ClinVar Miner

Submissions for variant NM_000041.4(APOE):c.805C>G (p.Arg269Gly)

gnomAD frequency: 0.00032  dbSNP: rs267606661
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001565388 SCV001788727 uncertain significance not provided 2022-09-12 criteria provided, single submitter clinical testing Identified in several unrelated individuals with hyperlipidemia in published literature (van den Maagdenberg et al., 1993; Zhao et al., 1994; Richard et al., 1997; Kang et al., 1997; Marduel et al., 2013; Abou Khalil et al., 2022); Identified in both symptomatic and asymptomatic relatives of probands with hypertriglyceridemia, which authors attribute to reduced penetrance and other genetic factors influencing disease expression (van den Maagdenberg et al., 1993; Zhao et al., 1994; Richard et al., 1997; Kang et al., 1997); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as R251G; This variant is associated with the following publications: (PMID: 9360638, 9279208, 22949395, 1648586, 35628605, 34058468, 8488843, 8156744, 35120450)
Fulgent Genetics, 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
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.
CeGaT Center for Human Genetics Tuebingen RCV001565388 SCV004011074 uncertain significance not provided 2023-06-01 criteria provided, single submitter clinical testing APOE: PP4, BP4
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.

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