NM_000041.4:c.388T>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 3P and 12B. PM1PP2BP4_StrongBA1

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

Scores

1
17

Clinical Significance

Conflicting classifications of pathogenicity; other; risk factor criteria provided, conflicting classifications P:6U:3B:1O:4

Conservation

PhyloP100: 0.840

Publications

3290 publications found
Variant links:
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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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
APOENM_000041.4 linkc.388T>C p.Cys130Arg missense_variant Exon 4 of 4 ENST00000252486.9 NP_000032.1 P02649A0A0S2Z3D5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
APOEENST00000252486.9 linkc.388T>C p.Cys130Arg missense_variant Exon 4 of 4 1 NM_000041.4 ENSP00000252486.3 P02649
APOEENST00000425718.1 linkc.388T>C p.Cys130Arg missense_variant Exon 3 of 3 1 ENSP00000410423.1 E7ERP7
APOEENST00000434152.5 linkc.466T>C p.Cys156Arg missense_variant Exon 4 of 4 2 ENSP00000413653.2 H0Y7L5
APOEENST00000446996.5 linkc.388T>C p.Cys130Arg missense_variant Exon 4 of 4 2 ENSP00000413135.1 E9PEV4

Frequencies

GnomAD3 genomes
AF:
0.157
AC:
23875
AN:
151972
Hom.:
1998
Cov.:
32
show subpopulations
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
show subpopulations
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
show subpopulations
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
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.479
Heterozygous variant carriers
0
13015
26031
39046
52062
65077
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
6004
12008
18012
24016
30020
<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:
0.157
AC:
23933
AN:
152092
Hom.:
2010
Cov.:
32
AF XY:
0.161
AC XY:
11948
AN XY:
74354
show subpopulations
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
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.502
Heterozygous variant carriers
0
1023
2046
3069
4092
5115
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
274
548
822
1096
1370
<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:
0.0334
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:6Uncertain:3Benign:1Other:4
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Pathogenic:1Uncertain:2Other: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

Publications

Other links and lift over

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