ClinVar Genomic variation as it relates to human health
NM_000636.4(SOD2):c.47T>C (p.Val16Ala)
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.
Likely risk allele(1); Benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000636.4(SOD2):c.47T>C (p.Val16Ala)
Variation ID: 14751 Accession: VCV000014751.5
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 6q25.3 6: 159692840 (GRCh38) [ NCBI UCSC ] 6: 160113872 (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 Oct 23, 2020 Jun 24, 2022 Jan 1, 2007 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000636.4:c.47T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000627.2:p.Val16Ala missense NM_001024465.3:c.47T>C NP_001019636.1:p.Val16Ala missense NM_001024466.3:c.47T>C NP_001019637.1:p.Val16Ala missense NM_001322814.2:c.47T>C NP_001309743.1:p.Val16Ala missense NM_001322815.2:c.47T>C NP_001309744.1:p.Val16Ala missense NM_001322816.2:c.47T>C NP_001309745.1:p.Val16Ala missense NM_001322817.2:c.-92T>C 5 prime UTR NM_001322819.2:c.-92T>C 5 prime UTR NM_001322820.2:c.-92T>C 5 prime UTR NC_000006.12:g.159692840A>G NC_000006.11:g.160113872A>G NG_008729.3:g.74690T>C - Protein change
- V16A
- Other names
- A16V
- Canonical SPDI
- NC_000006.12:159692839:A:G
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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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0.41074 (G)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 30x 0.41412
1000 Genomes Project 0.41074
The Genome Aggregation Database (gnomAD), exomes 0.48395
Exome Aggregation Consortium (ExAC) 0.50239
Trans-Omics for Precision Medicine (TOPMed) 0.47172
The Genome Aggregation Database (gnomAD) 0.47242
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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SOD2 | - | - |
GRCh38 GRCh37 |
15 | 48 |
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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Benign (1) |
no assertion criteria provided
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Jan 1, 2007 | RCV000015872.11 | |
Likely risk allele; risk factor (2) |
no assertion criteria provided
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Jan 1, 2007 | RCV000015873.11 |
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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risk factor
(Jan 01, 2007)
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no assertion criteria provided
Method: literature only
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MICROVASCULAR COMPLICATIONS OF DIABETES, SUSCEPTIBILITY TO, 6
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000036140.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 23, 2020 |
Comment on evidence:
Rosenblum et al. (1996) identified a 47C-T transition in the SOD2 gene, which resulted in a change from GCT (alanine) to GTT (valine) at codon … (more)
Rosenblum et al. (1996) identified a 47C-T transition in the SOD2 gene, which resulted in a change from GCT (alanine) to GTT (valine) at codon 16 (ala16 to val; A16V). Hiroi et al. (1999) observed that processing efficiency of the V-type SOD2 leader peptide in the presence of mitochondria was significantly lower than that of the A type, by 11 +/- 4%. Bastaki et al. (2006) analyzed SOD2 activity in isolated mitochondria from healthy nonsmokers and found that activity was 15% higher in females than in males, and 33% higher in individuals with the CT or TT genotype of the 47C-T polymorphism versus CC individuals. Susceptibility to Microvascular Complications of Diabetes 6 Among Japanese patients with type 2 diabetes (125853), Nomiyama et al. (2003) found a significantly higher frequency of the VV genotype than the AA or VA genotypes in patients with diabetic nephropathy (MVCD6; 612634). They concluded that the A16V polymorphism may be unrelated to the etiology of type 2 diabetes, but is associated with diabetic nephropathy in Japanese patients with type 2 diabetes. Mollsten et al. (2007) analyzed the SOD2 A16V polymorphism (rs4880) in 1,510 Finnish and Swedish patients with type 1 diabetes (222100), including 955 patients with diabetic nephropathy and 555 controls with diabetes for more than 20 years without albuminuria or antihypertensive treatment. After controlling for age at onset, diabetes duration, hemoglobin A1C, smoking, and gender, the VV genotype was associated with an increase in the risk of diabetic nephropathy (odds ratio, 1.32; p = 0.049). Logistic regression analysis showed that the high-risk group, VV patients who had ever smoked, had a 2.52-fold increased risk for diabetic nephropathy compared to the low-risk group, supporting the hypothesis that oxidative stress contributes to the development of diabetic nephropathy. Associations Pending Confirmation Hiroi et al. (1999) found an increased frequency for the SOD2-VV genotype (homozygosity for the valine (V) allele vs the alanine allele) in Japanese with nonfamilial idiopathic dilated cardiomyopathy (CMD; see 115200) and suggested that this polymorphism may collaborate with the DRP1*1401 allele of the HLA-DRB1 gene (142857) in controlling the susceptibility to nonfamilial idiopathic cardiomyopathy. The val16 allele disrupts the alpha-helix structure of SOD2 and causes the protein to be retained at the level of the mitochondrial inner membrane. The mutant protein has 30 to 40% lower activity and increases susceptibility to oxidative stress. Valenti et al. (2004) found a significantly increased frequency of the val16 allele among 217 unrelated patients with hereditary hemochromatosis (235200) who developed dilated or nondilated cardiomyopathy compared to HH patients without cardiomyopathy and controls (frequencies of 0.67, 0.45, and 0.52, respectively). The val/val genotype conferred a 10.1-fold increased risk for cardiomyopathy in the HH patients. The association was independent of cirrhosis, diabetes, arthropathy, and hypogonadism, and did not apply to ischemic heart disease. Valenti et al. (2004) concluded that the val16 allele increased the risk of cardiomyopathy due to iron overload toxicity and oxidation in HH patients as a result of decreased activity of the SOD2 enzyme. (less)
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Benign
(Jan 01, 2007)
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no assertion criteria provided
Method: literature only
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SUPEROXIDE DISMUTASE 2 POLYMORPHISM
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000036139.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 23, 2020 |
Comment on evidence:
Rosenblum et al. (1996) identified a 47C-T transition in the SOD2 gene, which resulted in a change from GCT (alanine) to GTT (valine) at codon … (more)
Rosenblum et al. (1996) identified a 47C-T transition in the SOD2 gene, which resulted in a change from GCT (alanine) to GTT (valine) at codon 16 (ala16 to val; A16V). Hiroi et al. (1999) observed that processing efficiency of the V-type SOD2 leader peptide in the presence of mitochondria was significantly lower than that of the A type, by 11 +/- 4%. Bastaki et al. (2006) analyzed SOD2 activity in isolated mitochondria from healthy nonsmokers and found that activity was 15% higher in females than in males, and 33% higher in individuals with the CT or TT genotype of the 47C-T polymorphism versus CC individuals. Susceptibility to Microvascular Complications of Diabetes 6 Among Japanese patients with type 2 diabetes (125853), Nomiyama et al. (2003) found a significantly higher frequency of the VV genotype than the AA or VA genotypes in patients with diabetic nephropathy (MVCD6; 612634). They concluded that the A16V polymorphism may be unrelated to the etiology of type 2 diabetes, but is associated with diabetic nephropathy in Japanese patients with type 2 diabetes. Mollsten et al. (2007) analyzed the SOD2 A16V polymorphism (rs4880) in 1,510 Finnish and Swedish patients with type 1 diabetes (222100), including 955 patients with diabetic nephropathy and 555 controls with diabetes for more than 20 years without albuminuria or antihypertensive treatment. After controlling for age at onset, diabetes duration, hemoglobin A1C, smoking, and gender, the VV genotype was associated with an increase in the risk of diabetic nephropathy (odds ratio, 1.32; p = 0.049). Logistic regression analysis showed that the high-risk group, VV patients who had ever smoked, had a 2.52-fold increased risk for diabetic nephropathy compared to the low-risk group, supporting the hypothesis that oxidative stress contributes to the development of diabetic nephropathy. Associations Pending Confirmation Hiroi et al. (1999) found an increased frequency for the SOD2-VV genotype (homozygosity for the valine (V) allele vs the alanine allele) in Japanese with nonfamilial idiopathic dilated cardiomyopathy (CMD; see 115200) and suggested that this polymorphism may collaborate with the DRP1*1401 allele of the HLA-DRB1 gene (142857) in controlling the susceptibility to nonfamilial idiopathic cardiomyopathy. The val16 allele disrupts the alpha-helix structure of SOD2 and causes the protein to be retained at the level of the mitochondrial inner membrane. The mutant protein has 30 to 40% lower activity and increases susceptibility to oxidative stress. Valenti et al. (2004) found a significantly increased frequency of the val16 allele among 217 unrelated patients with hereditary hemochromatosis (235200) who developed dilated or nondilated cardiomyopathy compared to HH patients without cardiomyopathy and controls (frequencies of 0.67, 0.45, and 0.52, respectively). The val/val genotype conferred a 10.1-fold increased risk for cardiomyopathy in the HH patients. The association was independent of cirrhosis, diabetes, arthropathy, and hypogonadism, and did not apply to ischemic heart disease. Valenti et al. (2004) concluded that the val16 allele increased the risk of cardiomyopathy due to iron overload toxicity and oxidation in HH patients as a result of decreased activity of the SOD2 enzyme. (less)
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Likely risk allele
(Jan 01, 2007)
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no assertion criteria provided
Method: reference population
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Microvascular complications of diabetes 6
Affected status: unknown
Allele origin:
unknown
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iDNA Genomics
Accession: SCV002538652.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
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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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A functional polymorphism in the manganese superoxide dismutase gene and diabetic nephropathy. | Möllsten A | Diabetes | 2007 | PMID: 17192491 |
Genotype-activity relationship for Mn-superoxide dismutase, glutathione peroxidase 1 and catalase in humans. | Bastaki M | Pharmacogenetics and genomics | 2006 | PMID: 16538174 |
The mitochondrial superoxide dismutase A16V polymorphism in the cardiomyopathy associated with hereditary haemochromatosis. | Valenti L | Journal of medical genetics | 2004 | PMID: 15591282 |
The polymorphism of manganese superoxide dismutase is associated with diabetic nephropathy in Japanese type 2 diabetic patients. | Nomiyama T | Journal of human genetics | 2003 | PMID: 12624725 |
Polymorphisms in the SOD2 and HLA-DRB1 genes are associated with nonfamilial idiopathic dilated cardiomyopathy in Japanese. | Hiroi S | Biochemical and biophysical research communications | 1999 | PMID: 10425186 |
On signal sequence polymorphisms and diseases of distribution. | Rosenblum JS | Proceedings of the National Academy of Sciences of the United States of America | 1996 | PMID: 8633092 |
Text-mined citations for rs4880 ...
HelpRecord last updated Apr 20, 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.