VCV000502765.37 - ClinVar

NM_022436.3(ABCG5):c.1567A>G (p.Ile523Val)

Germline

Classification

criteria provided, conflicting classifications. Learn more about how ClinVar calculates review status.

Conflicting classifications of pathogenicity
Uncertain significance(2); Benign(2); Likely benign(4)

8 out of 11 submissions contributed to this 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.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_022436.3(ABCG5):c.1567A>G (p.Ile523Val)

Variation ID: 502765 Accession: VCV000502765.37

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2p21 2: 43819997 (GRCh38) [ NCBI UCSC ] 2: 44047136 (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 2, 2018	Apr 13, 2025	Feb 2, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_022436.3:c.1567A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_071881.1:p.Ile523Val	missense
NM_001348912.2:c.*16-7389T>C		intron variant
NM_001348913.2:c.*16-7389T>C		intron variant
NC_000002.12:g.43819997T>C
NC_000002.11:g.44047136T>C
NG_008883.1:g.23823A>G
NG_053008.1:g.50959T>C
LRG_1181:g.23823A>G
LRG_1181t1:c.1567A>G	LRG_1181p1:p.Ile523Val

... more HGVS ... less HGVS

Protein change

I523V

Other names

Canonical SPDI

NC_000002.12:43819996:T: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.

0.00040 (C)

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

1000 Genomes Project 30x 0.00062

The Genome Aggregation Database (gnomAD), exomes 0.00170

Exome Aggregation Consortium (ExAC) 0.00169

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00185

The Genome Aggregation Database (gnomAD) 0.00189

1000 Genomes Project 0.00040

Trans-Omics for Precision Medicine (TOPMed) 0.00124

Links

ClinGen: CA1636229 dbSNP: rs140899003 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	206	817
DYNC2LI1		-	-	GRCh38 GRCh37	186	750

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.
not specified	Conflicting classifications of pathogenicity (4)	criteria provided, conflicting classifications	May 7, 2024	RCV000595235.18
ABCG5-related disorder	Likely benign (1)	no assertion criteria provided	May 7, 2019	RCV003915740.2
Sitosterolemia 1	Uncertain significance (1)	criteria provided, single submitter	Apr 27, 2017	RCV001143372.12
Sitosterolemia	Benign (1)	criteria provided, single submitter	Feb 2, 2025	RCV001521409.16
Cardiovascular phenotype	Benign (1)	criteria provided, single submitter	Jul 12, 2019	RCV002404614.9
not provided	Likely benign (3)	criteria provided, multiple submitters, no conflicts	Oct 1, 2023	RCV001584407.23

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.
Uncertain significance (Apr 27, 2017) C Contributing to aggregate classification	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: SCV001303893.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Publications: PubMed (1) PubMed: 11668628 Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
Likely benign (Jul 30, 2020) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001812304.1 First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021	Comment: This variant is associated with the following publications: (PMID: 24503134)
Likely benign (Jun 17, 2021) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: no Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV002070903.1 First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022
Benign (Jul 12, 2019) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002707232.2 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)
Uncertain significance (May 07, 2024) C Contributing to aggregate classification	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: SCV005185385.1 First in ClinVar: Aug 11, 2024 Last updated: Aug 11, 2024	Publications: PubMed (2) PubMed: 24503134‚ 32088153 Comment: Variant summary: ABCG5 c.1567A>G (p.Ile523Val) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign … (more) Variant summary: ABCG5 c.1567A>G (p.Ile523Val) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0019 in 1614184 control chromosomes in the gnomAD database, including 10 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in ABCG5 causing Early Onset Coronary Artery Disease (0.0019 vs 0.005), allowing no conclusion about variant significance. c.1567A>G has been reported in the literaturein at-least one patient suspected of partial lipodystrophy without strong evidence for causality (example: Johansen_2014). These report(s) do not provide unequivocal conclusions about association of the variant with Early Onset Coronary Artery Disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 24503134, 32088153). ClinVar contains an entry for this variant (Variation ID: 502765). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. (less)
Benign (Feb 02, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Sitosterolemia Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001730749.5 First in ClinVar: Jun 15, 2021 Last updated: Feb 25, 2025
Likely benign (Oct 01, 2023) C Contributing to aggregate classification	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV004146001.12 First in ClinVar: Nov 20, 2023 Last updated: Mar 22, 2025	Comment: ABCG5: BP4, BS2 Number of individuals with the variant: 3
Likely benign (Jun 29, 2017) C Contributing to aggregate classification	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000709628.3 First in ClinVar: Apr 02, 2018 Last updated: Apr 13, 2025	Publications: PubMed (1) PubMed: 24503134 Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ABCG5 Number of individuals with the variant: 2 Zygosity: Single Heterozygote Sex: mixed
Likely benign (-) N Not contributing to aggregate classification	no assertion criteria provided Method: clinical testing	not provided 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: SCV001931328.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Benign (-) N Not contributing to aggregate classification	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: SCV001978780.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021
Likely benign (May 07, 2019) N Not contributing to aggregate classification	no assertion criteria provided Method: clinical testing	ABCG5-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004729677.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: This variant is classified as likely 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 variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

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:

Variant summary: ABCG5 c.1567A>G (p.Ile523Val) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0019 in 1614184 control chromosomes in the gnomAD database, including 10 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in ABCG5 causing Early Onset Coronary Artery Disease (0.0019 vs 0.005), allowing no conclusion about variant significance. c.1567A>G has been reported in the literaturein at-least one patient suspected of partial lipodystrophy without strong evidence for causality (example: Johansen_2014). These report(s) do not provide unequivocal conclusions about association of the variant with Early Onset Coronary Artery Disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 24503134, 32088153). ClinVar contains an entry for this variant (Variation ID: 502765). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

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
ABCG5 and ABCG8 genetic variants in familial hypercholesterolemia.	Reeskamp LF	Journal of clinical lipidology	2020	PMID: 32088153
LipidSeq: a next-generation clinical resequencing panel for monogenic dyslipidemias.	Johansen CT	Journal of lipid research	2014	PMID: 24503134
Mutations in ATP-cassette binding proteins G5 (ABCG5) and G8 (ABCG8) causing sitosterolemia.	Hubacek JA	Human mutation	2001	PMID: 11668628
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ABCG5	-	-	-	-

Text-mined citations for rs140899003 ...

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 Apr 13, 2025

ClinVar Genomic variation as it relates to human health

NM_022436.3(ABCG5):c.1567A>G (p.Ile523Val)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs140899003 ...