rs515726148

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM4_SupportingPP5_Very_Strong

The NM_000041.4(APOE):c.500_502delTCC(p.Leu167del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000412 in 1,553,850 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000043 ( 0 hom. )

Consequence

APOE
NM_000041.4 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7O:1

Conservation

PhyloP100: 1.04

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 Pathogenic. Variant got 11 ACMG points.

PM1

In a mutagenesis_site Increased binding to LDL receptor; when associated with R-157. (size 0) in uniprot entity APOE_HUMAN

PM4

Nonframeshift variant in NON repetitive region in NM_000041.4. Strenght limited to Supporting due to length of the change: 1aa.

PP5

Variant 19-44908791-GCTC-G is Pathogenic according to our data. Variant chr19-44908791-GCTC-G is described in ClinVar as [Pathogenic]. Clinvar id is 126456.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-44908791-GCTC-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOE	NM_000041.4 link	c.500_502delTCC	p.Leu167del	disruptive_inframe_deletion	Exon 4 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.500_502delTCC	p.Leu167del	disruptive_inframe_deletion	Exon 4 of 4	1	NM_000041.4	ENSP00000252486.3	P02649
APOE	ENST00000425718.1 link	c.500_502delTCC	p.Leu167del	disruptive_inframe_deletion	Exon 3 of 3	1		ENSP00000410423.1	E7ERP7
APOE	ENST00000434152.5 link	c.578_580delTCC	p.Leu193del	disruptive_inframe_deletion	Exon 4 of 4	2		ENSP00000413653.2	H0Y7L5
APOE	ENST00000446996.5 link	c.500_502delTCC	p.Leu167del	disruptive_inframe_deletion	Exon 4 of 4	2		ENSP00000413135.1	E9PEV4

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000200

AC:

AN:

149924

Hom.:

AF XY:

0.00

AC XY:

AN XY:

82392

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000784

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000170

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000428

AC:

AN:

1401718

Hom.:

AF XY:

0.0000375

AC XY:

AN XY:

692832

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000814

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000125

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000507

Gnomad4 OTH exome

AF:

0.0000172

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152132

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000264

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

APOE-related disorder

Pathogenic:3

Sep 25, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The APOE c.500_502delTCC variant is predicted to result in an in-frame deletion (p.Leu167del). This variant, also known as p.Leu149del in the literature, has been reported in more than 10 kindreds with a range of clinical phenotypes, including classic autosomal dominant hypercholesterolemia, familial combined hyperlipidemia, and splenomegaly with or without sea-blue histiocyte disease (Nguyen et al. 2000. PubMed ID: 11095479; Solanas-Barca et al. 2012. PubMed ID: 22481068; Marduel et al. 2013. PubMed ID: 22949395; Awan et al. 2013. PubMed ID: 24267230; Muñoz et al. 2020. PubMed ID: 32071839). Variable biochemical and clinical features have been documented in carriers of p.Leu167del, even within the same family (Okorodudu et al. 2013. PubMed ID: 24314356). This variant is reported in 0.0078% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as pathogenic. -

Nov 14, 2023

GENinCode PLC

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The APOE c.500_502del p.(Leu167del) variant has been reported in >=10 patients with a range of clinical phenotypes including familial hypercholesterolemia and familial combined hyperlipidemia (PS4_STRONG; PMIDs 22949395, 24267230, 27014949, 24314356, 26802169, 29204218, 30731287, 35628605, 37051929, 39566982, internal data) and at least one patient with a phenotype which was highly specific for FH after alternative causes of high cholesterol were excluded (PP4_SUPPORTING; PMID 24267230). This variant has also been found to co-segregate with disease in multiple unrelated families (PP1_STRONG; PMIDs 22481068, 22949395, 24267230, 25632026, 39566982). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00007839 in the Admixed American population (PM2_MODERATE). Functional studies indicate that this variant leads to increased uptake of VLDL and a subsequent decrease in LDLR membrane expression (PS3_STRONG; PMID 27014949). Based on the evidence listed above, we have classified this variant as Pathogenic. -

Nov 13, 2024

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3, PM4, PP1_Strong -

not provided

Pathogenic:2

Mar 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

APOE: PP1:Strong, PS3:Moderate, PS4:Moderate, PM2:Supporting, PM4:Supporting -

Oct 04, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In-frame deletion of one amino acid in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; Although a few functional analyses of this variant have been performed, a definitive disease mechanism was not established; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24267230, 24314356, 29204218, 11095479, 16094309, 22949395, 22481068, 27014949, 32071839, 31589614, 34456049, 35628605, 26802169, 18310149, 28965616, 19007590, 25632026, 35673444, 35339733) -

Sea-blue histiocyte syndrome

Pathogenic:1Other:1

Nov 01, 2005

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Cardiovascular phenotype

Pathogenic:1

Dec 19, 2018

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.500_502delTCC pathogenic mutation (also known as p.L167del) is located in coding exon 3 of the APOE gene. This pathogenic mutation results from an in-frame TCC deletion at nucleotide positions 500 to 502. This results in the in-frame deletion of a leucine at codon 167. This mutation has been reported (sometimes with legacy nomenclature L149del) in numerous individuals with hypercholesterolemia and has been shown to segregate with disease in multiple families (Marduel M et al. Hum. Mutat., 2013 Jan;34:83-7; Awan Z et al. Atherosclerosis, 2013 Dec;231:218-22; Stitziel NO et al. Circ Cardiovasc Genet, 2015 Apr;8:343-50; Cenarro A et al. J. Clin. Endocrinol. Metab., 2016 05;101:2113-21; Wintjens R et al. J. Lipid Res. 2016 Mar;57(3):482-91; Pirillo A et al. Atheroscler Suppl, 2017 Oct;29:17-24). This alteration has also been detected in individuals with splenomegaly and dyslipidemia and in familial combined hyperlipidemia cohorts (Nguyen TT et al. J. Clin. Endocrinol. Metab., 2000 Nov;85:4354-8; Faivre L et al. Eur. J. Hum. Genet., 2005 Nov;13:1186-91; Rahalkar AR et al. Clin. Chem., 2008 Mar;54:606-11; Solanas-Barca M et al. Atherosclerosis, 2012 Jun;222:449-55; Okorodudu DE et al. J Clin Lipidol Sep;7:566-72). Functional studies indicate L167del leads to increased uptake of VLDL and a subsequent decrease in LDLR membrane expression (Cenarro A et al. J. Clin. Endocrinol. Metab., 2016 05;101:2113-21). Molecular docking simulation suggests enhanced interaction of L167del and LDLR (Rashidi OM et al. Open Cardiovasc Med J, 2017 Sep;11:84-93). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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