NM_022436.3:c.593G>A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_022436.3(ABCG5):c.593G>A(p.Arg198Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00136 in 1,614,134 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0014 ( 3 hom. )

Consequence

ABCG5
NM_022436.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11B:3

Conservation

PhyloP100: 7.30

Publications

15 publications found

Variant links:

Genes affected

ABCG5 (HGNC:13886): (ATP binding cassette subfamily G member 5) 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 as a half-transporter to limit intestinal absorption and promote biliary excretion of sterols. It is expressed in a tissue-specific manner in the liver, colon, and intestine. This gene is tandemly arrayed on chromosome 2, in a head-to-head orientation with family member ABCG8. Mutations in this gene may contribute to sterol accumulation and atheroschlerosis, and have been observed in patients with sitosterolemia. [provided by RefSeq, Jul 2008]

ABCG5 links:

DYNC2LI1 (HGNC:24595): (dynein cytoplasmic 2 light intermediate chain 1) This gene encodes a protein that is a component of the dynein-2 microtubule motor protein complex that plays a role in the retrograde transport of cargo in primary cilia via the intraflagellar transport system. This gene is ubiquitously expressed and its protein, which localizes to the axoneme and Golgi apparatus, interacts directly with the cytoplasmic dynein 2 heavy chain 1 protein to form part of the multi-protein dynein-2 complex. Mutations in this gene produce defects in the dynein-2 complex which result in several types of ciliopathy including short-rib thoracic dysplasia 15 with polydactyly (SRTD15). Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Feb 2017]

DYNC2LI1 Gene-Disease associations (from GenCC):

short-rib thoracic dysplasia 15 with polydactyly
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
Ellis-van Creveld syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Jeune syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

DYNC2LI1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.11279681).

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCG5	NM_022436.3 link	c.593G>A	p.Arg198Gln	missense_variant	Exon 5 of 13	ENST00000405322.8	NP_071881.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
ABCG5	ENST00000405322.8 link	c.593G>A	p.Arg198Gln	missense_variant	Exon 5 of 13	1	NM_022436.3	ENSP00000384513.2
ABCG5	ENST00000486512.5 link	n.1598G>A		non_coding_transcript_exon_variant	Exon 4 of 9	1
ABCG5	ENST00000409962.1 link	n.1360G>A		non_coding_transcript_exon_variant	Exon 4 of 9	2
ABCG5	ENST00000644754.1 link	n.1247G>A		non_coding_transcript_exon_variant	Exon 4 of 10

Frequencies

GnomAD3 genomes

AF:

0.00106

AC:

162

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00170

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00182

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.00124

AC:

312

AN:

251200

AF XY:

0.00131

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.000521

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00171

Gnomad NFE exome

AF:

0.00217

Gnomad OTH exome

AF:

0.00130

GnomAD4 exome

AF:

0.00140

AC:

2040

AN:

1461834

Hom.:

Cov.:

AF XY:

0.00144

AC XY:

1048

AN XY:

727222

show subpopulations

African (AFR)

AF:

0.000209

AC:

AN:

33480

American (AMR)

AF:

0.000492

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0000765

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000104

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00144

AC:

AN:

53370

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00165

AC:

1837

AN:

1112006

Other (OTH)

AF:

0.00137

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

125

249

374

498

623

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

180

240

300

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00106

AC:

162

AN:

152300

Hom.:

Cov.:

AF XY:

0.00105

AC XY:

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.000241

AC:

AN:

41564

American (AMR)

AF:

0.000392

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00170

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00182

AC:

124

AN:

68026

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000966

Hom.:

Bravo

AF:

0.000907

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00163

AC:

ExAC

AF:

0.00143

AC:

174

EpiCase

AF:

0.00169

EpiControl

AF:

0.00196

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:11Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:5Benign:1

Jun 15, 2018

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 24, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PP3 -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 24, 2018

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The R198Q variant in the ABCG5 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The R198Q variant is observed in 276/126,586 (0.2%) alleles from individuals of non-Finnish European background in large population cohorts, and no individuals were reported to be homozygous (Lek et al., 2016). The R198Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret R198Q as a variant of uncertain significance. -

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ABCG5: BS2 -

not specified

Uncertain:2

Jun 19, 2017

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 16, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: ABCG5 c.593G>A (p.Arg198Gln) results in a conservative amino acid change located in the ABC transporter-like, ATP-binding domain (IPR003439) of the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 0.0012 in 251200 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ABCG5 causing Early Onset Coronary Artery Disease (0.0012 vs 0.005), allowing no conclusion about variant significance. c.593G>A has been reported in individuals affected with Hypercholesterolemias and Sitosterolemia (Lamiquiz-Moneo_2017, Dron_2020, Dong_2022,Toton-Zuranska_2023), without strong evidence for causality. 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: 35460704, 32041611, 29066094, 36648309). ClinVar contains an entry for this variant (Variation ID: 284636). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Sitosterolemia

Uncertain:1Benign:1

May 28, 2019

Mendelics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sitosterolemia 1

Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Sitosterolemia 2

Uncertain:1

Sep 26, 2023

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Uncertain:1

May 25, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R198Q variant (also known as c.593G>A), located in coding exon 5 of the ABCG5 gene, results from a G to A substitution at nucleotide position 593. The arginine at codon 198 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported as heterozygous in familial hypercholesterolemia cohorts (Lamiquiz-Moneo I et al. J Clin Lipidol, 2017 Oct;11:1432-1440.e4; Pillai KKB et al. Clin Chim Acta, 2022 Feb;527:47-55; Rutkowska L et al. Genes (Basel), 2022 Jun;13:[ePub ahead of print]). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

ABCG5-related disorder

Benign:1

Sep 19, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.064

BayesDel_noAF

Uncertain

0.13

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.69

D;D

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

.;D

M_CAP

Uncertain

0.23

MetaRNN

Benign

0.11

T;T

MetaSVM

Uncertain

0.76

MutationAssessor

Benign

1.2

L;L

PhyloP100

7.3

PrimateAI

Uncertain

0.49

PROVEAN

Uncertain

-3.2

D;.

REVEL

Pathogenic

0.78

Sift

Uncertain

0.010

D;.

Sift4G

Benign

0.36

T;.

Polyphen

1.0

D;D

Vest4

0.86

MVP

0.94

MPC

0.44

ClinPred

0.34

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.73

gMVP

0.83

Mutation Taster

=65/35

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over