Submissions for variant NM_000384.3(APOB):c.8550T>G (p.Ile2850Met)

gnomAD frequency: 0.00024  dbSNP: rs148498577

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000455427	SCV000538323	uncertain significance	not specified	2016-03-28	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: Only 1 paper (lower freq in cases than controls); ExAC: 13/66698 European
Labcorp Genetics (formerly Invitae), Labcorp	RCV001837901	SCV000659304	likely benign	Hypercholesterolemia, autosomal dominant, type B; Familial hypobetalipoproteinemia 1	2023-12-28	criteria provided, single submitter	clinical testing
Robarts Research Institute, Western University	RCV000660701	SCV000782886	uncertain significance	Hypercholesterolemia, familial, 1	2018-01-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000985342	SCV001133427	uncertain significance	not provided	2018-12-11	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals suspected of being affected with familial hypercholesterolemia (PMIDs: 24503134 (2014), 32770674 (2020), 35913489 (2022)) or affected with a cardiomyopathy (PMID: 32009526 (2020)). The frequency of this variant in the general population, 0.00057 (29/50706 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 predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Illumina Laboratory Services, Illumina	RCV001142145	SCV001302555	uncertain significance	Familial hypobetalipoproteinemia 1	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.
Illumina Laboratory Services, Illumina	RCV001142146	SCV001302556	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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000660701	SCV001433156	uncertain significance	Hypercholesterolemia, familial, 1	2019-04-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000985342	SCV001874940	uncertain significance	not provided	2022-06-06	criteria provided, single submitter	clinical testing	Identified in a patient with dyslipidemia (Johansen et al., 2014) and in a control individual (Beaudoin et al., 2012) in published literature; In silico analysis supports that this missense variant does not alter protein structure/function; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 402376; ClinVar); This variant is associated with the following publications: (PMID: 24503134, 22923420, 27535533)
Ambry Genetics	RCV002411423	SCV002675512	likely benign	Cardiovascular phenotype	2022-09-27	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000985342	SCV003799479	uncertain significance	not provided	2022-09-20	criteria provided, single submitter	clinical testing	The APOB c.8550T>G; p.Ile2850Met variant (rs148498577) is reported in the literature in an individual with suspected monogenic dyslipidemia (Johansen 2014). This variant is also reported in ClinVar (Variation ID: 402376) and is found in the general population with an allele frequency of 0.017% (48/282,426 alleles) in the Genome Aggregation Database. The isoleucine at codon 2850 is moderately conserved, but computational analyses predict that this variant is neutral (REVEL: 0.037). However, given the lack of clinical and functional data, the significance of the p.Ile2850Met variant is uncertain at this time. References: Johansen CT et al. LipidSeq: a next-generation clinical resequencing panel for monogenic dyslipidemias. J Lipid Res. 2014 Apr;55(4):765-72. PMID: 24503134.
CeGaT Center for Human Genetics Tuebingen	RCV000985342	SCV004183718	likely benign	not provided	2023-11-01	criteria provided, single submitter	clinical testing	APOB: BP4
Clinical Genetics, Academic Medical Center	RCV000455427	SCV001921323	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000985342	SCV001965122	likely benign	not provided		no assertion criteria provided	clinical testing