Submissions for variant NM_000384.3(APOB):c.9175C>T (p.Arg3059Cys)

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000497061	SCV000588446	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000844614	SCV000731607	likely pathogenic	Homozygous familial hypercholesterolemia	2019-03-26	criteria provided, single submitter	clinical testing	The p.Arg3059Cys variant in APOB has been reported in 3 individuals with autosomal dominant hypercholesterolemia, and segregated with disease in 8 affected relatives of one family, though 2 other family members had the variant but only had mildly elevated high cholesterol (Motazacker et al. 2012). In vitro functional studies looking at LDL uptake provide some evidence that the p.Arg3059Cys variant may impact APOB function (Motazacker et al. 2012). The variant has been reported by other clinical laboratories in ClinVar (Variation ID 69508) and has also been identified in 2/245754 chromosomes of the general population in gnomAD (http://gnomad.broadinstitute.org; dbSNP rs146377316). Conservation analysis shows a lack of conservation at this amino acid site, though replacement by a cysteine has not been observed across species. In summary, although additional studies are required to fully establish its clinical significance, the p.Arg3059Cys variant is likely pathogenic. (ACMG/AMP codes applied: PP1_Strong, PS3_Moderate). Please note that pathogenic variants in APOB can have reduced penetrance and a less severe phenotype than disease-causing LDLR or PCSK9 variants (Youngblom and Knowles, GeneReviews).
Invitae	RCV001837447	SCV000777012	pathogenic	Hypercholesterolemia, autosomal dominant, type B; Familial hypobetalipoproteinemia 1	2023-12-19	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 3059 of the APOB protein (p.Arg3059Cys). This variant is present in population databases (rs146377316, gnomAD 0.003%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 22408029, 29290422; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 69508). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt APOB protein function with a negative predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001248933	SCV001422710	uncertain significance	not specified	2020-01-22	criteria provided, single submitter	curation	The p.Arg3059Cys variant in APOB has been reported in 9 individuals with high LDL, segregated with disease in these 9 affected relatives from 1 family (PMID: 22408029), and has been identified in 0.003% (1/30616) of South Asian chromosomes and 0.0009% (1/113322) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs146377316). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. 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, the clinical significance of the p.Arg3059Cys variant is uncertain. ACMG/AMP Criteria applied: PP1, PM2, BP4 (Richards 2015).
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001800368	SCV002046115	likely pathogenic	not provided	2023-09-05	criteria provided, single submitter	clinical testing	The APOB c.9175C>T (p.Arg3059Cys) variant has been reported in the published literature in individuals with hypercholesterolemia (PMIDs: 29290422 (2018), 33269076 (2021), 34456049 (2022), 36105085 (2022)) and is reported to segregate with the disease in one family (PMID: 22408029 (2012)). In addition, functional studies have shown that this variant results in a significant reduction in low density lipoprotein (LDL) uptake (PMID: 22408029 (2012)). The frequency of this variant in the general population, 0.000008 (2/250928 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as likely pathogenic.
Ambry Genetics	RCV002371903	SCV002685738	uncertain significance	Cardiovascular phenotype	2021-11-12	criteria provided, single submitter	clinical testing	The p.R3059C variant (also known as c.9175C>T), located in coding exon 26 of the APOB gene, results from a C to T substitution at nucleotide position 9175. The arginine at codon 3059 is replaced by cysteine, an amino acid with highly dissimilar properties. In one study, this alteration was reported in a family with hypercholesterolemia and appeared to segregate with disease in multiple individuals; however, two carrier and two non-carrier family members were identified with similar mildly elevated LDL-C levels. The same study detected this variant in two additional unrelated individuals with elevated LDL-C, but clinical details were limited. In vitro functional analyses indicated some reduction in LDL-uptake with this variant compared to wild-type (Motazacker MM et al. Eur. Heart J., 2012 Jun;33:1360-6). Additionally, this alteration has been reported in familial hypercholesterolemia cohorts (Canepa M et al. Int. J. Cardiol., 2018 Mar;255:215-220; Miroshnikova VV et al. Biomed Rep, 2021 Jan;14:15). This amino acid position is poorly 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.
Revvity Omics, Revvity	RCV001800368	SCV003826857	uncertain significance	not provided	2022-01-10	criteria provided, single submitter	clinical testing
GeneDx	RCV001800368	SCV003919457	uncertain significance	not provided	2023-04-18	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Published in vitro functional studies showed some reduction in LDL uptake compared to wildtype receptor; however, it is unclear if this reduction is sufficient to cause disease (Motazacker et al., 2012); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as R3032C; This variant is associated with the following publications: (PMID: 31447099, 22408029, 33269076, 30270084, 29290422, 34456049)
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000497061	SCV000605970	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research