ClinVar Miner

Submissions for variant NM_000384.3(APOB):c.10672C>T (p.Arg3558Cys) (rs12713559)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000219069 SCV000271505 uncertain significance not specified 2019-01-30 criteria provided, single submitter clinical testing The p.Arg3558Cys variant in APOB (alternative nomenclature p.Arg3531Cys) has bee n reported in at least 10 individuals with hypercholesterolemia and segregated w ith disease in >10 relatives from multiple families (Pullinger 1995, Wenham 1997 , Rabes 2000, Beaudoin 2012, Bertolini 2013, Pirillo 2017, Marmontel 2018). Howe ver, several nonsegregations (family members with high LDL or total cholesterol levels who did not carry the variant) have also been reported (Pullinger 1995, W enham 1997, Pullinger 1999, Rabes 2000). In 2 studies, variant carriers were fou nd to be double heterozygous for variations in LDLR that were sufficient to expl ain their disease (Rabes 2000, Bertolini 2013), and in another study the cholest erol levels of carriers of this variant were not statistically different from no n-carriers (Tybjaerg-Hansen 1998). This variant has also been identified in 71/1 26264 European chromosomes by the Genome Aggregation Database (gnomAD, http://gn omad.broadinstitute) and is reported in ClinVar (Variation ID:17897). In vitro f unctional studies provide some evidence that the p.Arg3558Cys variant may impact protein function (Pullinger 1995 and 1999); however, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analysis suggest that the p.Arg3558Cys variant may impact the prot ein, though this information is not predictive enough to determine pathogenicity . In summary, due to the presence of conflicting data, the clinical significance of the p.Arg3558Cys variant is uncertain. ACMG/AMP Criteria applied: PS4_Modera te, PP3, PS3_Supporting, BS4.
Invitae RCV000226811 SCV000284755 uncertain significance Familial hypercholesterolemia 2; Hypobetalipoproteinemia, familial, 1 2018-11-12 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 3558 of the APOB protein (p.Arg3558Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs12713559, ExAC 0.05%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in several individuals and families affected with familial hypercholesterolemia (FH) (PMID: 7883971, 9603795, 9105560, 9925662, 15797858, 23375686, 11031227, 26802169) and in a myocardial infarction patient (PMID: 22923420). There is conflicting evidence regarding the segregation of this variant with disease, several studies have shown segregation with FH (PMID: 7883971, 9105560, 23375686). However, in one large kindred, the p.Arg3558Cys variant was not found to segregate with disease (PMID: 11031227). This variant is also known in the literature as p.Arg3531Cys. ClinVar contains an entry for this variant (Variation ID: 17897). Functional studies have a shown a reduction on LDL binding (PMID: 7883971, 9925662) and total cholesterol levels were higher in affected carriers when compared to non-carriers (PMID: 9603795, 9105560, 9925662). However, in a smaller population-based study the effect on cholesterol levels was not observed (PMID: 9603795), the clinical significance of these findings is unclear. 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.
Laboratory of Genetics and Molecular Cardiology, University of São Paulo RCV000019486 SCV000588453 uncertain significance Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Fundacion Hipercolesterolemia Familiar RCV000019486 SCV000607386 uncertain significance Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Integrated Genetics/Laboratory Corporation of America RCV000587550 SCV000696657 uncertain significance not provided 2016-11-15 criteria provided, single submitter clinical testing Variant summary: The APOB c.10672C>T (p.Arg3558Cys) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 49/141186 (0.0003471) control chromosomes. This frequency is about 2 times the estimated maximal expected allele frequency of a pathogenic APOB variant (0.0001563), suggesting this is likely a benign polymorphism. This variant has been reported in multiple kindreds and none of them had clear evidence for co-segregation of variant with disease. Some of the family members also carried a pathogenic LDLR variant, which in isolation can well explain the phenotype of those individuals. In vitro functional studies provide conflicting results on the effect of this variant. Although one lab classified this variant as pathogenic, multiple clinical diagnostic laboratories classified this variant as VUS. Taken together, this variant is classified as VUS-possibly benign until more information becomes available.
Color RCV000776123 SCV000911048 uncertain significance Familial hypercholesterolemia 2018-05-29 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This variant (also known as p.Arg3521Cys in the mature protein) is a missense variant located in the beta 2 domain of the APOB protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. Experimental studies have demonstrated an impact on the binding affinity of APOB for LDLR and have shown a partial defect in a LDL-induced cell growth assay (PMID: 7883971, 9925662). The variant has been identified in multiple unrelated individuals diagnosed with familial hypercholesterolemia, however, segregation analyses are inconclusive (PMID: 7883971, 9105560, 9925662, 11031227, 23375686, 24607922). This variant has also been identified in 98/276648 chromosomes (71/126264 European) in the general population by the Genome Aggregation Database (gnomAD). Disease association studies have shown that carrier individuals in the general population do not have higher-than-normal plasma cholesterol levels or an increased risk of ischemic heart disease (PMID: 9603795). Although functional studies indicate this variant may be partially defective for LDLR binding in vitro, segregation and disease association analyses do not support a causative role in disease. Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
OMIM RCV000412657 SCV000039783 pathogenic Familial hypercholesterolemia 2 1995-03-01 no assertion criteria provided literature only
GeneReviews RCV000412657 SCV000490150 pathogenic Familial hypercholesterolemia 2 2016-12-08 no assertion criteria provided literature only
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000019486 SCV000605962 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research

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