ClinVar Genomic variation as it relates to human health
NM_000454.5(SOD1):c.272A>C (p.Asp91Ala)
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.
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(5); Likely pathogenic(5); Uncertain significance(4)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000454.5(SOD1):c.272A>C (p.Asp91Ala)
Variation ID: 14766 Accession: VCV000014766.51
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 21q22.11 21: 31667290 (GRCh38) [ NCBI UCSC ] 21: 33039603 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 4, 2013 Apr 15, 2024 Feb 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000454.5:c.272A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000445.1:p.Asp91Ala missense NC_000021.9:g.31667290A>C NC_000021.8:g.33039603A>C NG_008689.1:g.12669A>C LRG_652:g.12669A>C LRG_652t1:c.272A>C LRG_652p1:p.Asp91Ala P00441:p.Asp91Ala - Protein change
- D91A
- Other names
- D90A
- Canonical SPDI
- NC_000021.9:31667289:A:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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0.00040 (C)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00030
1000 Genomes Project 0.00040
1000 Genomes Project 30x 0.00047
Exome Aggregation Consortium (ExAC) 0.00112
The Genome Aggregation Database (gnomAD) 0.00126
The Genome Aggregation Database (gnomAD), exomes 0.00143
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 | ||
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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. |
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SOD1 | - | - |
GRCh38 GRCh37 |
199 | 311 |
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. |
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Conflicting interpretations of pathogenicity (8) |
criteria provided, conflicting classifications
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Dec 18, 2023 | RCV000015888.43 | |
Pathogenic (1) |
no assertion criteria provided
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Apr 10, 2007 | RCV000015889.27 | |
Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
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Feb 1, 2024 | RCV000713399.30 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Mar 30, 2023 | RCV001843455.4 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jan 16, 2024 | RCV003415711.5 |
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. |
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Likely pathogenic
(Dec 12, 2016)
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criteria provided, single submitter
Method: clinical testing
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Amyotrophic lateral sclerosis 1
Affected status: yes
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV000597223.1
First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
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Uncertain significance
(Jan 29, 2016)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000329527.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
Comment:
The D91A variant in the SOD1 gene has been reported multiple times, using alternate nomenclature (D90A), in association with familial ALS. When found in the … (more)
The D91A variant in the SOD1 gene has been reported multiple times, using alternate nomenclature (D90A), in association with familial ALS. When found in the homozygous and compound heterozygous state D91A has been reported as a disease-associated variant (Hand et al., 2001; Andersen et al., 1995; Felbecker et al., 2010). However, in the heterozygous state the pathogenicity of the the D91A variant is debated (Al-Chalabi et al., 1998; Felbecker et al., 2010). The D91A variant is found with significant frequency among Scandinavian populations (Al-Chalabi et al., 1998); and the NHLBI ESP Exome Sequencing Project reports D91A was observed at a frequency of 0.08%, 7/8600 alleles, from individuals of European ancestry, indicating it may be a rare variant in this population. The D91A variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is not conserved across species. Functional studies suggest that the D91A variant may not alter protein activity and stability to the same degree as other established SOD1 variants associated with familial ALS (Själander et al., 1995; Fujisawa et al., 2012; Lindberg et al., 2002). Given the available information, we interpret D91A as a variant of unknown significance. (less)
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Likely pathogenic
(Mar 31, 2020)
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criteria provided, single submitter
Method: research
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Amyotrophic lateral sclerosis type 1
Affected status: yes
Allele origin:
germline
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Suna and Inan Kirac Foundation Neurodegeneration Research Laboratory, Koc University
Accession: SCV001251054.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Number of individuals with the variant: 9
Geographic origin: Anatolian Peninsula
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Likely pathogenic
(Oct 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
(Autosomal unknown)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001448077.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Gait ataxia (present) , Spasticity (present) , Areflexia (present) , Nonprogressive cerebellar ataxia (present)
Sex: male
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Uncertain significance
(Oct 14, 2019)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: unknown
Allele origin:
germline
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001715589.1
First in ClinVar: Jun 15, 2021 Last updated: Jun 15, 2021 |
Number of individuals with the variant: 2
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Uncertain significance
(Sep 13, 2021)
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criteria provided, single submitter
Method: clinical testing
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Amyotrophic lateral sclerosis type 1
Affected status: yes
Allele origin:
germline
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MGZ Medical Genetics Center
Accession: SCV002580444.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PS4_SUP, PP3, BS1_SUP
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Number of individuals with the variant: 1
Sex: male
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Pathogenic
(Jun 22, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Athena Diagnostics Inc
Accession: SCV000844000.3
First in ClinVar: Oct 20, 2018 Last updated: Dec 31, 2022 |
Comment:
This is a founder variant with reported recessive and dominant disease inheritance (PMID 12442272), and so its frequency in the general population is consistent with … (more)
This is a founder variant with reported recessive and dominant disease inheritance (PMID 12442272), and so its frequency in the general population is consistent with pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant is also referred to as p.Asp90Ala in published literature. This variant associates with disease in multiple families reported to exhibit both autosomal dominant and autosomal recessive inheritance. This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls. Assessment of experimental evidence suggests this variant results in abnormal protein function. Experiments show this variant causes increased protein aggregation causing motor neuron degeneration (PMID 17146286, 18319614, 19483195, 25806427). (less)
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Likely pathogenic
(Feb 23, 2023)
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criteria provided, single submitter
Method: clinical testing
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Amyotrophic lateral sclerosis type 1
Affected status: yes
Allele origin:
unknown
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3billion
Accession: SCV003841801.1
First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023 |
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.150%). The variant is observed as homozygous in … (more)
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.150%). The variant is observed as homozygous in at least two unrelated individuals/adults in the gnomAD v.2.1.1 dataset. The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (3Cnet: 0.84). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with SOD1 related disorder (ClinVar ID: VCV000014766 / PMID: 7647793). Different missense changes at the same codon (p.Asp91Asn, p.Asp91Val) have been reported to be associated with SOD1 related disorder (PMID: 22632444). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Hand tremor (present) , Distal muscle weakness (present) , Distal amyotrophy (present) , Distal sensory impairment (present) , Babinski sign (present) , Foot dorsiflexor weakness … (more)
Hand tremor (present) , Distal muscle weakness (present) , Distal amyotrophy (present) , Distal sensory impairment (present) , Babinski sign (present) , Foot dorsiflexor weakness (present) , Tongue fasciculations (present) , Pes cavus (present) , Emotional lability (present) , Type 2 diabetes mellitus (present) , Dysphagia (present) , Dysarthria (present) , Cerebellar atrophy (present) , Anterior horn disorder (present) (less)
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Pathogenic
(Mar 30, 2023)
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criteria provided, single submitter
Method: clinical testing
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Amyotrophic lateral sclerosis type 1
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001141287.2
First in ClinVar: Jan 09, 2020 Last updated: Apr 01, 2023 |
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Uncertain significance
(Dec 18, 2023)
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criteria provided, single submitter
Method: clinical testing
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Amyotrophic lateral sclerosis type 1
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000766153.6
First in ClinVar: May 03, 2018 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces aspartic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 91 of the SOD1 protein … (more)
This sequence change replaces aspartic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 91 of the SOD1 protein (p.Asp91Ala). This variant is present in population databases (rs80265967, gnomAD 1.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individuals with autosomal recessive amyotrophic lateral sclerosis (PMID: 7647793, 10809943, 11220750, 11284995, 11369193, 14506936, 18608106, 19703565, 20460594, 22264771, 23062701, 23280792). This variant has been reported in individual(s) with autosomal dominant amyotrophic lateral sclerosis (PMID: 8909456, 10809943, 14506936, 19922148, 22264771); however, the role of the variant in this condition is currently unclear. This variant is also known as p.Asp90Ala. ClinVar contains an entry for this variant (Variation ID: 14766). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects SOD1 function (PMID: 7655469, 12482932, 16945901, 17420412, 18319614, 19635794, 19703565, 20189984, 22264771, 25509359, 25792239). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Likely pathogenic
(Jan 16, 2024)
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criteria provided, single submitter
Method: clinical testing
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SOD1-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004116564.2
First in ClinVar: Nov 20, 2023 Last updated: Mar 16, 2024 |
Comment:
The SOD1 c.272A>C variant is predicted to result in the amino acid substitution p.Asp91Ala. The c.272A>C change, previously described as p.Asp90Ala using legacy nomenclature, is … (more)
The SOD1 c.272A>C variant is predicted to result in the amino acid substitution p.Asp91Ala. The c.272A>C change, previously described as p.Asp90Ala using legacy nomenclature, is a known founder variant found within the Scandinavian population and has previously been reported in autosomal recessive amyotrophic lateral sclerosis/ALS (Andersen et al. 1995. PubMed ID: 7647793; Gellera et al. 2001. PubMed ID: 11369193; Hand et al. 2001. PubMed ID: 11220750; Felbecker et al. 2010. PubMed ID: 20460594). Patients homozygous for the c.272A>C change present with longer duration of disease compared to autosomal dominant SOD1 mediated ALS (Tripolszki et al. 2017. PubMed ID: 28222900; Luisa Conforti et al. 2009. PubMed ID: 18608106). Heterozygous individuals with the c.272A>C variant have been reported in a few cases with some patients presenting with atypical ALS (Origone et al. 2009. PubMed ID: 19922148; Dalla Bella et al. 2014. PubMed ID: 24591457; Khoris et al. 2000. PubMed ID: 10809943). This variant is reported in 1.2% of alleles in individuals of European (Finnish) descent in gnomAD. This variant is interpreted as likely pathogenic. (less)
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Pathogenic
(Feb 01, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001153538.21
First in ClinVar: Feb 03, 2020 Last updated: Apr 15, 2024 |
Comment:
SOD1: PM1, PM5, PS4:Moderate, PM2:Supporting, PP2, PP4, PS3:Supporting
Number of individuals with the variant: 8
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Pathogenic
(Jan 01, 2022)
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criteria provided, single submitter
Method: research
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Amyotrophic Lateral Sclerosis
Affected status: yes
Allele origin:
germline
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Dept. of Medical Genetics, Telemark Hospital Trust, Telemark Hospital Trust
Accession: SCV002103163.1
First in ClinVar: Mar 12, 2022 Last updated: Mar 12, 2022 |
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Pathogenic
(Mar 30, 2023)
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criteria provided, single submitter
Method: clinical testing
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Amyotrophic lateral sclerosis
Affected status: unknown
Allele origin:
germline
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Molecular Genetics, Royal Melbourne Hospital
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV004812670.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
Comment:
This sequence change in SOD1 is predicted to replace aspartic acid with alanine at codon 91, p.(Asp91Ala). Historically this variant is known as p.(Asp90Ala) or … (more)
This sequence change in SOD1 is predicted to replace aspartic acid with alanine at codon 91, p.(Asp91Ala). Historically this variant is known as p.(Asp90Ala) or p.D90A. The apartic acid residue is weakly conserved (100 vertebrates, UCSC), and is located in the Sod Cu domain. There is a large physicochemical difference between aspartic acid and alanine. The highest population minor allele frequency in gnomAD v2.1 is 1.2% (298/25,122 alleles, 3 homozygotes) in the Finnish population. Whereas, the highest continental population minor allele frequency in gnomAD v2.1 is 0.07% (96/129,186 alleles, 1 homozygote) in the European (non-Finnish) population. The homozygous individuals are absent from the non-neuro cohort in gnomAD v2.1. The variant is one of the most commonly reported SOD1 variants associated with amyotrophic lateral sclerosis (ALS) and is a Scandinavian founder, which shows both autosomal dominant and recessive patterns in different populations (PMID: 9817920, 12442272). The prevalence of the heterozygous variant in affected individuals is significantly increased compared with the prevalence in controls (odds ratio 2.82, 95% CI: 1.40-5.67) (PMID: 19965850, 23100398, 28105640, 28222900, 28430856, 28444446; gnomAD v2.1 European non-Finnish non-neuro cohort). This variant has been detected in the homozygous state in many individuals with ALS and compound heterozygous with a second allele in at two affected families (PMID: 7647793, 11220750, 34668453). The recessive and dominant kindreds reported with the variant share a rare haplotype, however a recessive founder arose subsequently through a recombination event. The homozygous phenotype is characterised by prolonged survival and slow progression of disease, whereas the affected heterozygous phenotypes can vary (PMID: 12442272). In recessive kindreds segregation with ALS is reported in homozygous individuals and heterozygous individuals are unaffected (PMID: 7647793, 12442272). Whereas, in dominant kindreds segregation of the heterozygous variant with disease is reported with incomplete penetrance (PMID: 8909456, 10809943). A homozygous mouse model recapitulates the human ALS phenotype (PMID: 17146286). Multiple lines of computational evidence have conflicting predictions for the missense substitution (5/6 algorithms predict benign). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as PATHOGENIC. Following criteria are met: PS3, PP1_Strong, PM3, PS4_Supporting. (less)
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Pathogenic
(Apr 10, 2007)
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no assertion criteria provided
Method: literature only
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AMYOTROPHIC LATERAL SCLEROSIS 1
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000036155.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In 14 affected individuals from 4 unrelated Swedish or Finnish families with ALS (105400), Andersen et al. (1995) identified a homozygous mutation in exon 4 … (more)
In 14 affected individuals from 4 unrelated Swedish or Finnish families with ALS (105400), Andersen et al. (1995) identified a homozygous mutation in exon 4 of the SOD1 gene, resulting in an asp90-to-ala (D90A) substitution. Erythrocyte SOD1 activity was essentially normal. The findings suggested that this mutation caused ALS by a gain of function rather than by loss, and that the D90A mutation was less detrimental than previously reported mutations. Consanguinity was present in several of the families. The age at onset of symptoms ranged from 37 to 94 years in 1 family in which all patients showed very similar disease phenotypes; symptoms began with cramps in the legs, which progressed to muscular atrophy and weakness. Upper motor neuron signs appeared after 1-4 years disease duration in all patients; none of the patients showed signs of intellectual impairment. In a second family, onset in 2 sibs was at the age of 40, with a phenotype similar to that of the first family. In a third family, 3 sibs had onset at ages 20, 36, and 22 years, respectively. Four patients with apparently sporadic ALS were also found to carry the mutations. Andersen et al. (1995) concluded that familial ALS due to mutation in the SOD1 gene exists in both autosomal dominant and autosomal recessive forms. Robberecht et al. (1996) identified a heterozygous D90A mutation in affected members of 2 families with ALS and in a patient with apparently sporadic ALS. Aguirre et al. (1999) found the D90A mutation in heterozygous state in affected members of 2 families and in 1 apparently sporadic case of ALS. Direct sequencing of exons 1 through 5 showed no additional mutations in the SOD1 gene in these patients and the D90A mutation was not found on 150 normal chromosomes. In a worldwide haplotype study of 28 pedigrees with the D90A mutation, Al-Chalabi et al. (1998) found that 20 recessive families shared the same founder haplotype, regardless of geographic location, whereas several founders existed for the 8 dominant families. The findings confirmed that D90A can act in a dominant fashion in keeping with all other SOD1 mutations. Al-Chalabi et al. (1998) proposed that a tightly linked protective factor modifies the toxic effect of mutant SOD1 in recessive families. Gellera et al. (2001) found homozygosity for the D90A mutation in a sporadic case of ALS. In 2 sibs with ALS from a family described by Khoris et al. (2000), Hand et al. (2001) identified compound heterozygosity for D90A and D96N (147450.0032). A third sib with the disease died before testing. Further examination of the family identified the D90A mutation alone in 2 unaffected members and the D96N mutation alone in 4 unaffected members. There were no individuals homozygous for either mutation, and no unaffected individual with both mutations was identified. Hand et al. (2001) concluded that both mutations, which occur in the same region of the protein, are required for disease. The authors emphasized that this is the first report of compound heterozygosity for the SOD1 gene in an ALS patient and suggested that the findings may have implications for the interpretation of inheritance patterns in ALS families. Using PET scanning, Turner et al. (2007) found that ALS patients homozygous for the D90A substitution had a 12% decrease in 5-HT1A receptor (5HTRA1; 109760) binding potential compared to healthy controls. The decreased binding among patients was most significant in the temporal lobes. Patients with sporadic ALS without the D90A substitution had a 21% decrease in binding potential. Turner et al. (2007) suggested that patients with the D90A mutation may have decreased cortical vulnerability compared to other ALS patients, which may correlate with the slower progression observed in D90A carriers. (less)
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Pathogenic
(Apr 10, 2007)
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no assertion criteria provided
Method: literature only
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AMYOTROPHIC LATERAL SCLEROSIS 1, AUTOSOMAL RECESSIVE
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000036156.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In 14 affected individuals from 4 unrelated Swedish or Finnish families with ALS (105400), Andersen et al. (1995) identified a homozygous mutation in exon 4 … (more)
In 14 affected individuals from 4 unrelated Swedish or Finnish families with ALS (105400), Andersen et al. (1995) identified a homozygous mutation in exon 4 of the SOD1 gene, resulting in an asp90-to-ala (D90A) substitution. Erythrocyte SOD1 activity was essentially normal. The findings suggested that this mutation caused ALS by a gain of function rather than by loss, and that the D90A mutation was less detrimental than previously reported mutations. Consanguinity was present in several of the families. The age at onset of symptoms ranged from 37 to 94 years in 1 family in which all patients showed very similar disease phenotypes; symptoms began with cramps in the legs, which progressed to muscular atrophy and weakness. Upper motor neuron signs appeared after 1-4 years disease duration in all patients; none of the patients showed signs of intellectual impairment. In a second family, onset in 2 sibs was at the age of 40, with a phenotype similar to that of the first family. In a third family, 3 sibs had onset at ages 20, 36, and 22 years, respectively. Four patients with apparently sporadic ALS were also found to carry the mutations. Andersen et al. (1995) concluded that familial ALS due to mutation in the SOD1 gene exists in both autosomal dominant and autosomal recessive forms. Robberecht et al. (1996) identified a heterozygous D90A mutation in affected members of 2 families with ALS and in a patient with apparently sporadic ALS. Aguirre et al. (1999) found the D90A mutation in heterozygous state in affected members of 2 families and in 1 apparently sporadic case of ALS. Direct sequencing of exons 1 through 5 showed no additional mutations in the SOD1 gene in these patients and the D90A mutation was not found on 150 normal chromosomes. In a worldwide haplotype study of 28 pedigrees with the D90A mutation, Al-Chalabi et al. (1998) found that 20 recessive families shared the same founder haplotype, regardless of geographic location, whereas several founders existed for the 8 dominant families. The findings confirmed that D90A can act in a dominant fashion in keeping with all other SOD1 mutations. Al-Chalabi et al. (1998) proposed that a tightly linked protective factor modifies the toxic effect of mutant SOD1 in recessive families. Gellera et al. (2001) found homozygosity for the D90A mutation in a sporadic case of ALS. In 2 sibs with ALS from a family described by Khoris et al. (2000), Hand et al. (2001) identified compound heterozygosity for D90A and D96N (147450.0032). A third sib with the disease died before testing. Further examination of the family identified the D90A mutation alone in 2 unaffected members and the D96N mutation alone in 4 unaffected members. There were no individuals homozygous for either mutation, and no unaffected individual with both mutations was identified. Hand et al. (2001) concluded that both mutations, which occur in the same region of the protein, are required for disease. The authors emphasized that this is the first report of compound heterozygosity for the SOD1 gene in an ALS patient and suggested that the findings may have implications for the interpretation of inheritance patterns in ALS families. Using PET scanning, Turner et al. (2007) found that ALS patients homozygous for the D90A substitution had a 12% decrease in 5-HT1A receptor (5HTRA1; 109760) binding potential compared to healthy controls. The decreased binding among patients was most significant in the temporal lobes. Patients with sporadic ALS without the D90A substitution had a 21% decrease in binding potential. Turner et al. (2007) suggested that patients with the D90A mutation may have decreased cortical vulnerability compared to other ALS patients, which may correlate with the slower progression observed in D90A carriers. (less)
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Pathogenic
(Apr 25, 2018)
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no assertion criteria provided
Method: clinical testing
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Amyotrophic lateral sclerosis type 1
Affected status: yes
Allele origin:
germline
|
Institute of Human Genetics, Cologne University
Accession: SCV000787782.1
First in ClinVar: May 03, 2018 Last updated: May 03, 2018 |
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Compound heterozygous P67S/D91A SOD1 mutations in an ALS family with apparently sporadic case. | De La Cruz E | Amyotrophic lateral sclerosis & frontotemporal degeneration | 2022 | PMID: 34668453 |
Frequency of C9orf72 hexanucleotide repeat expansion and SOD1 mutations in Portuguese patients with amyotrophic lateral sclerosis. | Gromicho M | Neurobiology of aging | 2018 | PMID: 29861044 |
Comparison of the clinical and cognitive features of genetically positive ALS patients from the largest tertiary center in Serbia. | Marjanović IV | Journal of neurology | 2017 | PMID: 28444446 |
A comprehensive analysis of rare genetic variation in amyotrophic lateral sclerosis in the UK. | Morgan S | Brain : a journal of neurology | 2017 | PMID: 28430856 |
Genetic analysis of the SOD1 and C9ORF72 genes in Hungarian patients with amyotrophic lateral sclerosis. | Tripolszki K | Neurobiology of aging | 2017 | PMID: 28222900 |
The genotype-phenotype landscape of familial amyotrophic lateral sclerosis in Australia. | McCann EP | Clinical genetics | 2017 | PMID: 28105640 |
Generation and expansion of highly pure motor neuron progenitors from human pluripotent stem cells. | Du ZW | Nature communications | 2015 | PMID: 25806427 |
Primary fibroblasts cultures reveal TDP-43 abnormalities in amyotrophic lateral sclerosis patients with and without SOD1 mutations. | Sabatelli M | Neurobiology of aging | 2015 | PMID: 25792239 |
Targeted exon capture and sequencing in sporadic amyotrophic lateral sclerosis. | Couthouis J | PLoS genetics | 2014 | PMID: 25299611 |
[SOD1 gene mutations in patients with amyotrophic lateral sclerosis: potential for the method of molecular]. | Lysogorskaia EV | Molekuliarnaia biologiia | 2013 | PMID: 25509359 |
Genetic analysis and SOD1 mutation screening in Iranian amyotrophic lateral sclerosis patients. | Alavi A | Neurobiology of aging | 2013 | PMID: 23062701 |
A novel monoclonal antibody reveals a conformational alteration shared by amyotrophic lateral sclerosis-linked SOD1 mutants. | Fujisawa T | Annals of neurology | 2012 | PMID: 23280792 |
Extensive genetics of ALS: a population-based study in Italy. | Chiò A | Neurology | 2012 | PMID: 23100398 |
An ALS case with a novel D90N-SOD1 heterozygous missense mutation. | Calvo A | Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases | 2012 | PMID: 22632444 |
ALS patients with mutations in the SOD1 gene have an unique metabolomic profile in the cerebrospinal fluid compared with ALS patients without mutations. | Wuolikainen A | Molecular genetics and metabolism | 2012 | PMID: 22264771 |
Four familial ALS pedigrees discordant for two SOD1 mutations: are all SOD1 mutations pathogenic? | Felbecker A | Journal of neurology, neurosurgery, and psychiatry | 2010 | PMID: 20460594 |
SOD1 mutations targeting surface hydrogen bonds promote amyotrophic lateral sclerosis without reducing apo-state stability. | Byström R | The Journal of biological chemistry | 2010 | PMID: 20189984 |
Large-scale SOD1 mutation screening provides evidence for genetic heterogeneity in amyotrophic lateral sclerosis. | van Es MA | Journal of neurology, neurosurgery, and psychiatry | 2010 | PMID: 19965850 |
Heterozygous D90A-SOD1 mutation in an Italian ALS patient with atypical presentation. | Origone P | Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases | 2009 | PMID: 19922148 |
Superoxide dismutase in amyotrophic lateral sclerosis patients homozygous for the D90A mutation. | Jonsson PA | Neurobiology of disease | 2009 | PMID: 19703565 |
A common property of amyotrophic lateral sclerosis-associated variants: destabilization of the copper/zinc superoxide dismutase electrostatic loop. | Molnar KS | The Journal of biological chemistry | 2009 | PMID: 19635794 |
Variation in aggregation propensities among ALS-associated variants of SOD1: correlation to human disease. | Prudencio M | Human molecular genetics | 2009 | PMID: 19483195 |
Further evidence that D90A-SOD1 mutation is recessively inherited in ALS patients in Italy. | Luisa Conforti F | Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases | 2009 | PMID: 18608106 |
SOD1 gene mutations in ALS patients from British Columbia, Canada: clinical features, neurophysiology and ethical issues in management. | Eisen A | Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases | 2008 | PMID: 18428003 |
Transduction of familial amyotrophic lateral sclerosis-related mutant PEP-1-SOD proteins into neuronal cells. | An JJ | Molecules and cells | 2008 | PMID: 18319614 |
Cortical 5-HT1A receptor binding in patients with homozygous D90A SOD1 vs sporadic ALS. | Turner MR | Neurology | 2007 | PMID: 17420412 |
Motor neuron disease in mice expressing the wild type-like D90A mutant superoxide dismutase-1. | Jonsson PA | Journal of neuropathology and experimental neurology | 2006 | PMID: 17146286 |
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 |
Sixteen novel mutations in the Cu/Zn superoxide dismutase gene in amyotrophic lateral sclerosis: a decade of discoveries, defects and disputes. | Andersen PM | Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases | 2003 | PMID: 14506936 |
Common denominator of Cu/Zn superoxide dismutase mutants associated with amyotrophic lateral sclerosis: decreased stability of the apo state. | Lindberg MJ | Proceedings of the National Academy of Sciences of the United States of America | 2002 | PMID: 12482932 |
D90A-SOD1 mediated amyotrophic lateral sclerosis: a single founder for all cases with evidence for a Cis-acting disease modifier in the recessive haplotype. | Parton MJ | Human mutation | 2002 | PMID: 12442272 |
Superoxide dismutase gene mutations in Italian patients with familial and sporadic amyotrophic lateral sclerosis: identification of three novel missense mutations. | Gellera C | Neuromuscular disorders : NMD | 2001 | PMID: 11369193 |
Sporadic ALS associated with the D90A Cu,Zn superoxide dismutase mutation in Russia. | Skvortsova VI | European journal of neurology | 2001 | PMID: 11284995 |
Compound heterozygous D90A and D96N SOD1 mutations in a recessive amyotrophic lateral sclerosis family. | Hand CK | Annals of neurology | 2001 | PMID: 11220750 |
Coexistence of dominant and recessive familial amyotrophic lateral sclerosis with the D90A Cu,Zn superoxide dismutase mutation within the same country. | Khoris J | European journal of neurology | 2000 | PMID: 10809943 |
Mutational analysis of the Cu/Zn superoxide dismutase gene in 23 familial and 69 sporadic cases of amyotrophic lateral sclerosis in Belgium. | Aguirre T | European journal of human genetics : EJHG | 1999 | PMID: 10439968 |
Recessive amyotrophic lateral sclerosis families with the D90A SOD1 mutation share a common founder: evidence for a linked protective factor. | Al-Chalabi A | Human molecular genetics | 1998 | PMID: 9817920 |
Phenotypic heterogeneity in motor neuron disease patients with CuZn-superoxide dismutase mutations in Scandinavia. | Andersen PM | Brain : a journal of neurology | 1997 | PMID: 9365366 |
D90A heterozygosity in the SOD1 gene is associated with familial and apparently sporadic amyotrophic lateral sclerosis. | Robberecht W | Neurology | 1996 | PMID: 8909456 |
Autosomal recessive adult-onset amyotrophic lateral sclerosis associated with homozygosity for Asp90Ala CuZn-superoxide dismutase mutation. A clinical and genealogical study of 36 patients. | Andersen PM | Brain : a journal of neurology | 1996 | PMID: 8813280 |
The D90A mutation results in a polymorphism of Cu,Zn superoxide dismutase that is prevalent in northern Sweden and Finland. | Själander A | Human molecular genetics | 1995 | PMID: 7655469 |
Amyotrophic lateral sclerosis associated with homozygosity for an Asp90Ala mutation in CuZn-superoxide dismutase. | Andersen PM | Nature genetics | 1995 | PMID: 7647793 |
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Text-mined citations for rs80265967 ...
HelpRecord last updated May 01, 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.