2-21011802-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:11
• Conservation: PhyloP100: 1.25

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1047526).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APOB	NM_000384.3	c.5066G>A	p.Arg1689His	missense_variant	26/29	ENST00000233242.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APOB	ENST00000233242.5	c.5066G>A	p.Arg1689His	missense_variant	26/29	1	NM_000384.3	P1
APOB	ENST00000673739.2	c.*4372G>A		3_prime_UTR_variant, NMD_transcript_variant	25/25

Frequencies

GnomAD3 genomes AF: 0.00136 AC: 207 AN: 152082 Hom.: 0 Cov.: 33

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

GnomAD3 exomes AF: 0.00128 AC: 322 AN: 251174 Hom.: 1 AF XY: 0.00128 AC XY: 174 AN XY: 135730

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 SAS exome AF: 0.000131

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.: 2 Cov.: 34 AF XY: 0.00173 AC XY: 1255 AN XY: 727232

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0000927

Gnomad4 FIN exome AF: 0.000768

Gnomad4 NFE exome AF: 0.00217

Gnomad4 OTH exome AF: 0.000960

GnomAD4 genome AF: 0.00136 AC: 207 AN: 152200 Hom.: 0 Cov.: 33 AF XY: 0.00117 AC XY: 87 AN XY: 74404

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000472

Gnomad4 NFE AF: 0.00268

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.00221 Hom.: 1

Bravo AF: 0.00116

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00291 AC: 25

ExAC AF: 0.00134 AC: 163

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00218

EpiControl AF: 0.00172

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:11

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 22, 2021	This variant is associated with the following publications: (PMID: 20657596, 27153395, 26036859, 26415676, 19602640, 30681615, 26582918) -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 10, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 27, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	APOB: BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 09, 2023	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 12, 2023	- -

Hypercholesterolemia, familial, 1 Uncertain:2 Benign:1

Likely benign, criteria provided, single submitter	research	Institute for Integrative and Experimental Genomics, University of Luebeck	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Robarts Research Institute, Western University	-	- -
Uncertain significance, criteria provided, single submitter	research	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	Mar 01, 2016	- -

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

Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	Apr 20, 2021	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. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 02, 2017	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). -
Likely benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Mar 12, 2019	- -

Familial hypobetalipoproteinemia 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Oct 03, 2018

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

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Oct 03, 2018

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

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 04, 2022

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

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 27, 2018

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

Likely benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

May 02, 2018

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	T
BayesDel_noAF	Benign	-0.38
Cadd	Pathogenic	26
Dann	Pathogenic	1.0
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Benign	0.66	D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.90	D
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.22
Sift	Uncertain	0.0030	D
Sift4G	Pathogenic	0.0	D
Vest4		0.72
MVP		0.70
MPC		0.29
ClinPred		0.068	T
GERP RS		6.0
gMVP		0.61

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

LitVar

Other links and lift over

dbSNP: rs151009667; hg19: chr2-21234674; COSMIC: COSV51927981;