rs429358

chr19-44908684-T-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 3P and 9B. PM1 PP5 BP4 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. 14/20 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:2 O:4
• Conservation: PhyloP100: 0.840

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

Verdict is Likely_benign. Variant got -6 ACMG points.

• PM1: In a region_of_interest 8 X 22 AA approximate tandem repeats (size 175) in uniprot entity APOE_HUMAN there are 20 pathogenic changes around while only 7 benign (74%) in NM_000041.4
• PP5: Variant 19-44908684-T-C is Pathogenic according to our data. Variant chr19-44908684-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity, other, risk_factor]. Clinvar id is 17864.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, risk_factor=2, Likely_pathogenic=2, Uncertain_significance=2, other=1}. Variant chr19-44908684-T-C is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.0037242472).. Strength limited to SUPPORTING due to the PP5.
• 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/exons	MANE	UniProt
APOE	NM_000041.4	c.388T>C	p.Cys130Arg	missense_variant	4/4	ENST00000252486.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APOE	ENST00000252486.9	c.388T>C	p.Cys130Arg	missense_variant	4/4	1	NM_000041.4	P1
APOE	ENST00000425718.1	c.388T>C	p.Cys130Arg	missense_variant	3/3	1
APOE	ENST00000434152.5	c.466T>C	p.Cys156Arg	missense_variant	4/4	2
APOE	ENST00000446996.5	c.388T>C	p.Cys130Arg	missense_variant	4/4	2

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

GnomAD3 exomes AF: 0.138 AC: 23502 AN: 169692 Hom.: 1663 AF XY: 0.136 AC XY: 12553 AN XY: 92210

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 SAS exome AF: 0.100

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

Gnomad4 AFR exome AF: 0.227

Gnomad4 AMR exome AF: 0.104

Gnomad4 ASJ exome AF: 0.120

Gnomad4 EAS exome AF: 0.0979

Gnomad4 SAS exome AF: 0.100

Gnomad4 FIN exome AF: 0.191

Gnomad4 NFE exome AF: 0.151

Gnomad4 OTH exome AF: 0.139

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

Gnomad4 AFR AF: 0.216

Gnomad4 AMR AF: 0.113

Gnomad4 ASJ AF: 0.119

Gnomad4 EAS AF: 0.0977

Gnomad4 SAS AF: 0.105

Gnomad4 FIN AF: 0.195

Gnomad4 NFE AF: 0.138

Gnomad4 OTH AF: 0.115

Alfa AF: 0.0744 Hom.: 502

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:2 Other:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1 Other:2

other, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 17, 2017	- Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles).
Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Mar 29, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2022	- -
risk factor, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	-	- -

Alzheimer disease 2 Pathogenic:2

Established risk allele, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 27, 2022	- -

Alzheimer disease Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	Jun 27, 2019	- -
Established risk allele, no assertion criteria provided	research	Department of Pathology and Laboratory Medicine, Sinai Health System	-	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

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Mar 24, 2020

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

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Jan 01, 2019

- -

Warfarin response Other:1

drug response, no assertion criteria provided

research

Pharmacogenomics Lab, Chungbuk National University

Aug 31, 2010

- likely responsive

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

risk factor, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 16, 2019

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;.;.;.
MutationTaster	Benign	1.0	P
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

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