rs121918399

Variant names:

• chr19-44907843-C-T
• rs121918399
• NM_000041.4:c.127C>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2 PP2 PP5_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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 1.34
• Publications: 21 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: Pathogenic. The variant received 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.
• PP5: Variant 19-44907843-C-T is Pathogenic according to our data. Variant chr19-44907843-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId 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	c.127C>T	p.Arg43Cys	missense_variant	Exon 3 of 4	ENST00000252486.9	NP_000032.1

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000799 AC: 2 AN: 250366 AF XY: 0.00

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 FIN exome AF: 0.0000465

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461668 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727124

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53356

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111900

Other (OTH) AF: 0.00 AC: 0 AN: 60370

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Lipoprotein glomerulopathy Pathogenic:3

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3billion

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. -

Dec 13, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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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 -

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

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.047	T
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T;T;.;.
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.83	T;T;T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.58	D;D;D;D
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	0.55	N;.;.;.
PhyloP100		1.3
PrimateAI	Benign	0.34	T
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	T
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.48
gMVP		0.50
Mutation Taster		=27/73	disease causing (ClinVar)

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: rs121918399; hg19: chr19-45411100; COSMIC: COSV52986041; COSMIC: COSV52986041;