Total submissions: 8
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Department of Pathology and Laboratory Medicine, |
RCV005367405 | SCV005917061 | uncertain significance | Alzheimer disease 2 | 2023-08-22 | criteria provided, single submitter | research | |
| Mayo Clinic Laboratories, |
RCV001565388 | SCV005408859 | uncertain significance | not provided | 2024-03-29 | criteria provided, single submitter | clinical testing | PS4_moderate |
| Ambry Genetics | RCV003352927 | SCV004062389 | uncertain significance | Cardiovascular phenotype | 2023-09-05 | criteria provided, single submitter | clinical testing | 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. |
| Ce |
RCV001565388 | SCV004011074 | uncertain significance | not provided | 2023-06-01 | criteria provided, single submitter | clinical testing | APOE: PP4, BP4 |
| New York Genome Center | RCV003227792 | SCV003925294 | uncertain significance | Familial type 3 hyperlipoproteinemia | 2022-08-28 | criteria provided, single submitter | clinical testing | 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. |
| Fulgent Genetics, |
RCV002483522 | SCV002791386 | uncertain significance | Alzheimer disease 3; Alzheimer disease 2; Alzheimer disease 4; Age related macular degeneration 1; Sea-blue histiocyte syndrome; Lipoprotein glomerulopathy; Familial type 3 hyperlipoproteinemia | 2022-04-23 | criteria provided, single submitter | clinical testing | |
| Gene |
RCV001565388 | SCV001788727 | uncertain significance | not provided | 2024-05-07 | criteria provided, single submitter | clinical testing | 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) |
| Prevention |
RCV004730981 | SCV005336877 | uncertain significance | APOE-related disorder | 2024-03-14 | no assertion criteria provided | clinical testing | 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. |