Submissions for variant NM_000384.3(APOB):c.2258G>A (p.Gly753Glu)

gnomAD frequency: 0.00012  dbSNP: rs148502464

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002442595	SCV002734183	likely benign	Cardiovascular phenotype	2023-12-28	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Fulgent Genetics, Fulgent Genetics	RCV002493417	SCV002786887	uncertain significance	Hypercholesterolemia, autosomal dominant, type B; Familial hypobetalipoproteinemia 1	2021-11-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002493417	SCV002934768	likely benign	Hypercholesterolemia, autosomal dominant, type B; Familial hypobetalipoproteinemia 1	2024-10-03	criteria provided, single submitter	clinical testing
New York Genome Center	RCV002493417	SCV003925220	uncertain significance	Hypercholesterolemia, autosomal dominant, type B; Familial hypobetalipoproteinemia 1	2022-07-11	criteria provided, single submitter	clinical testing	The c.2258G>A variant in the APOB has previously been reported in individuals with isolated hypertriglyceridemia, nonalcoholic fatty liver disease (NAFLD) with hepatocellular carcinoma (HCC) and with sudden unexplained death (SUD) [PMID: 30842500, 33303402, 32101375] and it has been deposited in ClinVar [ClinVar ID:630345] as Variant of Uncertain Significance in association with Familial hypercholesterolemia. The c.2258G>A variant is observed in 115 alleles (0.0146% minorallele frequency with 0 homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8, All of Us). The c.2258G>A variant in the APOB is located in exon 16 of this 29-exon gene and predicted to replace an evolutionarily conserved glycine amino acid with glutamic acid at position 753 of the encoded protein. In silico predictions are inconclusive of the p.(Gly753Glu) variant's effect [(CADD v1.6 = 26.1, REVEL = 0.186)]; however, there are no functional studies to support or refute these predictions. Based on available evidence this c.2258G>A p.(Gly753Glu) variant identified in the APOB is classified as a Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003478468	SCV004221785	uncertain significance	not provided	2024-03-19	criteria provided, single submitter	clinical testing	The APOB c.2258G>A (p.Gly753Glu) variant has been reported in the published literature in individuals with familial hypercholesterolemia (FH) (PMID: 35913489 (2022)), hypertriglyceridemia (PMID: 33303402 (2021)), and nonalcoholic fatty liver disease (PMID: 32101375 (2020)). The frequency of this variant in the general population, 0.0011 (13/11454 chromosomes in Southern European subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV003478468	SCV004848474	uncertain significance	not provided	2022-05-12	criteria provided, single submitter	clinical testing	The p.Gly753Glu variant in APOB has been not reported in individuals with familial hypercholesterolemia, but has been reported in one individual with non-alcoholic fatty liver disease and 1 individual with hypertriglyceridemia (Pelusi 2019 PMID: 30842500, Gill 2021 PMID: 33303402). It has been identified in 0.04% (16/34534) of Latino/Admixed American chromosomes in gnomAD (https://gnomad.broadinstitute.org/variant/2-21247983-C-T). This variant has also been reported in ClinVar (Variation ID 630345). Computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: BP4.
Metabolic Liver Diseases Lab, Fondazione IRCCS Ca Granda Policlinico, University of Milan	RCV001027456	SCV001190024	likely pathogenic	Familial hypobetalipoproteinemia 1	2018-12-01	no assertion criteria provided	case-control