rs7412

Variant names:

• chr19-44908822-C-T
• rs7412
• NM_000041.4:c.526C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 3P and 12B. PM1 PP2 BP4_Strong BA1

The NM_000041.4(APOE):​c.526C>T​(p.Arg176Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0742 in 1,540,810 control chromosomes in the GnomAD database, including 4,609 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★).

• Frequency:
  • Genomes: 𝑓 0.078 (546 hom., cov: 32)
  • Exomes 𝑓: 0.074 (4063 hom.)
• Consequence: APOE NM_000041.4 missense
• Clinical Significance: drug response reviewed by expert panel P:1 U:1 B:4 O:4
• Conservation: PhyloP100: 0.906

Genes affected

APOE (HGNC:613): (apolipoprotein E) The protein encoded by this gene is a major apoprotein of the chylomicron. It binds to a specific liver and peripheral cell receptor, and is essential for the normal catabolism of triglyceride-rich lipoprotein constituents. This gene maps to chromosome 19 in a cluster with the related apolipoprotein C1 and C2 genes. Mutations in this gene result in familial dysbetalipoproteinemia, or type III hyperlipoproteinemia (HLP III), in which increased plasma cholesterol and triglycerides are the consequence of impaired clearance of chylomicron and VLDL remnants. [provided by RefSeq, Jun 2016]

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• PM1: In a helix (size 31) in uniprot entity APOE_HUMAN there are 17 pathogenic changes around while only 2 benign (89%) in NM_000041.4
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 16 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 0.74028 (below the threshold of 3.09). Trascript score misZ: -1.1391 (below the threshold of 3.09). GenCC associations: The gene is linked to hyperlipoproteinemia type 3, lipoprotein glomerulopathy, sea-blue histiocyte syndrome, Alzheimer disease 2.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0021114647).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.102 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOE	NM_000041.4	c.526C>T	p.Arg176Cys	missense_variant	Exon 4 of 4	ENST00000252486.9	NP_000032.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APOE	ENST00000252486.9	c.526C>T	p.Arg176Cys	missense_variant	Exon 4 of 4	1	NM_000041.4	ENSP00000252486.3
APOE	ENST00000425718.1	c.526C>T	p.Arg176Cys	missense_variant	Exon 3 of 3	1		ENSP00000410423.1
APOE	ENST00000434152.5	c.604C>T	p.Arg202Cys	missense_variant	Exon 4 of 4	2		ENSP00000413653.2
APOE	ENST00000446996.5	c.526C>T	p.Arg176Cys	missense_variant	Exon 4 of 4	2		ENSP00000413135.1

Frequencies

GnomAD3 genomes AF: 0.0779 AC: 11838 AN: 152004 Hom.: 546 Cov.: 32

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.0419

Gnomad ASJ AF: 0.0695

Gnomad EAS AF: 0.0803

Gnomad SAS AF: 0.0368

Gnomad FIN AF: 0.0419

Gnomad MID AF: 0.0446

Gnomad NFE AF: 0.0795

Gnomad OTH AF: 0.0761

GnomAD2 exomes AF: 0.0615 AC: 8425 AN: 136984 AF XY: 0.0613

Gnomad AFR exome AF: 0.108

Gnomad AMR exome AF: 0.0312

Gnomad ASJ exome AF: 0.0797

Gnomad EAS exome AF: 0.0742

Gnomad FIN exome AF: 0.0454

Gnomad NFE exome AF: 0.0751

Gnomad OTH exome AF: 0.0608

GnomAD4 exome AF: 0.0738 AC: 102550 AN: 1388698 Hom.: 4063 Cov.: 34 AF XY: 0.0726 AC XY: 49779 AN XY: 685974

Gnomad4 AFR exome AF: 0.107 AC: 3392 AN: 31704

Gnomad4 AMR exome AF: 0.0319 AC: 1151 AN: 36044

Gnomad4 ASJ exome AF: 0.0748 AC: 1873 AN: 25038

Gnomad4 EAS exome AF: 0.0577 AC: 2080 AN: 36054

Gnomad4 SAS exome AF: 0.0419 AC: 3331 AN: 79482

Gnomad4 FIN exome AF: 0.0499 AC: 1873 AN: 37554

Gnomad4 NFE exome AF: 0.0782 AC: 84522 AN: 1080474

Gnomad4 Remaining exome AF: 0.0703 AC: 4058 AN: 57756

GnomAD4 genome AF: 0.0778 AC: 11840 AN: 152112 Hom.: 546 Cov.: 32 AF XY: 0.0745 AC XY: 5538 AN XY: 74372

Gnomad4 AFR AF: 0.104 AC: 0.104456 AN: 0.104456

Gnomad4 AMR AF: 0.0419 AC: 0.0418793 AN: 0.0418793

Gnomad4 ASJ AF: 0.0695 AC: 0.0694524 AN: 0.0694524

Gnomad4 EAS AF: 0.0801 AC: 0.0801394 AN: 0.0801394

Gnomad4 SAS AF: 0.0373 AC: 0.0372517 AN: 0.0372517

Gnomad4 FIN AF: 0.0419 AC: 0.0418715 AN: 0.0418715

Gnomad4 NFE AF: 0.0794 AC: 0.0794307 AN: 0.0794307

Gnomad4 OTH AF: 0.0772 AC: 0.077178 AN: 0.077178

Alfa AF: 0.0797 Hom.: 1660

Bravo AF: 0.0781

TwinsUK AF: 0.0917 AC: 340

ALSPAC AF: 0.0924 AC: 356

ESP6500AA AF: 0.0867 AC: 271

ESP6500EA AF: 0.0562 AC: 356

ExAC AF: 0.0360 AC: 3513

Asia WGS AF: 0.0820 AC: 285 AN: 3460

ClinVar

Significance: drug response

Submissions summary: Pathogenic:1 Uncertain:1 Benign:4 Other:4

Revision: reviewed by expert panel

Submissions by phenotype

not provided Uncertain:1 Benign:2 Other:2

Aug 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

APOE: PM5, BS1, BS2 -

Feb 11, 2016

Eurofins Ntd Llc (ga)

Significance: other

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles).

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The APOE p.Arg176Cys variant, also known as the APOE ε2 allele, was identified in dbSNP (ID: rs7412), ClinVar (reported by EGL Genetics in relation to drug metabolism), Clinvitae, MutDB and LOVD 3.0. The variant was identified in control databases in 10996 of 168078 chromosomes (465 homozygous) at a frequency of 0.065422 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1632 of 15264 chromosomes (freq: 0.1069), Ashkenazi Jewish in 664 of 8410 chromosomes (freq: 0.07895), European (non-Finnish) in 5202 of 67810 chromosomes (freq: 0.07671), East Asian in 947 of 12608 chromosomes (freq: 0.07511), Other in 328 of 5174 chromosomes (freq: 0.06339), European (Finnish) in 472 of 10686 chromosomes (freq: 0.04417), South Asian in 947 of 22604 chromosomes (freq: 0.0419), and Latino in 804 of 25522 chromosomes (freq: 0.0315). Homozygous individuals with the APOE ε2 genotype are at a higher risk of developing type III hyperlipoproteinemia and mouse models with the APOE ε2 genotype develop a clear type III hyperlipoproteinemia phenotype (Breslow_1982_PMID: 7175379; Sullivan_1998_PMID: 9649566). However, this variant does not show full penetrance for type III hyperlipoproteinemia and other variants in conjunction with the APOE ε2 genotype have been suggested to contribute to the phenotype (Sakuma_2014_PMID: 24953047). Another study found that carriers of the APOE ε2 allele had lower baseline LDL cholesterol levels as well as a greater reduction of LDL-C from atorvastatin and pravastatin treatment compared to APOE ε4 carriers, implicating this variant as a pharmacogenetic variant (Meg_2009_PMID: 19667110). The p.Arg176 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, and BLOSUM) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

-

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: risk factor

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial type 3 hyperlipoproteinemia Pathogenic:1

Oct 01, 2005

OMIM

Significance: Pathogenic

Review Status: flagged submission

Collection Method: literature only

- -

not specified Benign:1

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hypercholesterolemia Benign:1

Jan 01, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

atorvastatin response - Efficacy Other:1

Mar 24, 2021

PharmGKB

Significance: drug response

Review Status: reviewed by expert panel

Collection Method: curation

PharmGKB Level of Evidence 2B: Variants in Level 2B clinical annotations are not in PharmGKB’s Tier 1 VIPs. These clinical annotations describe variant-drug combinations with a moderate level of evidence supporting the association. For example, the association may be found in multiple cohorts, but there may be a minority of studies that do not support the majority assertion. Level 2B clinical annotations must be supported by at least two independent publications. Drug-variant association: Efficacy

Warfarin response Other:1

Aug 31, 2010

Pharmacogenomics Lab, Chungbuk National University

Significance: drug response

Review Status: no assertion criteria provided

Collection Method: research

- likely responsive

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D;T;.;.
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Benign	0.39	N
LIST_S2	Uncertain	0.93	D;D;D;D
MetaRNN	Benign	0.0021	T;T;T;T
MetaSVM	Benign	-0.60	T
MutationAssessor	Uncertain	2.3	M;.;.;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.9	D;D;.;D
REVEL	Uncertain	0.59
Sift	Uncertain	0.012	D;D;.;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.28
MPC		1.9
ClinPred		0.031	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.45
gMVP		0.61
Mutation Taster		=43/57	polymorphism (auto)

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: rs7412; hg19: chr19-45412079; COSMIC: COSV52986153; COSMIC: COSV52986153;