chr19-44909101-C-G

Position:

chr19-44909101-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP3BS1_Supporting

The NM_000041.4(APOE):c.805C>G(p.Arg269Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000653 in 1,587,584 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. R269R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00069 ( 0 hom. )

Consequence

APOE
NM_000041.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 1.32

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.772

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.00069 (990/1435384) while in subpopulation NFE AF= 0.000824 (910/1104338). AF 95% confidence interval is 0.000779. There are 0 homozygotes in gnomad4_exome. There are 484 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APOE	NM_000041.4 linkuse as main transcript	c.805C>G	p.Arg269Gly	missense_variant	4/4	ENST00000252486.9	NP_000032.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APOE	ENST00000252486.9 linkuse as main transcript	c.805C>G	p.Arg269Gly	missense_variant	4/4	1	NM_000041.4	ENSP00000252486	P1

Frequencies

GnomAD3 genomes

AF:

0.000302

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000485

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000387

AC:

AN:

198936

Hom.:

AF XY:

0.000354

AC XY:

AN XY:

110184

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000619

Gnomad ASJ exome

AF:

0.000219

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000364

Gnomad FIN exome

AF:

0.000182

Gnomad NFE exome

AF:

0.000533

Gnomad OTH exome

AF:

0.00115

GnomAD4 exome

AF:

0.000690

AC:

990

AN:

1435384

Hom.:

Cov.:

AF XY:

0.000679

AC XY:

484

AN XY:

713280

show subpopulations

Gnomad4 AFR exome

AF:

0.000151

Gnomad4 AMR exome

AF:

0.000502

Gnomad4 ASJ exome

AF:

0.000233

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000119

Gnomad4 FIN exome

AF:

0.000141

Gnomad4 NFE exome

AF:

0.000824

Gnomad4 OTH exome

AF:

0.000688

GnomAD4 genome

AF:

0.000302

AC:

AN:

152200

Hom.:

Cov.:

AF XY:

0.000256

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.000458

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.000485

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000404

Hom.:

Bravo

AF:

0.000355

ExAC

AF:

0.000200

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	APOE: PP4, BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 07, 2024	Identified in several unrelated individuals with hyperlipidemia in published literature (PMID: 8488843, 8156744, 9279208, 9360638, 22949395, 35628605); Identified in both symptomatic and asymptomatic relatives of probands with hypertriglyceridemia, which authors attribute to reduced penetrance and other genetic factors influencing disease expression (PMID: 8488843, 8156744, 9279208, 9360638); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(R251G); This variant is associated with the following publications: (PMID: 9360638, 9279208, 22949395, 1648586, 35120450, 34058468, 8488843, 35628605, 8156744) -

APOE-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 14, 2024

The APOE c.805C>G variant is predicted to result in the amino acid substitution p.Arg269Gly. This variant, also reported as p.Arg251Gly using legacy nomenclature, has been reported in individuals with varying hyperlipidemias (van den Maagdenberg et al. 1993. PubMed ID: 8488843; Richard et al. 1997. PubMed ID: 9279208; Dong et al. 2022. PubMed ID: 35460704; Abou Khalil et al. 2022. PubMed ID: 35628605). This variant has also been reported in an individual with early-onset Alzheimer disease (Pagnon de la Vega et al. 2022. PubMed ID: 35120450). However, a large case-control study of Alzheimer disease patients and cognitively normal controls suggest this variant results in a decreased risk for Alzheimer disease through a possible protective effect and seems to be always co-inherited with the well-established risk allele, APOE e4 (Le Guen et al. 2022. PubMed ID: 35639372). However, more studies are needed to support this possible effect. This variant is reported in 0.063% of alleles in individuals of Latino descent in gnomAD and has been consistently interpreted as uncertain in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/478884/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Familial type 3 hyperlipoproteinemia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

Aug 28, 2022

The c.805C>G variant in APOE has previously been reported in individuals with hyperlipoproteinemia [PMID: 9279208, 35628605] and it has been deposited in ClinVar [ClinVar ID: 478884] as variant of uncertain significance. The c.805C>G variant is observed in 186 alleles (~0.034% minor allele frequency with 0 homozygote)in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8), suggesting it is not a common benign variant in the populations represented in those databases, which might include individuals with chronic conditions. The c.805C>G variant in APOE is located in exon 4 of this 4-exon gene, and is predicted to replace a moderately conserved arginine amino acid with glycine at position 269 (p.(Arg269Gly)) in the lipid-binding and lipoprotein association domain [UniProtKB:P02649] of the encoded protein. In silico predictions are not strongly in favor of damaging effect for the p.(Arg269Gly) variant [CADD v1.6 = 23.3, REVEL =0.581]; however, there are no functional studies to support or refute these predictions. Based on available evidence this c.805C>G p.(Arg269Gly) variant identified in APOE is classified as a Variant of Uncertain Significance. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 05, 2023

The p.R269G variant (also known as c.805C>G), located in coding exon 3 of the APOE gene, results from a C to G substitution at nucleotide position 805. The arginine at codon 269 is replaced by glycine, an amino acid with dissimilar properties. This variant (also referred to as R251G or Arg251Gly) has been detected in individuals with hyperlipidemia or hypertriglyceridemia; however, in some studies gene analysis was limited, and this variant has also been detected in normolipidemic individuals (van den Maagdenberg AM et al. Am J Hum Genet, 1993 May;52:937-46; Kang AK et al. Mutat Res, 1997 Sep;382:57-65; Richard P et al. Clin Sci (Lond), 1997 Jul;93:89-95; Marduel M et al. Hum Mutat, 2013 Jan;34:83-7; Abou Khalil Y et al. Int J Mol Sci, 2022 May;23). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 23, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.092

BayesDel_noAF

Uncertain

0.0

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.32

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.44

FATHMM_MKL

Benign

0.53

LIST_S2

Benign

0.82

M_CAP

Uncertain

0.24

MetaRNN

Pathogenic

0.77

MetaSVM

Benign

-0.44

MutationAssessor

Uncertain

2.3

MutationTaster

Benign

0.96

PrimateAI

Benign

0.42

PROVEAN

Uncertain

-2.9

REVEL

Uncertain

0.58

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.014

Polyphen

0.55

Vest4

0.80

MVP

0.84

MPC

1.3

ClinPred

0.079

GERP RS

1.6

Varity_R

0.26

gMVP

0.84

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