rs121918399

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_000041.4(APOE):c.127C>T(p.Arg43Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,668 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

APOE
NM_000041.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 1.34

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 19-44907843-C-T is Pathogenic according to our data. Variant chr19-44907843-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 17880.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOE	NM_000041.4 link	c.127C>T	p.Arg43Cys	missense_variant	Exon 3 of 4	ENST00000252486.9	NP_000032.1	P02649A0A0S2Z3D5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
APOE	ENST00000252486.9 link	c.127C>T	p.Arg43Cys	missense_variant	Exon 3 of 4	1	NM_000041.4	ENSP00000252486.3	P02649
APOE	ENST00000425718.1 link	c.127C>T	p.Arg43Cys	missense_variant	Exon 2 of 3	1		ENSP00000410423.1	E7ERP7
APOE	ENST00000434152.5 link	c.205C>T	p.Arg69Cys	missense_variant	Exon 3 of 4	2		ENSP00000413653.2	H0Y7L5
APOE	ENST00000446996.5 link	c.127C>T	p.Arg43Cys	missense_variant	Exon 3 of 4	2		ENSP00000413135.1	E9PEV4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000799

AC:

AN:

250366

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135532

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000545

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000465

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461668

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727124

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Lipoprotein glomerulopathy

Pathogenic:3

Precision Medicine Center, Zhengzhou University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PM2:at extremely low frequency in gnomAD PP2:Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease PP3:Multiple lines of computational evidence support a deleterious effect on the gene or gene product PP4:Patient's phenotype is highly specific for a disease -

Dec 13, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

3billion, Medical Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Missense changes are a common disease-causing mechanism. Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 10432380). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.60; 3Cnet: 0.07). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000017880 / PMID: 10529625). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Cardiovascular phenotype

Pathogenic:1

Oct 31, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R43C likely pathogenic variant (also known as c.127C>T), located in coding exon 2 of the APOE gene, results from a C to T substitution at nucleotide position 127. The arginine at codon 43 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant (also referred to as p.R25C, p.R69C, and APOE Kyoto) has been detected in numerous individuals, frequently of Asian ancestry, with features consistent with APOE-related lipoprotein glomerulopathy (LPG). However, this variant has also been detected in multiple unaffected individuals (Matsunaga A et al. Kidney Int, 1999 Aug;56:421-7; Wu Y et al. BMC Nephrol, 2013 Feb;14:53; Rovin BH et al. N Engl J Med, 2007 Dec;357:2522-4; Li W et al. Kidney Blood Press Res, 2014 Oct;39:330-9; Hu Z et al. Kidney Int, 2014 Feb;85:416-24; Usui R et al. CEN Case Rep, 2016 Nov;5:148-153; Katsarou M et al. J Lipid Res, 2018 Dec;59:2339-2348; Lui DTW et al. J Clin Lipidol, 2019 Dec;13:251-253; Yang M et al. Mol Genet Genomic Med, 2020 Aug;8:e1281; Song Y et al. Front Pediatr, 2021 Aug;9:684814; Zhu X et al. Front Med (Lausanne), 2022 Jul;9:885178; Wang R et al. J Med Case Rep, 2022 Feb;16:78; Qin Y et al. Ren Fail, 2024 Dec;46:2332491). This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic; however, it may exhibit reduced penetrance. -

Familial type 3 hyperlipoproteinemia;C0036489:Sea-blue histiocyte syndrome;C1843013:Alzheimer disease 3;C1847200:Alzheimer disease 4;C1863051:Alzheimer disease 2;C1864205:Age related macular degeneration 1;C2673196:Lipoprotein glomerulopathy

Pathogenic:1

Feb 24, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Uncertain

0.047

BayesDel_noAF

Uncertain

0.0

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.35

T;T;.;.

Eigen

Benign

-0.17

Eigen_PC

Benign

-0.12

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.83

T;T;T;T

M_CAP

Uncertain

0.11

MetaRNN

Uncertain

0.58

D;D;D;D

MetaSVM

Benign

-0.57

MutationAssessor

Benign

0.55

N;.;.;.

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.3

N;N;.;N

REVEL

Uncertain

0.60

Sift

Uncertain

0.0080

D;D;.;D

Sift4G

Uncertain

0.021

D;D;T;D

Polyphen

0.68

P;.;.;.

Vest4

0.76

MutPred

0.78

Gain of catalytic residue at W44 (P = 0.001);Gain of catalytic residue at W44 (P = 0.001);.;Gain of catalytic residue at W44 (P = 0.001);

MVP

0.93

MPC

0.92

ClinPred

0.32

GERP RS

2.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.48

gMVP

0.50

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over