2-21011802-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_000384.3(APOB):c.5066G>A(p.Arg1689His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00171 in 1,614,062 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1689C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0014 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0017 ( 2 hom. )

Consequence

APOB
NM_000384.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:11

Conservation

PhyloP100: 1.25

Publications

17 publications found

Variant links:

Genes affected

APOB (HGNC:603): (apolipoprotein B) This gene product is the main apolipoprotein of chylomicrons and low density lipoproteins (LDL), and is the ligand for the LDL receptor. It occurs in plasma as two main isoforms, apoB-48 and apoB-100: the former is synthesized exclusively in the gut and the latter in the liver. The intestinal and the hepatic forms of apoB are encoded by a single gene from a single, very long mRNA. The two isoforms share a common N-terminal sequence. The shorter apoB-48 protein is produced after RNA editing of the apoB-100 transcript at residue 2180 (CAA->UAA), resulting in the creation of a stop codon, and early translation termination. Mutations in this gene or its regulatory region cause hypobetalipoproteinemia, normotriglyceridemic hypobetalipoproteinemia, and hypercholesterolemia due to ligand-defective apoB, diseases affecting plasma cholesterol and apoB levels. [provided by RefSeq, Dec 2019]

APOB Gene-Disease associations (from GenCC):

hypercholesterolemia, autosomal dominant, type B
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
familial hypobetalipoproteinemia 1
Inheritance: AR, AD, SD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen
homozygous familial hypercholesterolemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

APOB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.1047526).

BP6

Variant 2-21011802-C-T is Benign according to our data. Variant chr2-21011802-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 189304.

BS2

High Homozygotes in GnomAdExome4 at 2 AD,AR,SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOB	NM_000384.3 link	c.5066G>A	p.Arg1689His	missense_variant	Exon 26 of 29	ENST00000233242.5	NP_000375.3	P04114Q7Z7Q0Q59HB3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
APOB	ENST00000233242.5 link	c.5066G>A	p.Arg1689His	missense_variant	Exon 26 of 29	1	NM_000384.3	ENSP00000233242.1	P04114
APOB	ENST00000673739.2 link	n.*4372G>A		non_coding_transcript_exon_variant	Exon 25 of 25			ENSP00000501110.2	A0A669KB70
APOB	ENST00000673739.2 link	n.*4372G>A		3_prime_UTR_variant	Exon 25 of 25			ENSP00000501110.2	A0A669KB70

Frequencies

GnomAD3 genomes

AF:

0.00136

AC:

207

AN:

152082

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000472

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00268

Gnomad OTH

AF:

0.000957

GnomAD2 exomes

AF:

0.00128

AC:

322

AN:

251174

AF XY:

0.00128

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.000376

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.000740

Gnomad NFE exome

AF:

0.00245

Gnomad OTH exome

AF:

0.000653

GnomAD4 exome

AF:

0.00174

AC:

2546

AN:

1461862

Hom.:

Cov.:

AF XY:

0.00173

AC XY:

1255

AN XY:

727232

show subpopulations

African (AFR)

AF:

0.000299

AC:

AN:

33478

American (AMR)

AF:

0.000313

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.000151

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000927

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000768

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00217

AC:

2408

AN:

1111998

Other (OTH)

AF:

0.000960

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

178

356

533

711

889

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

180

270

360

450

<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:

0.00136

AC:

207

AN:

152200

Hom.:

Cov.:

AF XY:

0.00117

AC XY:

AN XY:

74404

show subpopulations

African (AFR)

AF:

0.000241

AC:

AN:

41538

American (AMR)

AF:

0.000523

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.000472

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00268

AC:

182

AN:

68002

Other (OTH)

AF:

0.000947

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

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:

0.00219

Hom.:

Bravo

AF:

0.00116

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00291

AC:

ExAC

AF:

0.00134

AC:

163

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00218

EpiControl

AF:

0.00172

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:11

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:3

Mar 19, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The APOB c.5066G>A; p.Arg1689His variant (rs151009667), also known as Arg1662His for legacy nomenclature, is reported in the literature in individuals with familial hypercholesterolemia (Johansen 2010, Radovica-Spalvina 2015), but is also reported to not segregate with disease in one study (Braenne 2016). However, this variant is reported to be positively associated with familial hypercholesterolemia in a Saudi population with an odds ratio of 45.07 (95% CI: 2.67-759.1; p=0.0001) and may be a risk factor (Batais 2019). The p.Arg1689His variant is reported in ClinVar (Variation ID: 189304). It is observed in the general population with an overall allele frequency of 0.1% (387/282574 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.222). Due to conflicting information, the significance of this variant is uncertain at this time. References: Batais MA et al. Screening of common genetic variants in the APOB gene related to familial hypercholesterolemia in a Saudi population: A case-control study. Medicine (Baltimore). 2019 Jan;98(4):e14247. PMID: 30681615. Braenne I et al. Systematic analysis of variants related to familial hypercholesterolemia in families with premature myocardial infarction. Eur J Hum Genet. 2016 Feb;24(2):191-7. PMID: 26036859. Johansen CT et al. Excess of rare variants in genes identified by genome-wide association study of hypertriglyceridemia. Nat Genet. 2010 Aug;42(8):684-7. PMID: 20657596. Radovica-Spalvina I et al. Next-generation-sequencing-based identification of familial hypercholesterolemia-related mutations in subjects with increased LDL-C levels in a latvian population. BMC Med Genet. 2015 Sep 28;16:86. PMID: 26415676. -

Apr 10, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 22, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 20657596, 27153395, 26036859, 26415676, 19602640, 30681615, 26582918) -

Dec 27, 2019

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 12, 2023

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

APOB: BP4 -

Hypercholesterolemia, familial, 1

Uncertain:2Benign:1

Mar 01, 2016

Laboratory of Genetics and Molecular Cardiology, University of São Paulo

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Robarts Research Institute, Western University

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Institute for Integrative and Experimental Genomics, University of Luebeck

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Hypercholesterolemia, autosomal dominant, type B;C4551990:Familial hypobetalipoproteinemia 1

Uncertain:1Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 20, 2021

New York Genome Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.5066G>A (p.Arg1689His) variant identified in the APOB gene substitutes a conserved Arginine for Histidine at amino acid 1689/4564 (exon 26/29). This variant is found in gnomAD(v3.1.1) (207 heterozygotes, 0 homozygotes; allele frequency: 1.36e-3), and there is one homozygote present in population data from gnomAD(v2.1.1) (387 heterozygotes, 1 homozygote; allele frequency: 1.37e-3). In silico algorithms predict this variant to be Damaging (SIFT; score:0.003) and Benign (REVEL; 0.222) to the function of the canonical transcript. This variant is reported as both a Variant of Uncertain Significance and Likely Benign in ClinVar (VarID:189304). This variant has been reported in several affected individuals in the literature [PMID: 20657596,26415676,26036859, 30681615], although it does not segregate with disease in some studies [PMID:26036859]. The p.Arg1689 residue is not within a mapped domain of APOB (UniProtKB:P04114). The c.5066G>A (p.Arg1689His) variant identified in the APOB gene is reported as a Variant of Uncertain Significance. -

not specified

Benign:2

Mar 12, 2019

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 02, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Arg1689His in exon 26 of APOB: This variant is not expected to have clinical significance because it was identified in 0.3% (342/126440) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs151009667). In addition, while it has been reported in 5 individuals with hypertriglyceridemia or a history of early myocardial infarction, it did not segregate with disease in 3 affected relatives from 3 families (Johansen 2010, Braenne 2015). This variant is reported in ClinVar (Variation ID:189304). ACMG/AMP Criteria applied: BS1, BS4 (Richards 2015). -

Familial hypobetalipoproteinemia 1

Uncertain:1

Oct 03, 2018

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. -

Hypercholesterolemia, autosomal dominant, type B

Benign:1

Oct 03, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

APOB-related disorder

Benign:1

Feb 04, 2022

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). -

Cardiovascular phenotype

Benign:1

Jul 27, 2018

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely 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. -

Familial hypercholesterolemia

Benign:1

May 02, 2018

Color Diagnostics, LLC DBA Color Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Likely Benign variant based on current evidence: This missense variant (also known as p.Arg1662His in the mature protein) is located in the beta 1 domain of the APOB protein. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. To our knowledge this variant has not been investigated for functional impact in experimental studies nor has the variant been reported in individuals affected with familial hypercholesterolemia in the literature. In a study of individuals affected with myocardial infarction, carrier status of this variant showed no correlation with cholesterol levels (PMID: 26036859). This variant has been identified in 342/126440 non-Finnish European chromosomes (0.27%) in the general population by the Genome Aggregation Database (gnomAD). This variant allele frequency is greater than expected for the disorder based on prevalence, penetrance, and genetic/allelic heterogeneity. Based on available evidence, this variant is classified as Likely Benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.38

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Benign

0.66

M_CAP

Benign

0.018

MetaRNN

Benign

0.10

MetaSVM

Benign

-1.0

PhyloP100

1.3

PrimateAI

Benign

0.37

PROVEAN

Uncertain

-3.1

REVEL

Benign

0.22

Sift

Uncertain

0.0030

Sift4G

Pathogenic

0.0

Vest4

0.72

MVP

0.70

MPC

0.29

ClinPred

0.068

GERP RS

6.0

gMVP

0.61

Mutation Taster

=90/10

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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