VCV000005066.28 - ClinVar

NM_000777.5(CYP3A5):c.219-237A>G

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.

(4)

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.

association; drug response; risk factor

no assertion criteria provided

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000777.5(CYP3A5):c.219-237A>G

Variation ID: 5066 Accession: VCV000005066.28

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7q22.1 7: 99672916 (GRCh38) [ NCBI UCSC ] 7: 99270539 (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	Apr 4, 2013	Nov 13, 2022	Apr 15, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_000777.5:c.219-237A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NM_001190484.3:c.219-237A>G		intron variant
NM_001291829.2:c.-253-1A>G		splice acceptor
NM_001291830.2:c.189-237A>G		intron variant
NC_000007.14:g.99672916T>C
NC_000007.13:g.99270539=
NG_007938.2:g.12083A>G

... more HGVS ... less HGVS

Protein change

Other names

CYP3A5*3
6986A-G

Canonical SPDI

NC_000007.14:99672915:T:C

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

effect on protein activity; Variation Ontology [ VariO:0053]

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.

1000 Genomes Project 30x 0.61540

Trans-Omics for Precision Medicine (TOPMed) 0.70069

The Genome Aggregation Database (gnomAD) 0.72319

Links

Genetic Testing Registry (GTR): GTR000613302 OMIM: 605325.0001 dbSNP: rs776746 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.
CYP3A5		-	-	GRCh38 GRCh37	-	67
ZSCAN25	-	-	-	GRCh38 GRCh37	40	141

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.
Hypertension, salt-sensitive essential, susceptibility to	risk factor (1)	no assertion criteria provided	Dec 1, 2004	RCV000005370.3
refractory myasthenia gravis	association (1)	no assertion criteria provided	Mar 23, 2022	RCV002227926.2
Tacrolimus response	drug response (2)	no assertion criteria provided	Apr 15, 2022	RCV002292440.3

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.
risk factor (Dec 01, 2004)	no assertion criteria provided Method: literature only	HYPERTENSION, SALT-SENSITIVE ESSENTIAL, SUSCEPTIBILITY TO Affected status: not provided Allele origin: germline	OMIM Accession: SCV000025550.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Publications: PubMed (5) PubMed: 11279519‚ 12065767‚ 11740341‚ 12754175‚ 15492926 Comment on evidence: In many populations, total adult CYP3A protein content of tissues remains constant and consists largely of CYP3A4, whereas CYP3A5 expression has extreme interpopulation variability. This … (more) In many populations, total adult CYP3A protein content of tissues remains constant and consists largely of CYP3A4, whereas CYP3A5 expression has extreme interpopulation variability. This variation is largely due to a 6986A-G substitution in intron 3 of CYP3A5 (the CYP3A53 allele; SV1-CYP3A5) that results in improperly spliced mRNA and a nonfunctional protein truncated at amino acid 102 (Kuehl et al., 2001; Lin et al., 2002). The CYP3A53 allele is reported to have a frequency of approximately 27 to 50% among African Americans, 85 to 95% among whites (Hustert et al., 2001; Kuehl et al., 2001), and 60 to 73% among Asians (Hustert et al., 2001). Givens et al. (2003) found that, among renal microsomes from 21 organ donors, those from 1/3 individuals had at least 8-fold higher mean kidney microsomal CYP3A5 content and 18-fold higher mean CYP3A catalytic activity than did those from 3/3 individuals (p = 0.0001 and p = 0.0137, respectively). They also found significant associations between the 6986A-G polymorphism and systolic blood pressure (p = 0.0007), mean arterial pressure (p = 0.0075), and creatinine clearance (p = 0.0035) among 25 healthy African American adults. The associations remained significant when sex, age, and body mass index were considered. The mean systolic blood pressure of homozygous CYP3A5 expressors (1/1) exceeded that of homozygous nonexpressors (3/3) by 19.3 mm Hg. Givens et al. (2003) speculated that a high CYPA5 expressor allele frequency among African Americans may contribute to a high prevalence of salt-sensitive hypertension (145500) in this population. Thompson et al. (2004) found that the CYP3A53 allele is significantly correlated with distance from the equator. They noted that a met235-to-thr SNP in the AGT gene (M235T; 106150.0001), previously implicated in hypertension and preeclampsia, exhibited a similar geographic distribution and had a significantly correlated frequency with CYP3A51/*3. Thompson et al. (2004) concluded that variants that influence salt homeostasis are the targets of a shared selective pressure that results from an environmental variable correlated with latitude. (less)
drug response (Apr 15, 2022)	no assertion criteria provided Method: research	tacrolimus response Drug used for tacrolimus exposure after transplantation Affected status: yes Allele origin: germline	Pharmacy Department, Siriraj Hospital, Mahidol University Accession: SCV002500936.1 First in ClinVar: Oct 22, 2022 Last updated: Oct 22, 2022	Comments (2): The risk of immunological complications is generally highest during the early period after kidney transplantation. Adequate immunosuppression is crucial during this critical period since lower … (more) The risk of immunological complications is generally highest during the early period after kidney transplantation. Adequate immunosuppression is crucial during this critical period since lower tacrolimus exposure at approximately one week post-kidney transplantation has been associated with subsequently higher rates of acute rejection [Undre 1999, Borobia 2009, O’Seaghdha 2009, Richards 2014]. The very low dosage of 60 mg/day diltiazem affects tacrolimus exposure in CYP3A5 expressers and may reduce tacrolimus dosage requirement in CYP3A5 expressers to achieve the same exposure of the drug in nonexpressers during the first week after kidney transplantation. (less) affected
association (Mar 23, 2022)	no assertion criteria provided Method: clinical testing	refractory myasthenia gravis Affected status: yes Allele origin: inherited	Department of Neurology lab, Tongji Hospital, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology Accession: SCV002503584.1 First in ClinVar: May 16, 2022 Last updated: May 16, 2022	Publications: DOI: 10.1016/j.jneuroim.2021.577… DOI: 10.1016/j.jneuroim.2021.577571 DOI: 10.1111/ene.13652 DOI: 10.1111/ene.13652 Comment: Genetic polymorphisms of CYP3A5 influence the blood trough concentration and efficacy of tacrolimus for myasthenia gravis patients. CYP3A5 rs776746 were predictive factors for refractory myasthenia … (more) Genetic polymorphisms of CYP3A5 influence the blood trough concentration and efficacy of tacrolimus for myasthenia gravis patients. CYP3A5 rs776746 were predictive factors for refractory myasthenia gravis. (less) Age: 2-74 years Ethnicity/Population group: Chinese Geographic origin: Wuhan Comment on evidence: About 10 to 20% of myasthenia gravis patients are classified as refractory due to a suboptimal response or intolerance to conventional treatment (Schneider-Gold et al. … (more) About 10 to 20% of myasthenia gravis patients are classified as refractory due to a suboptimal response or intolerance to conventional treatment (Schneider-Gold et al. 2019; Tran et al., 2021). CYP3A5 rs776746 can be predictive factors for refractory myasthenia gravis. (less)
drug response (Dec 31, 2021)	no assertion criteria provided Method: research	Tacrolimus response Drug used for Tacrolimus exposure, Intra-patient variability Affected status: no Allele origin: germline	Pharmacy Practice Department, Chulalongkorn University Accession: SCV002506611.1 First in ClinVar: Nov 13, 2022 Last updated: Nov 13, 2022	Comments (2): Fluctuation of tacrolimus exposure in an individual transplant recipient has been recognized as a tool for identifying patients at risk of poor outcomes (Shuker 2016, … (more) Fluctuation of tacrolimus exposure in an individual transplant recipient has been recognized as a tool for identifying patients at risk of poor outcomes (Shuker 2016, Gonzales 2020). No evidence of impact of the CYP3A5 genetic polymorphisms on tacrolimus intra-patient variability of dose-adjusted trough concentrations during 6 to 12 months after kidney transplantation was determined. However, significant influence of the polymorphisms on tacrolimus exposure was found when comparing CYP3A5 expressers with nonexpressers at months 6, 9, and 12 after transplantation, with large effect. (less) no evidence of effect Sex: mixed

Comments (2):

The risk of immunological complications is generally highest during the early period after kidney transplantation. Adequate immunosuppression is crucial during this critical period since lower tacrolimus exposure at approximately one week post-kidney transplantation has been associated with subsequently higher rates of acute rejection [Undre 1999, Borobia 2009, O’Seaghdha 2009, Richards 2014]. The very low dosage of 60 mg/day diltiazem affects tacrolimus exposure in CYP3A5 expressers and may reduce tacrolimus dosage requirement in CYP3A5 expressers to achieve the same exposure of the drug in nonexpressers during the first week after kidney transplantation.

affected

Comments (2):

Fluctuation of tacrolimus exposure in an individual transplant recipient has been recognized as a tool for identifying patients at risk of poor outcomes (Shuker 2016, Gonzales 2020). No evidence of impact of the CYP3A5 genetic polymorphisms on tacrolimus intra-patient variability of dose-adjusted trough concentrations during 6 to 12 months after kidney transplantation was determined. However, significant influence of the polymorphisms on tacrolimus exposure was found when comparing CYP3A5 expressers with nonexpressers at months 6, 9, and 12 after transplantation, with large effect.

no evidence of effect

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.
effect on protein activity (VariO:0053)	Method not provided	Result not provided	Pharmacy Department, Siriraj Hospital, Mahidol University Accession: SCV002500936.1
effect on protein activity (VariO:0053)	Method not provided	Result not provided	Pharmacy Practice Department, Chulalongkorn University Accession: SCV002506611.1

Comments (2):

affected

Comments (2):

no evidence of effect

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
CYP3A variation and the evolution of salt-sensitivity variants.	Thompson EE	American journal of human genetics	2004	PMID: 15492926
CYP3A5 genotype predicts renal CYP3A activity and blood pressure in healthy adults.	Givens RC	Journal of applied physiology (Bethesda, Md. : 1985)	2003	PMID: 12754175
Co-regulation of CYP3A4 and CYP3A5 and contribution to hepatic and intestinal midazolam metabolism.	Lin YS	Molecular pharmacology	2002	PMID: 12065767
The genetic determinants of the CYP3A5 polymorphism.	Hustert E	Pharmacogenetics	2001	PMID: 11740341
Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression.	Kuehl P	Nature genetics	2001	PMID: 11279519
-	-	-	-	DOI: 10.1016/j.jneuroim.2021.577571
-	-	-	-	DOI: 10.1111/ene.13652

Text-mined citations for rs776746 ...

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 Jul 23, 2024

ClinVar Genomic variation as it relates to human health

NM_000777.5(CYP3A5):c.219-237A>G

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs776746 ...