VCV000016899.12 - ClinVar

NM_000769.1(CYP2C19):c.636G>A (p.Trp212Ter)

Germline

Top reviewed classifications are shown here.

Submission summary:

6 submissions

5 submitters

5 conditions

Practice guidelines

Drug response

by Clinical Pharm…

for CYP2C19: no function

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

This variant is part of 34 Genotypes

Identifiers

NM_000769.1(CYP2C19):c.636G>A (p.Trp212Ter)

Variation ID: 16899 Accession: VCV000016899.12

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 10q23.33 10: 94780653 (GRCh38) [ NCBI UCSC ] 10: 96540410 (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	May 22, 2016	Sep 3, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_000769.4:c.636G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000760.1:p.Trp212Ter	nonsense
NM_000769.2:c.636G>A
NC_000010.11:g.94780653G>A
NC_000010.10:g.96540410G>A
NG_008384.3:g.22973G>A

... more HGVS ... less HGVS

Protein change

W212*

Other names

CYP2C19, TRP212TER (rs4986893)
CYP2C19m2
CYP2C19*3

Canonical SPDI

NC_000010.11:94780652:G:A

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.

0.01418 (A)

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

The Genome Aggregation Database (gnomAD) 0.00149

Trans-Omics for Precision Medicine (TOPMed) 0.00267

The Genome Aggregation Database (gnomAD), exomes 0.00538

Exome Aggregation Consortium (ExAC) 0.00551

1000 Genomes Project 30x 0.01312

1000 Genomes Project 0.01418

Links

Genetic Testing Registry (GTR): GTR000613418 OMIM: 124020.0003 dbSNP: rs4986893 PharmGKB Clinical Annotation: 981201917 ClinGen: CA126963 Genetic Testing Registry (GTR): GTR000501203 Genetic Testing Registry (GTR): GTR000556609 Genetic Testing Registry (GTR): GTR000569522 Genetic Testing Registry (GTR): GTR000576390 Genetic Testing Registry (GTR): GTR000613302 VarSome

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.
CYP2C19		-	-	GRCh38 GRCh37	238	671

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.
Mephenytoin, poor metabolism of	drug response (1)	no assertion criteria provided	Jun 1, 2009	RCV000018397.36
Proguanil, poor metabolism of	drug response (1)	no assertion criteria provided	Jun 1, 2009	RCV000018398.36
not provided	Benign; other (2)	criteria provided, multiple submitters, no conflicts	Aug 6, 2018	RCV000291495.14
CYP2C19: no function	drug response (1)	practice guideline	-	RCV000783656.9
Acute coronary syndrome	drug response (1)	no assertion criteria provided	-	RCV002280093.8

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 (-)	practice guideline (Clinical Pharmacogenetics Implementation Consortium) Method: curation	CYP2C19: no function Affected status: not applicable Allele origin: germline	Clinical Pharmacogenetics Implementation Consortium Accession: SCV000922179.1 First in ClinVar: Jun 17, 2019 Last updated: Jun 17, 2019	Other databases https://www.pharmgkb.org/haploty… https://www.pharmgkb.org/haplotype/PA166128326 https://cpicpgx.org https://cpicpgx.org
Benign (Aug 06, 2018)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001904711.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021	Comment: This variant is associated with the following publications: (PMID: 22865819, 20549256, 21855977, 22344438, 25087612, 25525159, 23874401, 7969038, 24906606)
other (Dec 28, 2015)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000331713.3 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CYP2C19 Number of individuals with the variant: 5 Sex: mixed
drug response (Jun 01, 2009)	no assertion criteria provided Method: literature only	MEPHENYTOIN, POOR METABOLISM OF Affected status: not provided Allele origin: germline	OMIM Accession: SCV000038679.2 First in ClinVar: Apr 04, 2013 Last updated: May 17, 2018	Publications: PubMed (3) PubMed: 7969038‚ 9093256‚ 19444287 Comment on evidence: This allelic variant is also known as CYP2C193 and CYP2C19m2. De Morais et al. (1994) identified a G-to-A mutation at nucleotide 636 in exon 4 … (more) This allelic variant is also known as CYP2C193 and CYP2C19m2. De Morais et al. (1994) identified a G-to-A mutation at nucleotide 636 in exon 4 of the CYP2C19 gene in Japanese poor metabolizers (609535). The mutation resulted in a premature termination codon (trp212 to ter; W212X). Using PCR, Kaneko et al. (1997) determined the distribution of the CYP2C192 (124020.0001) and CYP2C193 mutations in 493 individuals from 2 of the 80 islands of Vanuatu, where malaria is endemic. The CYP2C192 allele represented 698 of 986 alleles (70.6%), and the CYP2C193 allele represented 131 of 986 alleles (13.3%). Only 145 individuals had at least 1 wildtype allele. Further studies showed that homozygosity or compound heterozygosity for the mutations were associated with poor metabolism of proguanil, which is recommended for malaria chemoprophylaxis. The data suggested that 348 of the 493 individuals (70.6%) studied had the poor metabolizer phenotype, a finding with major implications for the efficacy of proguanil in this population. In a population-based study of 359 unrelated mainland Chinese, consisting of 103 Han, 107 Kazakh, and 149 Uygur individuals, Wang et al. (2009) found that the frequencies of the CYP2C19*3 allele were similar among the 3 groups (7.2%, 8.0%, and 9.4%, respectively) and higher than that reported in Caucasians (0%). (less)
drug response (Jun 01, 2009)	no assertion criteria provided Method: literature only	PROGUANIL, POOR METABOLISM OF Affected status: not provided Allele origin: germline	OMIM Accession: SCV000038680.2 First in ClinVar: Apr 04, 2013 Last updated: May 17, 2018	Publications: PubMed (3) PubMed: 7969038‚ 9093256‚ 19444287 Comment on evidence: This allelic variant is also known as CYP2C193 and CYP2C19m2. De Morais et al. (1994) identified a G-to-A mutation at nucleotide 636 in exon 4 … (more) This allelic variant is also known as CYP2C193 and CYP2C19m2. De Morais et al. (1994) identified a G-to-A mutation at nucleotide 636 in exon 4 of the CYP2C19 gene in Japanese poor metabolizers (609535). The mutation resulted in a premature termination codon (trp212 to ter; W212X). Using PCR, Kaneko et al. (1997) determined the distribution of the CYP2C192 (124020.0001) and CYP2C193 mutations in 493 individuals from 2 of the 80 islands of Vanuatu, where malaria is endemic. The CYP2C192 allele represented 698 of 986 alleles (70.6%), and the CYP2C193 allele represented 131 of 986 alleles (13.3%). Only 145 individuals had at least 1 wildtype allele. Further studies showed that homozygosity or compound heterozygosity for the mutations were associated with poor metabolism of proguanil, which is recommended for malaria chemoprophylaxis. The data suggested that 348 of the 493 individuals (70.6%) studied had the poor metabolizer phenotype, a finding with major implications for the efficacy of proguanil in this population. In a population-based study of 359 unrelated mainland Chinese, consisting of 103 Han, 107 Kazakh, and 149 Uygur individuals, Wang et al. (2009) found that the frequencies of the CYP2C19*3 allele were similar among the 3 groups (7.2%, 8.0%, and 9.4%, respectively) and higher than that reported in Caucasians (0%). (less)
drug response (-)	no assertion criteria provided Method: research	Acute coronary syndrome Affected status: unknown Allele origin: biparental	Cardiology Department, The First Affiliated Hospital of Nanjing Medical University Accession: SCV002568452.1 First in ClinVar: Sep 03, 2022 Last updated: Sep 03, 2022	Publications: PubMed (1) PubMed: 27441996 Number of individuals with the variant: 8

Germline Functional Evidence

Functional Help The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence	Method Help A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter.	Result Help A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
No function			Clinical Pharmacogenetics Implementation Consortium Accession: SCV000922179.1	Other databases https://www.pharmgkb.org/haploty… https://cpicpgx.org

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Standardizing terms for clinical pharmacogenetic test results: consensus terms from the Clinical Pharmacogenetics Implementation Consortium (CPIC).	Caudle KE	Genetics in medicine : official journal of the American College of Medical Genetics	2017	PMID: 27441996
Frequencies of genotypes and alleles of the functional SNPs in CYP2C19 and CYP2E1 in mainland Chinese Kazakh, Uygur and Han populations.	Wang SM	Journal of human genetics	2009	PMID: 19444287
High frequencies of CYP2C19 mutations and poor metabolism of proguanil in Vanuatu.	Kaneko A	Lancet (London, England)	1997	PMID: 9093256
Identification of a new genetic defect responsible for the polymorphism of (S)-mephenytoin metabolism in Japanese.	De Morais SM	Molecular pharmacology	1994	PMID: 7969038
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CYP2C19	-	-	-	-
https://cpicpgx.org	-	-	-	-
https://www.pharmgkb.org/haplotype/PA166128326	-	-	-	-

Text-mined citations for rs4986893 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_000769.1(CYP2C19):c.636G>A (p.Trp212Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs4986893 ...