rs137852988

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PM5PP5_Very_Strong

The NM_022437.3(ABCG8):c.1720G>A(p.Gly574Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000101 in 1,613,554 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G574E) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000088 ( 0 hom. )

Consequence

ABCG8
NM_022437.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 9.60

Variant links:

Genes affected

ABCG8 (HGNC:13887): (ATP binding cassette subfamily G member 8) The protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the White subfamily. The protein encoded by this gene functions to exclude non-cholesterol sterol entry at the intestinal level, promote excretion of cholesterol and sterols into bile, and to facilitate transport of sterols back into the intestinal lumen. It is expressed in a tissue-specific manner in the liver, intestine, and gallbladder. This gene is tandemly arrayed on chromosome 2, in a head-to-head orientation with family member ABCG5. Mutations in this gene may contribute to sterol accumulation and atherosclerosis, and have been observed in patients with sitosterolemia. [provided by RefSeq, Jul 2008]

ABCG8 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM1

In a transmembrane_region Helical; Name=5 (size 20) in uniprot entity ABCG8_HUMAN there are 8 pathogenic changes around while only 1 benign (89%) in NM_022437.3

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.

PP5

Variant 2-43875377-G-A is Pathogenic according to our data. Variant chr2-43875377-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4968.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-43875377-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCG8	NM_022437.3 link	c.1720G>A	p.Gly574Arg	missense_variant	Exon 11 of 13	ENST00000272286.4	NP_071882.1	Q9H221-1
ABCG8	NM_001357321.2 link	c.1717G>A	p.Gly573Arg	missense_variant	Exon 11 of 13		NP_001344250.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCG8	ENST00000272286.4 link	c.1720G>A	p.Gly574Arg	missense_variant	Exon 11 of 13	1	NM_022437.3	ENSP00000272286.2		Q9H221-1

Frequencies

GnomAD3 genomes

AF:

0.000223

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.0274

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000638

AC:

AN:

250674

Hom.:

AF XY:

0.0000590

AC XY:

AN XY:

135584

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000971

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.0000883

AC:

129

AN:

1461336

Hom.:

Cov.:

AF XY:

0.0000867

AC XY:

AN XY:

726976

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.000162

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.0000926

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.000223

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000153

Hom.:

Bravo

AF:

0.000268

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000577

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Sitosterolemia 1

Pathogenic:3

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense variant p.G574R in ABCG8 (NM_022437.3) has been reported as a common variant in the Amish population (Horenstein RB et al,2013; Ruiz XD et al). The variant has been submitted to ClinVar as Pathogenic.The p.G574R variant is observed in 11/1,13,234 (0.0097%) alleles from individuals of European (Non-Finnish) background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.G574R missense variant is predicted to be damaging by both SIFT and PolyPhen2. The nucleotide c.1720 in ABCG8 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. The variant has been detected in a heterozygous state in her parents. -

May 10, 2023

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 01, 2005

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Sitosterolemia

Pathogenic:3

May 31, 2018

SIB Swiss Institute of Bioinformatics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

This variant is interpreted as a Likely Pathogenic, for Sitosterolemia, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS3 => Well-established functional studies show a deleterious effect (PMID:15054092). -

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been previously reported as a compound heterozygous change with a nonsense variant in one individual with Sitosterolemia and as homozygous change in several individuals with Sitosterolemia (PMID: 11264985, 12124998, 25073796, 15996216). Functional studies have shown that this variant is associated decreased protein maturation (PMID: 15054092). The c.1720G>A (p.Gly574Arg) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.006% (18/282058) and thus is presumed to be rare. The allele frequency in the Amish population is 1.5% (15/984), suggesting a founder effect (PMID: 23241408). The c.1720G>A (p.Gly574Arg) variant affects a moderately conserved amino acid and is predicted by multiple in silico tools to have a discordant effect on protein function. Based on the available evidence, the c.1720G>A (p.Gly574Arg) variant is classified as Pathogenic. -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ABCG8 c.1720G>A (p.Gly574Arg) variant has been found in a homozygous state in at least six individuals with sitosterolemia, five of whom are from the Amish population (Berge et al. 2000; Lee et al. 2001; Solca et al. 2005; Horenstein et al. 2013; Ruiz et al. 2015). Horenstein et al. (2013) determined that the carrier frequency for the p.Gly574Arg variant was 0.76% in the healthy Amish population and identified a statistically significant increase in plant sterol plasma levels in carriers compared to non-carriers. Control data are unavailable for this variant, which is reported at a frequency of 0.00009 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the evidence, the p.Gly574Arg variant is classified as likely pathogenic for sitosterolemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

not provided

Pathogenic:2

Jun 02, 2016

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 574 of the ABCG8 protein (p.Gly574Arg). This variant is present in population databases (rs137852988, gnomAD 0.01%). This missense change has been observed in individual(s) with sitosterolemia (PMID: 11099417, 12124998, 15996216, 25073796, 32088153, 34969652). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 4968). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ABCG8 protein function with a positive predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on ABCG8 function (PMID: 15054092). This variant disrupts the p.Gly574 amino acid residue in ABCG8. Other variant(s) that disrupt this residue have been observed in individuals with ABCG8-related conditions (PMID: 11452359), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

ABCG8-related disorder

Pathogenic:1

Mar 21, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ABCG8 c.1720G>A variant is predicted to result in the amino acid substitution p.Gly574Arg. This variant has been reported in patients with autosomal recessive sitosterolemia and is a frequent variant among the Amish population (Berge et al. 2000. PubMed ID: 11099417; Heimerl et al. 2002. PubMed ID: 12124998; Horenstein et al. 2013. PubMed ID: 23241408). Carriers of variants in ABCG8 are reported to have elevated levels of plant sterols and hypercholesterolemia (Horenstein et al. 2013. PubMed ID: 23241408; Berge et al. 2000. PubMed ID: 11099417). Hemolytic anemia, stomatocyte formation, and macrothrombocytopenia are common hematologic findings in patients with sitosterolemia (Wang et al. 2014. PubMed ID: 24166850; Escolá-Gil et al. 2014. PubMed ID: 24821603). This variant is reported in 0.0093% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as likely pathogenic. -

Cardiovascular phenotype

Pathogenic:1

Oct 05, 2020

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G574R pathogenic mutation (also known as c.1720G>A), located in coding exon 11 of the ABCG8 gene, results from a G to A substitution at nucleotide position 1720. The glycine at codon 574 is replaced by arginine, an amino acid with dissimilar properties. This mutation has been reported in several homozygous sitosterolemia cases and has been described as an Amish founder mutation (Kwiterovich PO et al. Lancet, 1981 Feb;1:466-9; Berge KE et al. Science, 2000 Dec;290:1771-5; Heimerl S et al. Hum. Mutat., 2002 Aug;20:151; Solcà C et al. Clin. Genet., 2005 Aug;68:174-8; Horenstein RB et al, 2013 Feb;33:413-9). One in vitro study indicates that this alteration may impact protein function (Graf GA et al. J. Biol. Chem., 2004 Jun;279:24881-8). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Thonghin N et al, 2018 12;18:17). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Pathogenic

0.19

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.86

D;D

Eigen

Benign

0.10

Eigen_PC

Benign

-0.066

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.94

.;D

M_CAP

Uncertain

0.17

MetaRNN

Uncertain

0.49

T;T

MetaSVM

Uncertain

0.030

MutationAssessor

Uncertain

2.2

M;M

PrimateAI

Uncertain

0.53

PROVEAN

Pathogenic

-5.0

.;D

REVEL

Uncertain

0.49

Sift

Uncertain

0.0050

.;D

Sift4G

Uncertain

0.010

.;D

Polyphen

1.0

D;D

Vest4

0.94

MutPred

0.98

Gain of methylation at G574 (P = 0.0162);Gain of methylation at G574 (P = 0.0162);

MVP

0.78

MPC

0.12

ClinPred

0.90

GERP RS

2.8

Varity_R

0.98

gMVP

0.97

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over