VCV000016896.1 - ClinVar

NC_000022.11:g.(?_42126499)_(42130881_?)dup

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(1)

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.

drug response

no assertion criteria provided

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NC_000022.11:g.(?_42126499)_(42130881_?)dup

Variation ID: 16896 Accession: VCV000016896.1

Type and length

Duplication, 4,383 bp

Location

Cytogenetic: 22q13.1 22: 42126499-42130881 (GRCh38) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 4, 2013	Apr 4, 2013	Jan 30, 2015

HGVS

Nucleotide	Protein	Molecular consequence
NC_000022.11:g.(?_42126499)_(42130881_?)dup

Protein change

Other names

CYP2D6, DUP
DUP

Canonical SPDI

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

dbVar: nssv7487166 dbVar: nsv1197529 OMIM: 124030.0008 VarSome

Comment on variant

Whole-gene duplication of CYP2D6.

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
CYP2D6		-	-	GRCh38 GRCh38 GRCh38 GRCh38 GRCh38 GRCh38 GRCh37	246	337
LOC110740340	-	-	-	GRCh38 GRCh38 GRCh38 GRCh38 GRCh38 GRCh38	-	60

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.
Codeine response	drug response (1)	no assertion criteria provided	Jan 30, 2015	RCV000030944.27

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.
drug response (Jan 30, 2015)	no assertion criteria provided Method: literature only	CODEINE, ULTRARAPID METABOLISM OF Affected status: not provided Allele origin: germline	OMIM Accession: SCV000038674.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Publications: PubMed (4) PubMed: 15625333‚ 1782973‚ 9357098‚ 16920476 Comment on evidence: Gasche et al. (2004) described a patient who had developed life-threatening opioid intoxication after he was given small doses of codeine for the treatment of … (more) Gasche et al. (2004) described a patient who had developed life-threatening opioid intoxication after he was given small doses of codeine for the treatment of cough associated with bilateral pneumonia. CYP2D6 genotyping showed 3 or more functioning alleles, as a result of gene duplication, resulting in high levels of morphine and morphine-6 glucuronide. Reduction in CYP3A4 (124010) activity by other medications and acute renal failure causing glucuronide accumulation were also factors in the codeine toxicity. Codeine is ineffective at usual doses in 7 to 10% of the white population because of homozygosity for nonfunctional mutant CYP2D6 alleles (Desmeules et al., 1991). The concentration of O-demethylated metabolites can be as much as 45 times as high in persons with ultrarapid CYP2D6 metabolism (see 608902) as it is in those with poor metabolism (Yue et al., 1997). Koren et al. (2006) reported an infant boy who showed intermittent periods of difficulty in breastfeeding and lethargy beginning at day 7, and later was noted to have gray skin. He died on day 13. The mother had been taking codeine for episiotomy pain, and the infant was found to have high serum levels of morphine. Genotype analysis showed that the mother carried the CYP2D6 duplication and was an ultrarapid metabolizer of codeine, resulting in increased formation of morphine from codeine. The morphine was transferred to the baby through breast milk, resulting in opioid toxicity and neonatal death. Koren et al. (2006) concluded that maternal codeine use should not be considered safe for all infants during breastfeeding. (less)

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

Title	Author	Journal	Year	Link
Pharmacogenetics of morphine poisoning in a breastfed neonate of a codeine-prescribed mother.	Koren G	Lancet (London, England)	2006	PMID: 16920476
Codeine intoxication associated with ultrarapid CYP2D6 metabolism.	Gasche Y	The New England journal of medicine	2004	PMID: 15625333
Quantification of the O- and N-demethylated and the glucuronidated metabolites of codeine relative to the debrisoquine metabolic ratio in urine in ultrarapid, rapid, and poor debrisoquine hydroxylators.	Yue QY	Therapeutic drug monitoring	1997	PMID: 9357098
Impact of environmental and genetic factors on codeine analgesia.	Desmeules J	European journal of clinical pharmacology	1991	PMID: 1782973

Text-mined citations for this variant ...

Record last updated Apr 25, 2022

ClinVar Genomic variation as it relates to human health

NC_000022.11:g.(?_42126499)_(42130881_?)dup

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...