Submissions for variant NM_000384.3(APOB):c.3383G>A (p.Arg1128His)

gnomAD frequency: 0.00356  dbSNP: rs12713843

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000723752	SCV000331502	uncertain significance	not provided	2015-08-27	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000295629	SCV000538318	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: ExAC: 0.7% (116/16506) South Asian chromosomes
Labcorp Genetics (formerly Invitae), Labcorp	RCV001837821	SCV000659280	benign	Hypercholesterolemia, autosomal dominant, type B; Familial hypobetalipoproteinemia 1	2024-02-01	criteria provided, single submitter	clinical testing
Phosphorus, Inc.	RCV000578081	SCV000679805	uncertain significance	Hypercholesterolemia, autosomal dominant, type B	2017-08-01	criteria provided, single submitter	clinical testing
Phosphorus, Inc.	RCV000577967	SCV000679806	uncertain significance	Familial hypobetalipoproteinemia 1	2017-08-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000583315	SCV000687231	likely benign	Hypercholesterolemia, familial, 1	2017-06-26	criteria provided, single submitter	clinical testing
GeneDx	RCV000723752	SCV000730570	likely benign	not provided	2021-06-01	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 14732481, 28008009, 26332594, 21408211, 27153395, 20981092, 30782561, 31150472, 26582918)
Robarts Research Institute, Western University	RCV000583315	SCV000782840	likely benign	Hypercholesterolemia, familial, 1	2018-01-02	criteria provided, single submitter	clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000845396	SCV000987460	likely benign	Primary familial dilated cardiomyopathy		criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000723752	SCV001133405	benign	not provided	2022-06-30	criteria provided, single submitter	clinical testing
Mendelics	RCV000583315	SCV001135625	benign	Hypercholesterolemia, familial, 1	2023-08-22	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000723752	SCV001152158	likely benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	APOB: BP4
Illumina Laboratory Services, Illumina	RCV000578081	SCV001297957	uncertain significance	Hypercholesterolemia, autosomal dominant, type B	2018-05-18	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.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000578081	SCV001422586	likely benign	Hypercholesterolemia, autosomal dominant, type B	2020-01-22	criteria provided, single submitter	curation	The p.Arg1128His variant in APOB has been reported in 2 Caucasian individuals suspected to have familial hypercholesterolemia (DOI: 10.1016/S0735-1097(18)32309-X), and has been identified in 0.7219% (221/30614) of South Asian chromosomes, including 6 homozygotes, 0.4949% (639/129122) of European (non-Finnish) chromosomes, including 3 homozygotes, and 0.3753% (133/35438) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs12713843). This variant has also been reported in ClinVar as a VUS, likely benign, and benign variant (Variation ID: 281142). Computational prediction tools, including splice predictors, 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, although additional studies are required to fully establish its clinical significance, this variant is likely benign. ACMG/AMP Criteria applied: BS1, BP4 (Richards 2015).
Ambry Genetics	RCV002450797	SCV002618278	likely benign	Cardiovascular phenotype	2018-10-18	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.
PreventionGenetics, part of Exact Sciences	RCV004529460	SCV004103508	uncertain significance	APOB-related disorder	2023-02-13	criteria provided, single submitter	clinical testing	The APOB c.3383G>A variant is predicted to result in the amino acid substitution p.Arg1128His. This variant has been reported as a variant of uncertain significance in an individual with primary hypocholesterolemia (Blanco-Vaca et al. 2019. PubMed ID: 30782561). In addition, this variant has been identified in three individuals with low lipid levels (Neale et al. 2011. PubMed ID: 21408211). This variant is reported in 0.72% of alleles in individuals of South Asian descent, and in nine homozygotes in gnomAD (http://gnomad.broadinstitute.org/variant/2-21238367-C-T), which suggests that it may be too common to be a primary cause of disease. This variant has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from benign to likely benign, to uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/281142/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000723752	SCV004562152	likely benign	not provided	2023-10-23	criteria provided, single submitter	clinical testing
GENinCode PLC	RCV004584654	SCV005074063	benign	Familial hypercholesterolemia	2022-09-26	criteria provided, single submitter	clinical testing