VCV000004975.27 - ClinVar

NM_022437.3(ABCG8):c.55G>C (p.Asp19His)

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.

(14)

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.

Benign/Likely benign; association

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_022437.3(ABCG8):c.55G>C (p.Asp19His)

Variation ID: 4975 Accession: VCV000004975.27

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2p21 2: 43839108 (GRCh38) [ NCBI UCSC ] 2: 44066247 (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	Feb 13, 2015	Oct 8, 2024	Jan 31, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_022436.3:c.-429C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		genic upstream transcript variant
NM_022437.3:c.55G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_071882.1:p.Asp19His	missense
NM_001357321.2:c.55G>C	NP_001344250.1:p.Asp19His	missense
NC_000002.12:g.43839108G>C
NC_000002.11:g.44066247G>C
NG_008883.1:g.4712C>G
NG_008884.2:g.12167G>C
LRG_1181:g.4712C>G
LRG_1181t1:c.-429C>G
LRG_1182:g.12167G>C
LRG_1182t1:c.55G>C	LRG_1182p1:p.Asp19His
	Q9H221:p.Asp19His

... more HGVS ... less HGVS

Protein change

D19H

Other names

Canonical SPDI

NC_000002.12:43839107:G:C

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.

0.06050 (C)

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

Exome Aggregation Consortium (ExAC) 0.05616

1000 Genomes Project 0.06050

1000 Genomes Project 30x 0.06090

The Genome Aggregation Database (gnomAD) 0.06566

Trans-Omics for Precision Medicine (TOPMed) 0.06635

Links

ClinGen: CA117156 UniProtKB: Q9H221#VAR_012250 OMIM: 605460.0009 dbSNP: rs11887534 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.
ABCG5		-	-	GRCh38 GRCh37	193	784
ABCG8		-	-	GRCh38 GRCh37	767	838

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.
Gallbladder disease 4	Pathogenic (1)	no assertion criteria provided	Aug 1, 2007	RCV000005263.7
Sitosterolemia	Benign/Likely benign (2)	criteria provided, multiple submitters, no conflicts	May 28, 2019	RCV000269126.12
not specified	Benign/Likely benign (4)	criteria provided, multiple submitters, no conflicts	Jul 17, 2023	RCV000266053.7
Sitosterolemia 1	Benign (1)	criteria provided, single submitter	Mar 6, 2018	RCV001094725.7
not provided	Benign; association (3)	criteria provided, multiple submitters, no conflicts	Jan 31, 2024	RCV001705581.7
Cardiovascular phenotype	Benign (1)	criteria provided, single submitter	Dec 3, 2018	RCV002345232.4
Sitosterolemia 2	Likely benign (1)	criteria provided, single submitter	Sep 1, 2021	RCV002490320.3
ABCG8-related disorder	Benign (1)	no assertion criteria provided	Nov 15, 2023	RCV003982825.2

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.
Benign (Jul 05, 2018)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001841286.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021	Comment: This variant is associated with the following publications: (PMID: 29764733, 31327807, 30975109, 30036524, 11893785, 17632509, 20581104, 21039838, 22898925, 20163776, 20592455, 22675952, 20170916)
Likely benign (Sep 01, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Sitosterolemia 2 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002796617.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Likely benign (Jul 17, 2023)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV004029676.1 First in ClinVar: Aug 26, 2023 Last updated: Aug 26, 2023
association (Jan 31, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000949102.6 First in ClinVar: Aug 14, 2019 Last updated: Feb 20, 2024	Publications: PubMed (5) PubMed: 11893785‚ 17632509‚ 21039838‚ 21274884‚ 22898925 Comment: This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 19 of the ABCG8 protein … (more) This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 19 of the ABCG8 protein (p.Asp19His). This variant is present in population databases (rs11887534, gnomAD 10%), including at least one homozygous and/or hemizygous individual. Population-based case-control studies have shown that this variant is associated with reduced serum phytosterol levels and confers susceptibility to gallstone disease (PMID: 11893785, 17632509, 21039838, 21274884, 22898925). In a large meta-analysis with 4,381 cases and 3,765 controls (PMID: 22898925), individuals carrying this variant had an increased overall risk of gallstone disease (2.07, 95% CI: 1.65-2.60). ClinVar contains an entry for this variant (Variation ID: 4975). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense causes a gain of ABCG8 protein function in vitro, contrary to the loss of ABCG8 protein function associated with sitosterolemia (PMID: 22898925). In summary, this is a common variant that is associated with an increased risk for developing disease. For these reasons, this variant has been classified as an Increased Risk Allele. (less)
Benign (Dec 03, 2018)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002648864.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Comment: This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more) This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Likely benign (Jun 14, 2016)	criteria provided, single submitter (ICSL Variant Classification 20161018) Method: clinical testing	Sitosterolemia Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000430500.2 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016	Publications: PubMed (1) PubMed: 11893785
Benign (Mar 16, 2016)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000340356.4 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=ABCG8 Number of individuals with the variant: 2 Zygosity: Single Heterozygote Sex: mixed
Benign (May 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Sitosterolemia 1 Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001135671.1 First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020
Benign (Mar 06, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Sitosterolemia 1 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000483933.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005240549.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Pathogenic (Aug 01, 2007)	no assertion criteria provided Method: literature only	GALLBLADDER DISEASE 4 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000025441.3 First in ClinVar: Apr 04, 2013 Last updated: Sep 08, 2019	Publications: PubMed (1) PubMed: 17632509 Comment on evidence: Buch et al. (2007) identified a SNP (rs11887534) in the ABCG8 gene, a G-to-C transversion corresponding to an asp19-to-his (D19H) substitution, that was significantly associated … (more) Buch et al. (2007) identified a SNP (rs11887534) in the ABCG8 gene, a G-to-C transversion corresponding to an asp19-to-his (D19H) substitution, that was significantly associated with gallstones (GBD4; 611465) in 3 replication studies. In an initial genomewide screening panel among 280 affected individuals and 360 controls, the authors identified 235 significant SNPs, including D19H. A follow-up study in 1,105 additional affected individuals replicated the disease association of D19H (p = 4.1 x 10(-9), 1.1 x 10(-4) after Bonferroni correction). Additional significant replication was achieved in 728 Germans (p = 2.8 x 10(-7)). The overall odds ratio in the full German sample was 2.2 and 7.1 for heterozygous and homozygous H allele carriers, respectively, corresponding to a population risk of about 11%. The association was stronger in those with cholesterol gallstones, suggesting that his19 may be associated with increased efficiency of cholesterol transport into the bile lumen, causing cholesterol hypersaturation of bile and promoting the formation of gallstones. (less)
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001918137.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001929981.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021
Benign (Nov 15, 2023)	no assertion criteria provided Method: clinical testing	ABCG8-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004799801.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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Comment:

This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 19 of the ABCG8 protein (p.Asp19His). This variant is present in population databases (rs11887534, gnomAD 10%), including at least one homozygous and/or hemizygous individual. Population-based case-control studies have shown that this variant is associated with reduced serum phytosterol levels and confers susceptibility to gallstone disease (PMID: 11893785, 17632509, 21039838, 21274884, 22898925). In a large meta-analysis with 4,381 cases and 3,765 controls (PMID: 22898925), individuals carrying this variant had an increased overall risk of gallstone disease (2.07, 95% CI: 1.65-2.60). ClinVar contains an entry for this variant (Variation ID: 4975). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense causes a gain of ABCG8 protein function in vitro, contrary to the loss of ABCG8 protein function associated with sitosterolemia (PMID: 22898925). In summary, this is a common variant that is associated with an increased risk for developing disease. For these reasons, this variant has been classified as an Increased Risk Allele.

Comment:

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

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
Genetic and functional identification of the likely causative variant for cholesterol gallstone disease at the ABCG5/8 lithogenic locus.	von Kampen O	Hepatology (Baltimore, Md.)	2013	PMID: 22898925
Sterol transporter adenosine triphosphate-binding cassette transporter G8, gallstones, and biliary cancer in 62,000 individuals from the general population.	Stender S	Hepatology (Baltimore, Md.)	2011	PMID: 21274884
Role of ABCG8 D19H (rs11887534) variant in gallstone susceptibility in northern India.	Srivastava A	Journal of gastroenterology and hepatology	2010	PMID: 21039838
A genome-wide association scan identifies the hepatic cholesterol transporter ABCG8 as a susceptibility factor for human gallstone disease.	Buch S	Nature genetics	2007	PMID: 17632509
Heritability of plasma noncholesterol sterols and relationship to DNA sequence polymorphism in ABCG5 and ABCG8.	Berge KE	Journal of lipid research	2002	PMID: 11893785
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ABCG8	-	-	-	-

Text-mined citations for rs11887534 ...

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 Jan 13, 2025

ClinVar Genomic variation as it relates to human health

NM_022437.3(ABCG8):c.55G>C (p.Asp19His)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs11887534 ...