Submissions for variant NM_000384.3(APOB):c.7939A>C (p.Thr2647Pro)

gnomAD frequency: 0.00003  dbSNP: rs748143305

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001027449	SCV000427028	uncertain significance	Familial hypobetalipoproteinemia 1	2018-01-13	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	RCV000342877	SCV000427029	uncertain significance	Hypercholesterolemia, autosomal dominant, type B	2018-01-13	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.
Fulgent Genetics, Fulgent Genetics	RCV002487484	SCV002780161	uncertain significance	Hypercholesterolemia, autosomal dominant, type B; Familial hypobetalipoproteinemia 1	2021-08-16	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003298389	SCV004000631	uncertain significance	Cardiovascular phenotype	2023-03-29	criteria provided, single submitter	clinical testing	The p.T2647P variant (also known as c.7939A>C), located in coding exon 26 of the APOB gene, results from an A to C substitution at nucleotide position 7939. The threonine at codon 2647 is replaced by proline, an amino acid with highly similar properties. This amino acid position is not well conserved in available 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV004999333	SCV005624834	uncertain significance	not provided	2024-07-23	criteria provided, single submitter	clinical testing	The APOB c.7939A>C (p.Thr2647Pro) variant has been reported in the published literature in individuals with hepatocellular carcinoma (PMID: 30842500 (2019)). The frequency of this variant in the general population, 0.000044 (5/113328 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002487484	SCV005856295	likely benign	Hypercholesterolemia, autosomal dominant, type B; Familial hypobetalipoproteinemia 1	2024-02-14	criteria provided, single submitter	clinical testing
Metabolic Liver Diseases Lab, Fondazione IRCCS Ca Granda Policlinico, University of Milan	RCV001027449	SCV001190017	likely pathogenic	Familial hypobetalipoproteinemia 1	2018-12-01	no assertion criteria provided	case-control