the most common pathogenic SOD1 variant and has been associated with incomplete penetrance. The variant has been reported to segregate with amyotrophic lateral sclerosis (ALS) in multiple families, with at least two founder events identified in the Australian population (PMID: 32789025). Expression of the variant in human embryonic stem cell-derived motor neurones resulted in motor neurones with characteristics of ALS-related degeneration (PMID: 19259395). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (6/6 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as PATHOGENIC. Following criteria are met: PS4, PP1_Strong, PS3_Supporting, PP3.
Comment:
Variant confirmed as disease-causing by referring clinical team
Comment:
The SOD1 c.341T>C variant is predicted to result in the amino acid substitution p.Ile114Thr. This variant, previously described as p.Ile113Thr using legacy nomenclature, has been documented to be causative for amyotrophic lateral sclerosis (ALS, Rosen et al. 1993. PubMed ID: 8446170; Nakamura et al. 2014. PubMed ID: 23773010; Kikugawa et al. 1997. PubMed ID: 10732812; Morgan et al. 2017. PubMed ID: 28430856). This variant is reported in 0.011% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has been classified as pathogenic by multiple laboratories in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/197145/). 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:
This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls (http://gnomad.broadinstitute.org). This variant has been reported in multiple families with reduced penetrance and variable expressivity of disease. Assessment of experimental evidence suggests this variant results in abnormal protein function. Experiments demonstrate this variant increases protein aggregation (PMID 19483195), as well as accumulation of neurofilaments and mutant SOD1 protein in neuronal cells (PMID 12358759). Computational tools predict that this variant is damaging.
Comment:
Variant summary: SOD1 c.341T>C (p.Ile114Thr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 251478 control chromosomes. c.341T>C has been reported in the literature in multiple individuals affected with Amyotrophic Lateral Sclerosis (Pfister_2013). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence and showed that this mutation affects cell morphology and viability (Karumbayaram_2009). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and toxic gain of function are known mechanisms of disease in this gene and are associated with amyotrophic lateral sclerosis 1 (MIM#105400). Missense variants have been described with both a loss- and toxic gain of function effect, where protein expression and activity is reduced, but residual protein results in misfolded aggregates (OMIM, PMID: 34721532). (I) 0108 - This gene is known to be associated with both recessive and dominant disease (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from an isoleucine to a threonine. (I) 0251 - Variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (12 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in-silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. p.(Ile114Pro) has been previously reported in an individual with amyotrophic lateral sclerosis 1 (PMID: 16291929). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported eight times as pathogenic and once as likely pathogenic (ClinVar) and has been reported in many individuals with amyotrophic lateral sclerosis 1 (PMIDs: 28430856, 28105640). (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
Functional studies demonstrate that the I114T variant results in aberrant interaction between glial and neuronal cells, protein misfolding, as well as accumulation of neurofilaments and mutant SOD1 protein in neuronal cells (Kokubo et al., 1999; Ferri et al., 2004;Ip ei al., 2011 ).; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23736301, 10732812, 7643359, 30985904, 28430856, 23280792, 19259395, 15208263, 19483195, 23291526, 10593307, 28089114, 26707039, 25588603, 8446170, 23873540, 23773010, 16423367, 17543992, 30887850, 31579943, 30805795, 21549128, 26362407, 32789025)
Comment:
PS3, PS4_moderate, PM2, PP3, PP5
Comment:
This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 114 of the SOD1 protein (p.Ile114Thr). This variant is present in population databases (rs121912441, gnomAD 0.01%). This missense change has been observed in individuals with autosomal dominant amyotrophic lateral sclerosis (PMID: 2517465, 7673954, 7997024, 17543992). ClinVar contains an entry for this variant (Variation ID: 197145). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SOD1 function (PMID: 1259395, 19483195, 21549128, 23726301, 26362407). For these reasons, this variant has been classified as Pathogenic.
Comment:
This sequence change in SOD1 is predicted to replace isoleucine with threonine at codon 114, p.(Ile114Thr) (also known as p.Ile113Thr). The isoleucine residue is highly conserved (100 vertebrates, UCSC), and is located in copper/zinc superoxide dismutase domain. There is a moderate physicochemical difference between isoleucine and threonine. The highest population minor allele frequency in gnomAD v2.1 is 0.01% (12/113,758 alleles) in the European (non-Finnish) population. The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (odds ratio 200, 95% CI: 23.3-1711; cases - PMID: 28430856; controls - non-neuro non-Finnish European cohort gnomAD v2.1). It is the most common pathogenic SOD1 variant and has been associated with incomplete penetrance. The variant has been reported to segregate with amyotrophic lateral sclerosis (ALS) in multiple families, with at least two founder events identified in the Australian population (PMID: 32789025). Expression of the variant in human embryonic stem cell-derived motor neurones resulted in motor neurones with characteristics of ALS-related degeneration (PMID: 19259395). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (6/6 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as PATHOGENIC. Following criteria are met: PS4, PP1_Strong, PS3_Supporting, PP3.
Comment:
Variant confirmed as disease-causing by referring clinical team
Comment:
The SOD1 c.341T>C variant is predicted to result in the amino acid substitution p.Ile114Thr. This variant, previously described as p.Ile113Thr using legacy nomenclature, has been documented to be causative for amyotrophic lateral sclerosis (ALS, Rosen et al. 1993. PubMed ID: 8446170; Nakamura et al. 2014. PubMed ID: 23773010; Kikugawa et al. 1997. PubMed ID: 10732812; Morgan et al. 2017. PubMed ID: 28430856). This variant is reported in 0.011% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has been classified as pathogenic by multiple laboratories in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/197145/). This variant is interpreted as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| SOD1 Mutation Spectrum and Natural History of ALS Patients in a 15-Year Cohort in Southeastern China. | Chen LX | Frontiers in genetics | 2021 | PMID: 34721532 |
| Identity by descent analysis identifies founder events and links SOD1 familial and sporadic ALS cases. | Henden L | NPJ genomic medicine | 2020 | PMID: 32789025 |
| Better survival in female SOD1-mutant patients with ALS: a study of SOD1-related natural history. | Tang L | Translational neurodegeneration | 2019 | PMID: 30637102 |
| A comprehensive analysis of rare genetic variation in amyotrophic lateral sclerosis in the UK. | Morgan S | Brain : a journal of neurology | 2017 | PMID: 28430856 |
| Analysis of SOD1 mutations in a Chinese population with amyotrophic lateral sclerosis: a case-control study and literature review. | Wei Q | Scientific reports | 2017 | PMID: 28291249 |
| The genotype-phenotype landscape of familial amyotrophic lateral sclerosis in Australia. | McCann EP | Clinical genetics | 2017 | PMID: 28105640 |
| Genetic epidemiology of motor neuron disease-associated variants in the Scottish population. | Black HA | Neurobiology of aging | 2017 | PMID: 28089114 |
| Destabilization of the dimer interface is a common consequence of diverse ALS-associated mutations in metal free SOD1. | Broom HR | Protein science : a publication of the Protein Society | 2015 | PMID: 26362407 |
| 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 |
| An autopsy case of sporadic amyotrophic lateral sclerosis associated with the I113T SOD1 mutation. | Nakamura S | Neuropathology : official journal of the Japanese Society of Neuropathology | 2014 | PMID: 23773010 |
| The influence of topography on dynamic wetting. | Ramiasa M | Advances in colloid and interface science | 2014 | PMID: 23726301 |
| An unusual presentation for SOD1-ALS: isolated facial diplegia. | Fratta P | Muscle & nerve | 2013 | PMID: 23873540 |
| Familial amyotrophic lateral sclerosis in Alberta, Canada. | Pfister T | Amyotrophic lateral sclerosis & frontotemporal degeneration | 2013 | PMID: 23286750 |
| ALS-causing SOD1 mutations promote production of copper-deficient misfolded species. | Ip P | Journal of molecular biology | 2011 | PMID: 21549128 |
| Familial ALS with extreme phenotypic variability due to the I113T SOD1 mutation. | Lopate G | Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases | 2010 | PMID: 20184521 |
| Variation in aggregation propensities among ALS-associated variants of SOD1: correlation to human disease. | Prudencio M | Human molecular genetics | 2009 | PMID: 19483195 |
| Human embryonic stem cell-derived motor neurons expressing SOD1 mutants exhibit typical signs of motor neuron degeneration linked to ALS. | Karumbayaram S | Disease models & mechanisms | 2009 | PMID: 19259395 |
| SOD1 and amyotrophic lateral sclerosis: mutations and oligomerization. | Banci L | PloS one | 2008 | PMID: 18301754 |
| Lack of TDP-43 abnormalities in mutant SOD1 transgenic mice shows disparity with ALS. | Robertson J | Neuroscience letters | 2007 | PMID: 17543992 |
| Mutant SOD1-induced neuronal toxicity is mediated by increased mitochondrial superoxide levels. | Zimmerman MC | Journal of neurochemistry | 2007 | PMID: 17394531 |
| Sporadic amyotrophic lateral sclerosis and breast cancer: Hyaline conglomerate inclusions lead to identification of SOD1 mutation. | Hays AP | Journal of the neurological sciences | 2006 | PMID: 16423367 |
| Rapid disease progression correlates with instability of mutant SOD1 in familial ALS. | Sato T | Neurology | 2005 | PMID: 16291929 |
| 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 |
| Dimer destabilization in superoxide dismutase may result in disease-causing properties: structures of motor neuron disease mutants. | Hough MA | Proceedings of the National Academy of Sciences of the United States of America | 2004 | PMID: 15056757 |
| Selective loss of neurofilament expression in Cu/Zn superoxide dismutase (SOD1) linked amyotrophic lateral sclerosis. | Menzies FM | Journal of neurochemistry | 2002 | PMID: 12358759 |
| Differential gene expression in a cell culture model of SOD1-related familial motor neurone disease. | Kirby J | Human molecular genetics | 2002 | PMID: 12165567 |
| Accumulation of neurofilaments and SOD1-immunoreactive products in a patient with familial amyotrophic lateral sclerosis with I113T SOD1 mutation. | Kokubo Y | Archives of neurology | 1999 | PMID: 10593307 |
| Variation in the biochemical/biophysical properties of mutant superoxide dismutase 1 enzymes and the rate of disease progression in familial amyotrophic lateral sclerosis kindreds. | Ratovitski T | Human molecular genetics | 1999 | PMID: 10400992 |
| 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 |
| SOD1 mutation is associated with accumulation of neurofilaments in amyotrophic lateral sclerosis. | Rouleau GA | Annals of neurology | 1996 | PMID: 8572658 |
| Two novel mutations in the gene for copper zinc superoxide dismutase in UK families with amyotrophic lateral sclerosis. | Enayat ZE | Human molecular genetics | 1995 | PMID: 8528216 |
| 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 |
| Identification of a novel SOD1 mutation in an apparently sporadic amyotrophic lateral sclerosis patient and the detection of Ile113Thr in three others. | Jones CT | Human molecular genetics | 1994 | PMID: 8069312 |
| "Sporadic" motoneuron disease due to familial SOD1 mutation with low penetrance. | Suthers G | Lancet (London, England) | 1994 | PMID: 7997024 |
| Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. | Rosen DR | Nature | 1993 | PMID: 8446170 |
| The clinical and biochemical spectrum of human pyruvate dehydrogenase complex deficiency. | Brown GK | Annals of the New York Academy of Sciences | 1989 | PMID: 2517465 |
| Influence of cephalosporin antibiotics on blood coagulation and platelet function. | Natelson EA | Antimicrobial agents and chemotherapy | 1976 | PMID: 1259395 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SOD1 | - | - | - | - |
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Text-mined citations for rs121912441 ...
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Record last updated Nov 25, 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.