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)
ClinVar Genomic variation as it relates to human health
NM_000041.4(APOE):c.497TCC[1] (p.Leu167del)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(6)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic
6
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000041.4(APOE):c.497TCC[1] (p.Leu167del)
Variation ID: 126456 Accession: VCV000126456.18
- Type and length
-
Microsatellite, 3 bp
- Location
-
Cytogenetic: 19q13.32 19: 44908792-44908794 (GRCh38) [ NCBI UCSC ] 19: 45412049-45412051 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Dec 21, 2015 Oct 20, 2024 Oct 4, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000041.4:c.497TCC[1] MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000032.1:p.Leu167del inframe deletion NM_000041.3:c.500_502del NM_000041.3:c.500_502delTCC NM_001302688.2:c.575TCC[1] NP_001289617.1:p.Leu193del inframe deletion NM_001302689.2:c.497TCC[1] NP_001289618.1:p.Leu167del inframe deletion NM_001302690.2:c.497TCC[1] NP_001289619.1:p.Leu167del inframe deletion NM_001302691.2:c.497TCC[1] NP_001289620.1:p.Leu167del inframe deletion NC_000019.10:g.44908793TCC[1] NC_000019.9:g.45412050TCC[1] NG_007084.2:g.8012TCC[1] - Protein change
- L167del, L193del
- Other names
-
NM_000041.2:c.499_501delCTC
NP_000032.1:p.Leu149del
- Canonical SPDI
- NC_000019.10:44908791:CTCCTCC:CTCC
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| APOE | - | - |
GRCh38 GRCh37 |
190 | 209 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (2) |
no assertion criteria provided
|
Nov 1, 2005 | RCV000202536.11 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Dec 19, 2018 | RCV002336246.9 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Oct 4, 2023 | RCV003221804.19 | |
|
APOE-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
Sep 25, 2024 | RCV004755773.1 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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|---|---|---|---|---|---|
|
Pathogenic
(Oct 04, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV004169143.1
First in ClinVar: Nov 25, 2023 Last updated: Nov 25, 2023 |
Comment:
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 … (more)
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) (less)
|
|
|
Pathogenic
(Mar 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV003918146.13
First in ClinVar: Apr 23, 2023 Last updated: Oct 20, 2024 |
Comment:
APOE: PP1:Strong, PS3:Moderate, PS4:Moderate, PM2:Supporting, PM4:Supporting
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Dec 19, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002642401.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
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 … (more)
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. (less)
|
|
|
Pathogenic
(Nov 01, 2005)
|
no assertion criteria provided
Method: literature only
|
SEA-BLUE HISTIOCYTE DISEASE
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000039755.4
First in ClinVar: Apr 04, 2013 Last updated: Jan 24, 2018 |
Comment on evidence:
Nguyen et al. (2000) reported 2 kindreds in which the sea-blue histiocyte syndrome (269600) was associated with an apoE variant in the absence of severe … (more)
Nguyen et al. (2000) reported 2 kindreds in which the sea-blue histiocyte syndrome (269600) was associated with an apoE variant in the absence of severe dyslipidemia. Both patients presented with mild hypertriglyceridemia and splenomegaly. After splenectomy both patients developed severe hypertriglyceridemia. Pathologic evaluation of the spleen revealed the presence of sea-blue histiocytes. An APOE mutation was found: a 3-bp deletion resulting in the loss of leucine-149 in the receptor-binding region of APOE (delta149 leu). Although the probands were unrelated, they were of French Canadian ancestry, suggesting the possibility of a founder effect. In 2 brothers with splenomegaly, thrombocytopenia, and hypertriglyceridemia, Faivre et al. (2005) identified the delta149 leu mutation in the APOE gene. Their mother, who also had the mutation, had only isolated hypertriglyceridemia. One brother had a large beta band in the VLDL fraction and an elevated VLDL cholesterol-to-plasma triglyceride ratio; Faivre et al. (2005) suggested that the more severe phenotype might be explained by the presence of an APOE2 allele (107741.0001) in this patient. (less)
|
|
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Pathogenic
(Sep 25, 2024)
|
no assertion criteria provided
Method: clinical testing
|
APOE-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV005357275.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
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 … (more)
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. (less)
|
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
Sea-blue histiocyte syndrome
Affected status: yes
Allele origin:
germline
|
GeneReviews
Accession: SCV000148007.2
First in ClinVar: Dec 21, 2015 Last updated: Oct 01, 2022 |
|
Comment:
Comment:
APOE: PP1:Strong, PS3:Moderate, PS4:Moderate, PM2:Supporting, PM4:Supporting
Comment:
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.
Comment:
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.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
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)
Comment:
APOE: PP1:Strong, PS3:Moderate, PS4:Moderate, PM2:Supporting, PM4:Supporting
Comment:
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.
Comment:
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.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| ATP7A-Related Copper Transport Disorders. | Adam MP | - | 2021 | PMID: 20301586 |
| Interpreting the Mechanism of APOE (p.Leu167del) Mutation in the Incidence of Familial Hypercholesterolemia; An In-silico Approach. | Rashidi OM | The open cardiovascular medicine journal | 2017 | PMID: 29204218 |
| Spectrum of mutations in Italian patients with familial hypercholesterolemia: New results from the LIPIGEN study. | Pirillo A | Atherosclerosis. Supplements | 2017 | PMID: 28965616 |
| The p.Leu167del Mutation in APOE Gene Causes Autosomal Dominant Hypercholesterolemia by Down-regulation of LDL Receptor Expression in Hepatocytes. | Cenarro A | The Journal of clinical endocrinology and metabolism | 2016 | PMID: 27014949 |
| Global molecular analysis and APOE mutations in a cohort of autosomal dominant hypercholesterolemia patients in France. | Wintjens R | Journal of lipid research | 2016 | PMID: 26802169 |
| Exome sequencing in suspected monogenic dyslipidemias. | Stitziel NO | Circulation. Cardiovascular genetics | 2015 | PMID: 25632026 |
| Inherited lipemic splenomegaly and the spectrum of apolipoprotein E p.Leu167del mutation phenotypic variation. | Okorodudu DE | Journal of clinical lipidology | 2013 | PMID: 24314356 |
| APOE p.Leu167del mutation in familial hypercholesterolemia. | Awan Z | Atherosclerosis | 2013 | PMID: 24267230 |
| Description of a large family with autosomal dominant hypercholesterolemia associated with the APOE p.Leu167del mutation. | Marduel M | Human mutation | 2013 | PMID: 22949395 |
| Apolipoprotein E gene mutations in subjects with mixed hyperlipidemia and a clinical diagnosis of familial combined hyperlipidemia. | Solanas-Barca M | Atherosclerosis | 2012 | PMID: 22481068 |
| Frequency of low-density lipoprotein receptor gene mutations in patients with a clinical diagnosis of familial combined hyperlipidemia in a clinical setting. | Civeira F | Journal of the American College of Cardiology | 2008 | PMID: 19007590 |
| An unusual case of severe hypertriglyceridemia and splenomegaly. | Rahalkar AR | Clinical chemistry | 2008 | PMID: 18310149 |
| Variable expressivity of the clinical and biochemical phenotype associated with the apolipoprotein E p.Leu149del mutation. | Faivre L | European journal of human genetics : EJHG | 2005 | PMID: 16094309 |
| Familial splenomegaly: macrophage hypercatabolism of lipoproteins associated with apolipoprotein E mutation [apolipoprotein E (delta149 Leu)]. | Nguyen TT | The Journal of clinical endocrinology and metabolism | 2000 | PMID: 11095479 |
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Text-mined citations for rs515726148 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 25, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.