ClinVar Miner

Submissions for variant NM_000384.3(APOB):c.7698G>C (p.Glu2566Asp)

gnomAD frequency: 0.00006  dbSNP: rs149306841
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000454407 SCV000538333 uncertain significance not specified 2016-07-26 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in 1 patient
Invitae RCV001837903 SCV001004093 likely benign Hypercholesterolemia, autosomal dominant, type B; Familial hypobetalipoproteinemia 1 2023-12-14 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000863432 SCV001133421 uncertain significance not provided 2019-05-01 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV001142270 SCV001302690 uncertain significance Hypercholesterolemia, autosomal dominant, type B 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Ambry Genetics RCV002402223 SCV002668781 uncertain significance Cardiovascular phenotype 2018-03-08 criteria provided, single submitter clinical testing The p.E2566D variant (also known as c.7698G>C), located in coding exon 26 of the APOB gene, results from a G to C substitution at nucleotide position 7698. The glutamic acid at codon 2566 is replaced by aspartic acid, an amino acid with highly similar properties. This variant, reported as p.E2539D, was detected in a hypertriglyceridemia cohort; however, clinical details were not not provided (Johansen CT et al. Nat. Genet., 2010 Aug;42:684-7). This amino acid position is not well conserved in available vertebrate species, and aspartic acid is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
New York Genome Center RCV001837903 SCV002764336 uncertain significance Hypercholesterolemia, autosomal dominant, type B; Familial hypobetalipoproteinemia 1 2021-08-19 criteria provided, single submitter clinical testing The heterozygous c.7698G>C (p.Glu2566Asp) missense variant identified in the APOB gene has been reported in a single individual affected with hypertriglyceridemia [1/438 hypertriglyceridemia patients; PMID:20657596] and in a single patient with a combined hyperlipidemia phenotype [PMID: 33303402]. The variant has 0.00007228 allele frequency in the gnomAD (v3) database (11 out of 152184 heterozygous alleles, no homozygotes) suggesting it is not a common benign variant in the populations represented in that database. This variant has been reported in the ClinVar database as a variant of uncertain significance (4) and likelybenign (1) [Variation ID: 402380]. This variant affects a moderately conserved residue [Glu2566] which is located in the first amphiphatic alpha-helical domain [residues 2045 to 2587] of the APOB protein (PMID: 19200547). In silico tools provide conflicting predictions about potential pathogenicity of this variant (CADD score= 22.4, REVEL score = 0.128). Due to the lack of compelling evidence for its pathogenicity, the heterozygous c.7698G>C (p.Glu2566Asp) missense variant identified inthe APOB gene is reported as a Variant of Uncertain Significance.

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