Total submissions: 7
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV002336246 | SCV002642401 | pathogenic | Cardiovascular phenotype | 2018-12-19 | criteria provided, single submitter | 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. |
Ce |
RCV003221804 | SCV003918146 | pathogenic | not provided | 2023-03-01 | criteria provided, single submitter | clinical testing | APOE: PP1:Strong, PS3:Moderate, PS4:Moderate, PM2:Supporting, PM4:Supporting |
Gene |
RCV003221804 | SCV004169143 | pathogenic | not provided | 2023-10-04 | criteria provided, single submitter | 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) |
GENin |
RCV004755773 | SCV005684986 | pathogenic | APOE-related disorder | 2023-11-14 | criteria provided, single submitter | 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. |
OMIM | RCV000202536 | SCV000039755 | pathogenic | Sea-blue histiocyte syndrome | 2005-11-01 | no assertion criteria provided | literature only | |
Gene |
RCV000202536 | SCV000148007 | not provided | Sea-blue histiocyte syndrome | no assertion provided | literature only | ||
Prevention |
RCV004755773 | SCV005357275 | pathogenic | APOE-related disorder | 2024-09-25 | no assertion criteria provided | 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. |