Submissions for variant NM_000384.3(APOB):c.5066G>A (p.Arg1689His)

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute for Integrative and Experimental Genomics, University of Luebeck	RCV000172971	SCV000212149	likely benign	Hypercholesterolemia, familial, 1		criteria provided, single submitter	research
Robarts Research Institute, Western University	RCV000172971	SCV000484823	uncertain significance	Hypercholesterolemia, familial, 1		criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000455619	SCV000538326	benign	not specified	2017-10-02	criteria provided, single submitter	clinical testing	p.Arg1689His in exon 26 of APOB: This variant is not expected to have clinical significance because it was identified in 0.3% (342/126440) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs151009667). In addition, while it has been reported in 5 individuals with hypertriglyceridemia or a history of early myocardial infarction, it did not segregate with disease in 3 affected relatives from 3 families (Johansen 2010, Braenne 2015). This variant is reported in ClinVar (Variation ID:189304). ACMG/AMP Criteria applied: BS1, BS4 (Richards 2015).
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000172971	SCV000588437	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
GeneDx	RCV000558095	SCV000617638	likely benign	not provided	2021-06-22	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 20657596, 27153395, 26036859, 26415676, 19602640, 30681615, 26582918)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001837740	SCV000659286	likely benign	Hypercholesterolemia, autosomal dominant, type B; Familial hypobetalipoproteinemia 1	2025-02-03	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000771127	SCV000902878	likely benign	Familial hypercholesterolemia	2018-05-02	criteria provided, single submitter	clinical testing	Likely Benign variant based on current evidence: This missense variant (also known as p.Arg1662His in the mature protein) is located in the beta 1 domain of the APOB protein. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. To our knowledge this variant has not been investigated for functional impact in experimental studies nor has the variant been reported in individuals affected with familial hypercholesterolemia in the literature. In a study of individuals affected with myocardial infarction, carrier status of this variant showed no correlation with cholesterol levels (PMID: 26036859). This variant has been identified in 342/126440 non-Finnish European chromosomes (0.27%) in the general population by the Genome Aggregation Database (gnomAD). This variant allele frequency is greater than expected for the disorder based on prevalence, penetrance, and genetic/allelic heterogeneity. Based on available evidence, this variant is classified as Likely Benign.
CeGaT Center for Human Genetics Tuebingen	RCV000558095	SCV001152148	likely benign	not provided	2024-10-01	criteria provided, single submitter	clinical testing	APOB: BP4
Illumina Laboratory Services, Illumina	RCV001137737	SCV001297710	uncertain significance	Familial hypobetalipoproteinemia 1	2018-10-03	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	RCV001137738	SCV001297711	likely benign	Hypercholesterolemia, autosomal dominant, type B	2018-10-03	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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000455619	SCV001433279	likely benign	not specified	2019-03-12	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000558095	SCV001469340	likely benign	not provided	2023-04-10	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000558095	SCV001713962	uncertain significance	not provided	2019-12-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002336387	SCV002642768	likely benign	Cardiovascular phenotype	2018-07-27	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.
New York Genome Center	RCV001837740	SCV002764276	uncertain significance	Hypercholesterolemia, autosomal dominant, type B; Familial hypobetalipoproteinemia 1	2021-04-20	criteria provided, single submitter	clinical testing	The c.5066G>A (p.Arg1689His) variant identified in the APOB gene substitutes a conserved Arginine for Histidine at amino acid 1689/4564 (exon 26/29). This variant is found in gnomAD(v3.1.1) (207 heterozygotes, 0 homozygotes; allele frequency: 1.36e-3), and there is one homozygote present in population data from gnomAD(v2.1.1) (387 heterozygotes, 1 homozygote; allele frequency: 1.37e-3). In silico algorithms predict this variant to be Damaging (SIFT; score:0.003) and Benign (REVEL; 0.222) to the function of the canonical transcript. This variant is reported as both a Variant of Uncertain Significance and Likely Benign in ClinVar (VarID:189304). This variant has been reported in several affected individuals in the literature [PMID: 20657596,26415676,26036859, 30681615], although it does not segregate with disease in some studies [PMID:26036859]. The p.Arg1689 residue is not within a mapped domain of APOB (UniProtKB:P04114). The c.5066G>A (p.Arg1689His) variant identified in the APOB gene is reported as a Variant of Uncertain Significance.
Revvity Omics, Revvity	RCV000558095	SCV003826864	uncertain significance	not provided	2023-05-12	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000558095	SCV004562252	uncertain significance	not provided	2023-10-09	criteria provided, single submitter	clinical testing	The APOB c.5066G>A; p.Arg1689His variant (rs151009667), also known as Arg1662His for legacy nomenclature, is reported in the literature in individuals with familial hypercholesterolemia (Johansen 2010, Radovica-Spalvina 2015), but is also reported to not segregate with disease in one study (Braenne 2016). However, this variant is reported to be positively associated with familial hypercholesterolemia in a Saudi population with an odds ratio of 45.07 (95% CI: 2.67-759.1; p=0.0001) and may be a risk factor (Batais 2019). The p.Arg1689His variant is reported in ClinVar (Variation ID: 189304). It is observed in the general population with an overall allele frequency of 0.1% (387/282574 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.222). Due to conflicting information, the significance of this variant is uncertain at this time. References: Batais MA et al. Screening of common genetic variants in the APOB gene related to familial hypercholesterolemia in a Saudi population: A case-control study. Medicine (Baltimore). 2019 Jan;98(4):e14247. PMID: 30681615. Braenne I et al. Systematic analysis of variants related to familial hypercholesterolemia in families with premature myocardial infarction. Eur J Hum Genet. 2016 Feb;24(2):191-7. PMID: 26036859. Johansen CT et al. Excess of rare variants in genes identified by genome-wide association study of hypertriglyceridemia. Nat Genet. 2010 Aug;42(8):684-7. PMID: 20657596. Radovica-Spalvina I et al. Next-generation-sequencing-based identification of familial hypercholesterolemia-related mutations in subjects with increased LDL-C levels in a latvian population. BMC Med Genet. 2015 Sep 28;16:86. PMID: 26415676.
PreventionGenetics, part of Exact Sciences	RCV004535150	SCV004725482	likely benign	APOB-related disorder	2022-02-04	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).