VCV000014910.4 - ClinVar

HLA-B*57:01

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.

(3)

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.

Pathogenic/Likely risk allele; risk factor

no assertion criteria provided

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

HLA-B*57:01

Variation ID: 14910 Accession: VCV000014910.4

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 6p21.33 6: 31464003 (GRCh38) [ NCBI UCSC ] 6: 31431780 (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 28, 2017	Aug 30, 2023	Jul 28, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NR_040662.1:n.733T>G		non-coding transcript variant
NC_000006.12:g.31464003T>G
NC_000006.11:g.31431780T>G

Protein change

Other names

Canonical SPDI

NC_000006.12:31464002:T:G

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.

0.03335 (G)

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

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.02899

1000 Genomes Project 30x 0.03076

1000 Genomes Project 0.03335

The Genome Aggregation Database (gnomAD) 0.02358

Trans-Omics for Precision Medicine (TOPMed) 0.02388

The Genome Aggregation Database (gnomAD), exomes 0.02699

Exome Aggregation Consortium (ExAC) 0.02826

Links

Genetic Testing Registry (GTR): GTR000569522 Genetic Testing Registry (GTR): GTR000613302 OMIM: 142830.0003 dbSNP: rs2395029 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.
HCP5		-	-	GRCh38 GRCh38 GRCh38 GRCh38 GRCh37	-	12
HLA-B		-	-	GRCh38 GRCh38 GRCh38 GRCh38 GRCh38 GRCh38 GRCh37	37	49

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.
Drug-induced liver injury due to flucloxacillin	Pathogenic (1)	no assertion criteria provided	Jul 1, 2009	RCV000016043.26
Abacavir hypersensitivity	risk factor (1)	no assertion criteria provided	Jul 1, 2009	RCV000016042.3
Autism spectrum disorder	Likely risk allele (1)	no assertion criteria provided	Jul 28, 2023	RCV003313923.3

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 (Jul 01, 2009)	no assertion criteria provided Method: literature only	ABACAVIR HYPERSENSITIVITY, SUSCEPTIBILITY TO Affected status: not provided Allele origin: germline	OMIM Accession: SCV000036309.2 First in ClinVar: Apr 04, 2013 Last updated: Apr 28, 2017	Publications: PubMed (8) PubMed: 12462283‚ 15247624‚ 11888582‚ 11943262‚ 15247625‚ 15024131‚ 18256392‚ 19483685 Comment on evidence: Abacavir is an HIV reverse transcriptase inhibitor used in combination with other antivirals in the treatment of HIV infection. Its efficacy is equivalent to other … (more) Abacavir is an HIV reverse transcriptase inhibitor used in combination with other antivirals in the treatment of HIV infection. Its efficacy is equivalent to other HIV drugs, such as HIV protease inhibitors, and different combinations of drugs are used in clinical practice depending on patient response, side effects, and drug resistance profiles. Hypersensitivity reactions occur in approximately 5% of abacavir patients and are characterized by symptoms such as fever, rash, and acute respiratory symptoms, and can lead to potentially life-threatening hypotension if drug therapy is not discontinued (Clay, 2002). Veenstra (2004) noted that 2 studies had shown that patients with the HLA-B5701 genotype are at greater risk of a hypersensitivity reaction, with an odds ratio of 117 (95% CI = 29-481) in 1 study (Mallal et al., 2002) and 23.6 (95% CI = 8-70) in another (Hetherington et al., 2002). Hughes et al. (2004) presented a cost-effectiveness analysis of HLA-B5701 genotyping in preventing abacavir hypersensitivity. Martin et al. (2004) reported that the combination of HLA-B5701 and a haplotypic M493T polymorphism of HSP70-HOM (140559) is highly predictive of abacavir hypersensitivity. Mallal et al. (2008) found that HLA-B5701 screening reduced the risk of hypersensitivity reaction to abacavir used in the treatment of HIV infection. In a genomewide association study of 51 patients with flucloxacillin-induced liver injury and 282 controls, Daly et al. (2009) found an association with rs2395029 in the MHC region (p = 8.7 x 10(-33)). The SNP is in complete linkage disequilibrium with HLA-B5701. Further MHC genotyping of 64 flucloxacillin-tolerant controls confirmed the association with HLA-B5701 (odds ratio of 80.6; p = 9.0 x 10(-19)). The association was replicated in a second cohort of 23 patients. In HLA-B*5701 carriers, rs10937275 in the ST6GAL1 (109675) gene on chromosome 3q also showed genomewide significance (odds ratio of 4.1; p = 1.4 x 10(-8)). (less)
Pathogenic (Jul 01, 2009)	no assertion criteria provided Method: literature only	DRUG-INDUCED LIVER INJURY DUE TO FLUCLOXACILLIN Affected status: not provided Allele origin: germline	OMIM Accession: SCV000036310.2 First in ClinVar: Apr 04, 2013 Last updated: Apr 28, 2017	Publications: PubMed (8) PubMed: 12462283‚ 15247624‚ 11888582‚ 11943262‚ 15247625‚ 15024131‚ 18256392‚ 19483685 Comment on evidence: Abacavir is an HIV reverse transcriptase inhibitor used in combination with other antivirals in the treatment of HIV infection. Its efficacy is equivalent to other … (more) Abacavir is an HIV reverse transcriptase inhibitor used in combination with other antivirals in the treatment of HIV infection. Its efficacy is equivalent to other HIV drugs, such as HIV protease inhibitors, and different combinations of drugs are used in clinical practice depending on patient response, side effects, and drug resistance profiles. Hypersensitivity reactions occur in approximately 5% of abacavir patients and are characterized by symptoms such as fever, rash, and acute respiratory symptoms, and can lead to potentially life-threatening hypotension if drug therapy is not discontinued (Clay, 2002). Veenstra (2004) noted that 2 studies had shown that patients with the HLA-B5701 genotype are at greater risk of a hypersensitivity reaction, with an odds ratio of 117 (95% CI = 29-481) in 1 study (Mallal et al., 2002) and 23.6 (95% CI = 8-70) in another (Hetherington et al., 2002). Hughes et al. (2004) presented a cost-effectiveness analysis of HLA-B5701 genotyping in preventing abacavir hypersensitivity. Martin et al. (2004) reported that the combination of HLA-B5701 and a haplotypic M493T polymorphism of HSP70-HOM (140559) is highly predictive of abacavir hypersensitivity. Mallal et al. (2008) found that HLA-B5701 screening reduced the risk of hypersensitivity reaction to abacavir used in the treatment of HIV infection. In a genomewide association study of 51 patients with flucloxacillin-induced liver injury and 282 controls, Daly et al. (2009) found an association with rs2395029 in the MHC region (p = 8.7 x 10(-33)). The SNP is in complete linkage disequilibrium with HLA-B5701. Further MHC genotyping of 64 flucloxacillin-tolerant controls confirmed the association with HLA-B5701 (odds ratio of 80.6; p = 9.0 x 10(-19)). The association was replicated in a second cohort of 23 patients. In HLA-B*5701 carriers, rs10937275 in the ST6GAL1 (109675) gene on chromosome 3q also showed genomewide significance (odds ratio of 4.1; p = 1.4 x 10(-8)). (less)
Likely risk allele (Jul 28, 2023)	no assertion criteria provided Method: clinical testing	Autism spectrum disorder Affected status: yes Allele origin: unknown	Gene Friend Way, National Innovation Center Accession: SCV004013899.2 First in ClinVar: Jul 22, 2023 Last updated: Aug 30, 2023	Comment: A mutation in HLA complex P5. Many recent studies have shown that HCP5 SNP sequences are strongly associated with various chronic and infectious diseases. Several … (more) A mutation in HLA complex P5. Many recent studies have shown that HCP5 SNP sequences are strongly associated with various chronic and infectious diseases. Several alleles of HLA genes has been reported to be associated with autism, intellectual disability, schizophrenia (PMID: 30976114). rs2395029 is in complete linkage disequilibrium with HLA-B*5701 (PMID: 31421661), which is a risk allele of intellectual disability (PMID: 30976114). (less) Number of individuals with the variant: 14 Method: 800K direct targets snp array, validated with Sanger sequencing

Comment:

A mutation in HLA complex P5. Many recent studies have shown that HCP5 SNP sequences are strongly associated with various chronic and infectious diseases. Several alleles of HLA genes has been reported to be associated with autism, intellectual disability, schizophrenia (PMID: 30976114). rs2395029 is in complete linkage disequilibrium with HLA-B*5701 (PMID: 31421661), which is a risk allele of intellectual disability (PMID: 30976114).

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.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
HLA-B*5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin.	Daly AK	Nature genetics	2009	PMID: 19483685
HLA-B*5701 screening for hypersensitivity to abacavir.	Mallal S	The New England journal of medicine	2008	PMID: 18256392
Cost-effectiveness analysis of HLA B*5701 genotyping in preventing abacavir hypersensitivity.	Hughes DA	Pharmacogenetics	2004	PMID: 15247625
Bringing genomics to the bedside: a cost-effective pharmacogenomic test?	Veenstra DL	Pharmacogenetics	2004	PMID: 15247624
Predisposition to abacavir hypersensitivity conferred by HLA-B*5701 and a haplotypic Hsp70-Hom variant.	Martin AM	Proceedings of the National Academy of Sciences of the United States of America	2004	PMID: 15024131
The abacavir hypersensitivity reaction: a review.	Clay PG	Clinical therapeutics	2002	PMID: 12462283
Genetic variations in HLA-B region and hypersensitivity reactions to abacavir.	Hetherington S	Lancet (London, England)	2002	PMID: 11943262
Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir.	Mallal S	Lancet (London, England)	2002	PMID: 11888582
DailyMed Drug Label, ABACAVIR SULFATE, 2022	-	-	-	-

Text-mined citations for rs2395029 ...

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 19, 2024

ClinVar Genomic variation as it relates to human health

HLA-B*57:01

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs2395029 ...