Submissions for variant NM_000384.3(APOB):c.2068-4T>A

gnomAD frequency: 0.00108  dbSNP: rs41291161

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000454607	SCV000538319	likely benign	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: Not in splice consensus
Labcorp Genetics (formerly Invitae), Labcorp	RCV001837899	SCV000554800	benign	Hypercholesterolemia, autosomal dominant, type B; Familial hypobetalipoproteinemia 1	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000456524	SCV000730571	likely benign	not provided	2021-04-09	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 18492086, 23593297, 17570373, 26332594)
Robarts Research Institute, Western University	RCV000583520	SCV000782826	likely benign	Hypercholesterolemia, familial, 1	2018-01-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000776084	SCV000910832	benign	Familial hypercholesterolemia	2018-06-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000456524	SCV001152173	likely benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	APOB: BP4, BS2
Illumina Laboratory Services, Illumina	RCV001142906	SCV001303398	uncertain significance	Hypercholesterolemia, autosomal dominant, type B	2018-04-16	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.
Ambry Genetics	RCV002418345	SCV002725648	likely benign	Cardiovascular phenotype	2019-11-06	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000456524	SCV004221758	benign	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000456524	SCV001741069	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000454607	SCV001923747	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000456524	SCV001975873	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004539922	SCV004774043	uncertain significance	APOB-related disorder	2023-12-19	no assertion criteria provided	clinical testing	The APOB c.2068-4T>A variant is predicted to interfere with splicing. The c.2068-4T>A substitution is not predicted to alter mRNA splicing (Alamut Visual plus v1.6.1). However it was reported in the compound heterozygous state in two unrelated patients with familial hypobetalipoproteinemia (FHBL) who also harbored a second protein truncating variant in the APOB gene (Tarugi et al. 2007. PubMed ID: 17570373; Di Leo et al. 2008. PubMed ID: 18492086). Di Leo et al. also showed that in vitro the c.2068-4T>A substitution did not alter normal mRNA splicing. FHBL is inherited in a co-dominant manner and is almost always associated with protein truncating variants in the APOB gene (Tarugi et al. 2007. PubMed ID: 17570373). FHBL heterozygotes may be asymptomatic or display symptoms of FHBL to varying degrees. This variant is reported in 0.19% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.