Submissions for variant NM_000384.3(APOB):c.8045G>T (p.Ser2682Ile)

dbSNP: rs375053331

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001838367	SCV001236846	likely benign	Hypercholesterolemia, autosomal dominant, type B; Familial hypobetalipoproteinemia 1	2025-01-30	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001139649	SCV001299823	uncertain significance	Familial hypobetalipoproteinemia 1	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV001139650	SCV001299824	uncertain significance	Hypercholesterolemia, autosomal dominant, type B	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
New York Genome Center	RCV001838367	SCV002764332	uncertain significance	Hypercholesterolemia, autosomal dominant, type B; Familial hypobetalipoproteinemia 1	2021-08-13	criteria provided, single submitter	clinical testing	The c.8045G>T, p.Ser2682Ile variant identified in the APOB gene has not been reported in the literature in individuals with APOB-associated disorders. This variant has seven heterozygous individuals in the gnomAD(v3.1.1) database, suggesting it is not a common benign variant in the populations represented in that database. In silico algorithms do not agree on the effect of this variant, as it is predicted both damaging and benign to the function of thecanonical transcript. Given the lack of compelling evidence for its pathogenicity, the c.8045G>T, p.Ser2682Ile variant identified in the APOB gene is reported as a Variant of Uncertain Significance.
Ambry Genetics	RCV004031151	SCV003570136	uncertain significance	Cardiovascular phenotype	2021-08-10	criteria provided, single submitter	clinical testing	The c.8045G>T (p.S2682I) alteration is located in exon 26 (coding exon 26) of the APOB gene. This alteration results from a G to T substitution at nucleotide position 8045, causing the serine (S) at amino acid position 2682 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
GeneDx	RCV003329376	SCV004036258	uncertain significance	not provided	2023-03-21	criteria provided, single submitter	clinical testing	Identified in individuals with familial hyperlipidemia or combined hyperlipidemia in published literature, although detailed clinical information and segregation data was not available (Gill et al., 2021; Sustar et al., 2022); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 35913489, 33303402)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003329376	SCV005624835	uncertain significance	not provided	2024-04-01	criteria provided, single submitter	clinical testing	The APOB c.8045G>T (p.Ser2682Ile) variant has been reported in the published literature in individuals affected with familial hypercholesterolemia (PMID: 35913489 (2022)) and combined hyperlipidemia (PMID: 33303402 (2021)). The frequency of this variant in the general population, 0.000062 (8/128938 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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.