NM_000041.4:c.388T>C

Variant names:

• chr19-44908684-T-C
• rs429358
• NM_000041.4:c.388T>C

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.388T>C​(p.Cys130Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.149 in 1,567,892 control chromosomes in the GnomAD database, including 17,710 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity,other,risk factor (no stars).

• Frequency:
  • Genomes: 𝑓 0.16 (2010 hom., cov: 32)
  • Exomes 𝑓: 0.15 (15700 hom.)
• Consequence: APOE NM_000041.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity; other; risk factor criteria provided, conflicting classifications P:6 U:3 B:1 O:4
• Conservation: PhyloP100: 0.840
• Publications: 3290 publications found

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]

APOE Gene-Disease associations (from GenCC):

• Alzheimer disease 2

  Inheritance: AD, Unknown Classification: DEFINITIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hyperlipoproteinemia type 3

  Inheritance: AD, AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• lipoprotein glomerulopathy

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, Genomics England PanelApp
• sea-blue histiocyte syndrome

  Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

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

• PM1: In a region_of_interest 8 X 22 AA approximate tandem repeats (size 175) in uniprot entity APOE_HUMAN there are 12 pathogenic changes around while only 3 benign (80%) 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, sea-blue histiocyte syndrome, lipoprotein glomerulopathy, Alzheimer disease 2.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0037242472).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.212 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOE	NM_000041.4	c.388T>C	p.Cys130Arg	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.388T>C	p.Cys130Arg	missense_variant	Exon 4 of 4	1	NM_000041.4	ENSP00000252486.3
APOE	ENST00000425718.1	c.388T>C	p.Cys130Arg	missense_variant	Exon 3 of 3	1		ENSP00000410423.1
APOE	ENST00000434152.5	c.466T>C	p.Cys156Arg	missense_variant	Exon 4 of 4	2		ENSP00000413653.2
APOE	ENST00000446996.5	c.388T>C	p.Cys130Arg	missense_variant	Exon 4 of 4	2		ENSP00000413135.1

Frequencies

GnomAD3 genomes AF: 0.157 AC: 23875 AN: 151972 Hom.: 1998 Cov.: 32

Gnomad AFR AF: 0.215

Gnomad AMI AF: 0.136

Gnomad AMR AF: 0.112

Gnomad ASJ AF: 0.119

Gnomad EAS AF: 0.0975

Gnomad SAS AF: 0.105

Gnomad FIN AF: 0.195

Gnomad MID AF: 0.0673

Gnomad NFE AF: 0.138

Gnomad OTH AF: 0.110

GnomAD2 exomes AF: 0.138 AC: 23502 AN: 169692 AF XY: 0.136

Gnomad AFR exome AF: 0.224

Gnomad AMR exome AF: 0.103

Gnomad ASJ exome AF: 0.115

Gnomad EAS exome AF: 0.0874

Gnomad FIN exome AF: 0.209

Gnomad NFE exome AF: 0.150

Gnomad OTH exome AF: 0.131

GnomAD4 exome AF: 0.148 AC: 208931 AN: 1415800 Hom.: 15700 Cov.: 34 AF XY: 0.146 AC XY: 102105 AN XY: 700502

African (AFR) AF: 0.227 AC: 7291 AN: 32174

American (AMR) AF: 0.104 AC: 3877 AN: 37182

Ashkenazi Jewish (ASJ) AF: 0.120 AC: 3045 AN: 25280

East Asian (EAS) AF: 0.0979 AC: 3591 AN: 36698

South Asian (SAS) AF: 0.100 AC: 8181 AN: 81486

European-Finnish (FIN) AF: 0.191 AC: 9464 AN: 49490

Middle Eastern (MID) AF: 0.0681 AC: 384 AN: 5642

European-Non Finnish (NFE) AF: 0.151 AC: 164927 AN: 1089188

Other (OTH) AF: 0.139 AC: 8171 AN: 58660

GnomAD4 genome AF: 0.157 AC: 23933 AN: 152092 Hom.: 2010 Cov.: 32 AF XY: 0.161 AC XY: 11948 AN XY: 74354

African (AFR) AF: 0.216 AC: 8954 AN: 41512

American (AMR) AF: 0.113 AC: 1734 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.119 AC: 413 AN: 3468

East Asian (EAS) AF: 0.0977 AC: 503 AN: 5148

South Asian (SAS) AF: 0.105 AC: 505 AN: 4830

European-Finnish (FIN) AF: 0.195 AC: 2069 AN: 10600

Middle Eastern (MID) AF: 0.0685 AC: 20 AN: 292

European-Non Finnish (NFE) AF: 0.138 AC: 9368 AN: 67916

Other (OTH) AF: 0.115 AC: 243 AN: 2116

Alfa AF: 0.0334 Hom.: 751

Bravo AF: 0.155

TwinsUK AF: 0.140 AC: 518

ALSPAC AF: 0.154 AC: 593

ESP6500AA AF: 0.189 AC: 808

ESP6500EA AF: 0.117 AC: 961

ExAC AF: 0.100 AC: 11382

Asia WGS AF: 0.171 AC: 597 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity; other; risk factor

Submissions summary: Pathogenic:6 Uncertain:3 Benign:1 Other:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:2 Other:2

Mar 29, 2022

AiLife Diagnostics, AiLife Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 15, 2024

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

No Rules Apply -

Nov 17, 2017

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).

-

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: risk factor

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Alzheimer disease 2 Pathogenic:2

Jun 27, 2022

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Established risk allele

Review Status: no assertion criteria provided

Collection Method: clinical testing

The variant APOE c.388T>C (p.Cys130Arg) was identified in dsSNP (ID: rs429358) and Clinvar (classified as pathogenic by OMIM). Farrer et al. reported in a meta-analysis (5930 patients who met the criteria for Alzheimer disease (AD), and 8607 controls) that the p.Cys130Arg variant (also known as the e4 variant) represented a major risk factor for AD, with the risk of AD significantly increased among Caucasian subjects with genotypes e2/e4 (OR=2.6, 95% CI=1.6-4.0), e3/e4 (OR=3.2, 95% CI=2.8-3.8), and e4/e4 (OR=14.9, 95% CI 10.8-20.6). The association between p.Cys130Arg and AD was stronger in Japanese subjects with genotypes e3/e4 (OR=5.6, 95% CI 3.0-8.0) and e4/e4 (OR=33.1, 95% CI=13.6-80.5) (Farrer_1997_9343467). Another study using data from 1968 African American patients with Late-Onset Alzheimer Disease (LOAD) and 3928 control patients showed that SNPs such as p.Cys130Arg in the APOE region were significant for association with LOAD (P = 5.5 × 10–47) (Reitz_2013_ 23571587). In addition, another study involving 45 patients with AD and 53 controls of Ashkenazi Jewish ancestry observed an association signal for AD risk for the variant p.Cys130Arg (P =1.02×E−08, OR=0.6, 95% CI: 4.20–26.8) (Freudenberg-Hua_2016_27260402). In vivo and in vitro functional studies also provide evidence that the p.Cys130Arg variant may have an effect on increased amyloid beta accumulation, neurotoxicity, and neuritic dystrophy (Youmans_2012_23060451, Liu_2014_29216449). The variant was identified in control databases in 28,637 of 200,920 chromosomes (2,091 homozygous) at a frequency of 14.2529%, and was observed at the highest frequency in the European-Non Finnish (NFE) population in 12,460 of 83,842 chromosomes (freq: 14.8613%) (Genome Aggregation Database March 6, 2019, v2.1.1). The p.Cys130Arg residue is conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a deleterious effect on splicing. 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. However, this variant may act as a risk factor for Alzheimer's Disease. -

Alzheimer disease Pathogenic:2

Jun 27, 2019

Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Established risk allele

Review Status: no assertion criteria provided

Collection Method: research

The variant APOE c.388T>C (p.Cys130Arg) was identified in dsSNP (ID: rs429358) and Clinvar (classified as pathogenic by OMIM). Farrer et al. reported in a meta-analysis (5930 patients who met the criteria for Alzheimer disease (AD), and 8607 controls) that the p.Cys130Arg variant (also known as the e4 variant) represented a major risk factor for AD, with the risk of AD significantly increased among Caucasian subjects with genotypes e2/e4 (OR=2.6, 95% CI=1.6-4.0), e3/e4 (OR=3.2, 95% CI=2.8-3.8), and e4/e4 (OR=14.9, 95% CI 10.8-20.6). The association between p.Cys130Arg and AD was stronger in Japanese subjects with genotypes e3/e4 (OR=5.6, 95% CI 3.0-8.0) and e4/e4 (OR=33.1, 95% CI=13.6-80.5) (Farrer_1997_9343467). Another study using data from 1968 African American patients with Late-Onset Alzheimer Disease (LOAD) and 3928 control patients showed that SNPs such as p.Cys130Arg in the APOE region were significant for association with LOAD (P = 5.5 × 10–47) (Reitz_2013_ 23571587). In addition, another study involving 45 patients with AD and 53 controls of Ashkenazi Jewish ancestry observed an association signal for AD risk for the variant p.Cys130Arg (P =1.02×E−08, OR=0.6, 95% CI: 4.20–26.8) (Freudenberg-Hua_2016_27260402). In vivo and in vitro functional studies also provide evidence that the p.Cys130Arg variant may have an effect on increased amyloid beta accumulation, neurotoxicity, and neuritic dystrophy (Youmans_2012_23060451, Liu_2014_29216449). The variant was identified in control databases in 28,637 of 200,920 chromosomes (2,091 homozygous) at a frequency of 14.2529%, and was observed at the highest frequency in the European-Non Finnish (NFE) population in 12,460 of 83,842 chromosomes (freq: 14.8613%) (Genome Aggregation Database March 6, 2019, v2.1.1). The p.Cys130Arg residue is conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a deleterious effect on splicing. 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. However, this variant may act as a risk factor for Alzheimer's Disease. -

Alzheimer disease 4 Pathogenic:1

Mar 24, 2020

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PM4. This variant was detected in homozygous state. -

Lipoprotein glomerulopathy Uncertain:1

Jan 01, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Primary degenerative dementia of the Alzheimer type, presenile onset Other:1

Jan 16, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: risk factor

Review Status: criteria provided, single submitter

Collection Method: clinical testing

proposed classification - variant undergoing re-assessment, contact laboratory -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.036
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	17
DANN	Benign	0.22
DEOGEN2	Benign	0.099	T;T;.;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.24	T;T;T;T
MetaRNN	Benign	0.0037	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.5	N;.;.;.
PhyloP100		0.84
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	4.4	N;N;.;N
REVEL	Benign	0.23
Sift	Benign	1.0	T;T;.;T
Sift4G	Benign	0.83	T;T;T;T
Polyphen		0.0	B;.;.;.
Vest4		0.051
MPC		1.1
ClinPred		0.00022	T
GERP RS		3.0
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		4.0
Varity_R		0.21
gMVP		0.59
Mutation Taster		=89/11	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

Other links and lift over

dbSNP: rs429358; hg19: chr19-45411941; COSMIC: COSV52985231; COSMIC: COSV52985231;