ClinVar Genomic variation as it relates to human health
NM_000914.5(OPRM1):c.118A>G (p.Asn40Asp)
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000914.5(OPRM1):c.118A>G (p.Asn40Asp)
Variation ID: 9538 Accession: VCV000009538.75
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 6q25.2 6: 154039662 (GRCh38) [ NCBI UCSC ] 6: 154360797 (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 May 22, 2016 Jan 30, 2021 Apr 28, 2018 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000914.5:c.118A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000905.3:p.Asn40Asp missense NM_001008503.3:c.118A>G NP_001008503.2:p.Asn40Asp missense NM_001008504.4:c.118A>G NP_001008504.2:p.Asn40Asp missense NM_001008505.2:c.118A>G NP_001008505.2:p.Asn40Asp missense NM_001145279.4:c.397A>G NP_001138751.1:p.Asn133Asp missense NM_001145280.4:c.-11+28644A>G intron variant NM_001145281.3:c.47+29103A>G intron variant NM_001145282.2:c.118A>G NP_001138754.1:p.Asn40Asp missense NM_001145283.2:c.118A>G NP_001138755.1:p.Asn40Asp missense NM_001145284.3:c.118A>G NP_001138756.1:p.Asn40Asp missense NM_001145285.3:c.118A>G NP_001138757.1:p.Asn40Asp missense NM_001145286.3:c.118A>G NP_001138758.1:p.Asn40Asp missense NM_001285522.1:c.118A>G NP_001272451.1:p.Asn40Asp missense NM_001285523.3:c.118A>G NP_001272452.1:p.Asn40Asp missense NM_001285524.1:c.397A>G NP_001272453.1:p.Asn133Asp missense NR_104348.1:n.252A>G non-coding transcript variant NR_104349.1:n.252A>G non-coding transcript variant NR_104350.1:n.252A>G non-coding transcript variant NR_104351.1:n.252A>G non-coding transcript variant NC_000006.12:g.154039662A>G NC_000006.11:g.154360797A>G NG_021208.2:g.34162A>G LRG_1007:g.34162A>G LRG_1007t1:c.118A>G LRG_1007p1:p.Asn40Asp LRG_1007t2:c.118A>G LRG_1007p2:p.Asn40Asp P35372:p.Asn40Asp - Protein change
- N40D, N133D
- Other names
- OPRM1, 118A-G, ASN40ASP (rs1799971)
- Canonical SPDI
- NC_000006.12:154039661: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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0.22344 (G)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.09697
The Genome Aggregation Database (gnomAD) 0.11569
Trans-Omics for Precision Medicine (TOPMed) 0.11979
Exome Aggregation Consortium (ExAC) 0.18560
The Genome Aggregation Database (gnomAD), exomes 0.18842
1000 Genomes Project 30x 0.21408
1000 Genomes Project 0.22344
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
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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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OPRM1 | - | - |
GRCh38 GRCh37 |
483 | 527 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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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Uncertain significance (1) |
no assertion criteria provided
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Jun 30, 2009 | RCV000010146.15 | |
drug response (1) |
no assertion criteria provided
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Apr 28, 2018 | RCV001029180.10 |
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
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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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drug response
(Apr 28, 2018)
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no assertion criteria provided
Method: research
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Tramadol response
Affected status: yes
Allele origin:
somatic
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Bruce Budowle Laboratory, University of North Texas Health Science Center
Accession: SCV001191966.1
First in ClinVar: Mar 29, 2020 Last updated: Mar 29, 2020 |
Number of individuals with the variant: 204
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Uncertain significance
(Jun 30, 2009)
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no assertion criteria provided
Method: literature only
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RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000030367.6
First in ClinVar: Apr 04, 2013 Last updated: Jan 30, 2021 |
Comment on evidence:
This variant, formerly titled RESPONSE TO MORPHINE-6-GLUCURONIDE and SUSCEPTIBILITY TO OPIOID DEPENDENCE (Lotsch et al., 2002 and Bart et al., 2004), has been reclassified based … (more)
This variant, formerly titled RESPONSE TO MORPHINE-6-GLUCURONIDE and SUSCEPTIBILITY TO OPIOID DEPENDENCE (Lotsch et al., 2002 and Bart et al., 2004), has been reclassified based on the findings of Hollt (2002) and Arias et al. (2006). The 118A-G SNP in the OPRM1 gene results in an asn40-to-asp (N40D) substitution in the-N terminal region of the protein, and is predicted to result in the loss of a putative N-glycosylation site (Bond et al., 1998). The overall frequency of the 118G allele is about 10.5%, but varies significantly between different ethnic groups (African American, 0.016; Caucasian, 0.115; Hispanic, 0.142) (Bond et al., 1998). The 118G allele has a frequency varying from 0.078 to 0.341 in various populations (LaForge et al., 2000). It is present in 49 to 60% of those of Asian ancestry (Mague et al., 2009). Bond et al. (1998) found that the asp40 variant receptor bound the endogenous agonist beta-endorphin (see POMC, 176830) 3 times more tightly than the wildtype receptor in Xenopus oocytes. No differences in binding affinity were observed for other opioid alkaloids or peptides. In contrast, Beyer et al. (2004) and Mague et al. (2009) found no differences in binding affinities between the 2 SNP alleles for several agonists, including morphine, beta-endorphin, naxolone, and morphine-6-glucuronide in human embryonic kidney 293 cells and mouse brain, respectively. Zhang et al. (2005) observed that the OPRM1 118A mRNA allele was 1.5- to 2.5-fold more abundant than the 118G allele in heterozygous brain autopsy tissues. Transfection and inhibition studies showed that only 118G, and not substitutions at position 118 with A, T, or C, resulted in lower mRNA levels, in spite of equal stability. Moreover, 118G caused a 10-fold lower OPRM1 protein level as measured by Western blot and receptor binding analyses. Zhang et al. (2005) concluded that 118G is a functional variant that results in decreased levels of OPRM1 mRNA and protein. These results were confirmed by Mague et al. (2009) in mice. STUDIES OF PHENOTYPIC ASSOCIATIONS The 118A-G SNP in OPRM1 has been widely studied for its association in a variety of drug addiction and pain sensitivity phenotypes; however, the results are conflicting and the mechanisms underlying these potential associations remain elusive (Mague et al., 2009). Although Bart et al. (2004) and Drakenberg et al. (2006) independently reported an association between the 118G allele and opioid dependence (610064), a metaanalysis of 22 published papers on the subject (Arias et al., 2006) concluded that the N40D SNP does not affect the risk for substance dependence. Hollt (2002) also noted that association studies do not provide clear evidence that the 118A-G polymorphism is involved in opioid or alcohol addiction. In a study of 20 healthy individuals, comprising 10 118A/A homozygotes, Lotsch et al. (2002) presented evidence that the 118G allele is associated with decreased pupil constrictory effect of morphine-6-glucuronide, the major metabolite of morphine. However, in reviewing the findings of Lotsch et al. (2002), Hollt (2002) concluded that differences in potencies most probably reflected a much lower blood-brain barrier permeability of M6G compared to morphine, since the receptor affinities of the 2 drugs are comparable (Wu et al., 1997). In a study of 20 healthy individuals, comprising 10 118A/A homozygotes, 6 118G/G homozygotes, and 4 118A/G heterozygotes, Oertel et al. (2006) found that carriers of the 118G allele showed decreased tolerance to pain stimuli and decreased respiratory depression after alfentanil administration compared to those without the 118G allele. When compared to noncarriers, homozygous carriers needed 2 to 4 times higher alfentanil concentrations to produce the same amount of analgesia, and 10 to 12 times higher concentrations to produce the same degree of respiratory depression. Oertel et al. (2006) concluded that while both homozygous and heterozygous carriers of the 118G allele may show decreased opioid-induced analgesia, only homozygous carriers of 118G show decreased opioid-induced respiratory depressive effects. Mague et al. (2009) found that mice homozygous for the 118G allele failed to exhibit morphine-induced hyperactivity, as seen in wildtype mice. Homozygous G/G mice also showed a decrease in morphine-induced antinociception compared to wildtype mice. Although G/G males were similar to wildtype in preference to morphine-paired environments, G/G females did not show a preference to morphine-paired environments. (less)
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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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Mouse model of OPRM1 (A118G) polymorphism has sex-specific effects on drug-mediated behavior. | Mague SD | Proceedings of the National Academy of Sciences of the United States of America | 2009 | PMID: 19528658 |
The mu-opioid receptor gene polymorphism 118A>G depletes alfentanil-induced analgesia and protects against respiratory depression in homozygous carriers. | Oertel BG | Pharmacogenetics and genomics | 2006 | PMID: 16906017 |
Mu opioid receptor A118G polymorphism in association with striatal opioid neuropeptide gene expression in heroin abusers. | Drakenberg K | Proceedings of the National Academy of Sciences of the United States of America | 2006 | PMID: 16682632 |
Association of an Asn40Asp (A118G) polymorphism in the mu-opioid receptor gene with substance dependence: a meta-analysis. | Arias A | Drug and alcohol dependence | 2006 | PMID: 16387451 |
Allelic expression imbalance of human mu opioid receptor (OPRM1) caused by variant A118G. | Zhang Y | The Journal of biological chemistry | 2005 | PMID: 16046395 |
Effect of the A118G polymorphism on binding affinity, potency and agonist-mediated endocytosis, desensitization, and resensitization of the human mu-opioid receptor. | Beyer A | Journal of neurochemistry | 2004 | PMID: 15086512 |
Substantial attributable risk related to a functional mu-opioid receptor gene polymorphism in association with heroin addiction in central Sweden. | Bart G | Molecular psychiatry | 2004 | PMID: 15037869 |
The polymorphism A118G of the human mu-opioid receptor gene decreases the pupil constrictory effect of morphine-6-glucuronide but not that of morphine. | Lötsch J | Pharmacogenetics | 2002 | PMID: 11773859 |
A polymorphism (A118G) in the mu-opioid receptor gene affects the response to morphine-6-glucuronide in humans. | Höllt V | Pharmacogenetics | 2002 | PMID: 11773858 |
Opioid receptor and peptide gene polymorphisms: potential implications for addictions. | LaForge KS | European journal of pharmacology | 2000 | PMID: 11134674 |
Single-nucleotide polymorphism in the human mu opioid receptor gene alters beta-endorphin binding and activity: possible implications for opiate addiction. | Bond C | Proceedings of the National Academy of Sciences of the United States of America | 1998 | PMID: 9689128 |
Blood-brain barrier permeability to morphine-6-glucuronide is markedly reduced compared with morphine. | Wu D | Drug metabolism and disposition: the biological fate of chemicals | 1997 | PMID: 9193881 |
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Text-mined citations for rs1799971 ...
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.