ClinVar Miner

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

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Total submissions: 5
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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 Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Laboratory for Molecular Medicine,Partners HealthCare 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 RCV000655087 SCV000777012 uncertain significance Familial hypercholesterolemia 2; Hypobetalipoproteinemia, familial, 1 2017-08-30 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 3059 of the APOB protein (p.Arg3059Cys). The arginine residue is weakly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs146377316, ExAC 0.01%). This variant has been reported to segregate with hypercholesterolemia in a single family (PMID: 22408029). Experimental studies have shown that this missense change causes a large reduction in low density lipoprotein (LDL) uptake (PMID: 22408029). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000497061 SCV000605970 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research
Broad Institute Rare Disease Group, Broad Institute RCV001248933 SCV001422710 uncertain significance not specified 2020-01-22 no assertion criteria provided 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).

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