ClinVar Miner

Submissions for variant NM_174936.4(PCSK9):c.1487G>A (p.Arg496Gln)

gnomAD frequency: 0.00005  dbSNP: rs139669564
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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge RCV000505200 SCV000599433 uncertain significance Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter curation
Invitae RCV000525584 SCV000644862 likely benign Hypercholesterolemia, autosomal dominant, 3 2024-01-16 criteria provided, single submitter clinical testing
Robarts Research Institute, Western University RCV000505200 SCV000782978 uncertain significance Hypercholesterolemia, familial, 1 2018-01-02 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000780579 SCV000917975 benign not specified 2017-09-25 criteria provided, single submitter clinical testing Variant summary: The PCSK9 c.1487G>A (p.Arg496Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. 4/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). One functional study showed that this variant was associated with amounts of cell surface LDLR and LDL internalized that were comparable to that of wild-type levels (Cameron_2006). The variant was found in the control population dataset of gnomAD in 68/240046 control chromosomes at a frequency of 0.0002833, which is approximately 14 times the estimated maximal expected allele frequency of a pathogenic PCSK9 variant (0.00002), suggesting this variant is likely a benign polymorphism. One study found this variant in a subject homozygous for apolipoprotein E-2 who presented with Type III hyperlipoproteinaemia, without strong evidence for causality. This variant was found co-occurring with the pathogenic LDLR c.1775G>A, p.Gly592Glu mutation in an internal specimen, supporting a benign impact of the variant. One clinical diagnostic laboratory classified this variant as uncertain significance. Taken together, this variant is classified as benign.
Color Diagnostics, LLC DBA Color Health RCV001176519 SCV001340532 likely benign Familial hypercholesterolemia 2018-12-01 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000525584 SCV001429009 uncertain significance Hypercholesterolemia, autosomal dominant, 3 2019-06-20 criteria provided, single submitter clinical testing
GeneDx RCV001564604 SCV001787791 uncertain significance not provided 2020-10-08 criteria provided, single submitter clinical testing Identified in association with hyperlipoproteinemia (Cameron et al., 2006) and hypercholesterolemia with early onset coronary artery disease (CAD) (Cao et al., 2018); In silico analysis supports that this missense variant does not alter protein structure/function; Published in vitro functional studies demonstrate no effect on autocatalytic activity and LDL-receptor surface expression and internalized LDL levels comparable to wild-type; nevertheless, it is unclear how these studies may translate to a pathogenic role in vivo (Cameron et al., 2006); Reported in ClinVar (ClinVar Variant ID#438338; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 30526649, 19191301, 16571601)
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000780579 SCV002046473 benign not specified 2020-12-03 criteria provided, single submitter clinical testing
Ambry Genetics RCV002395216 SCV002701640 likely benign Cardiovascular phenotype 2022-03-31 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.
All of Us Research Program, National Institutes of Health RCV000525584 SCV004834744 likely benign Hypercholesterolemia, autosomal dominant, 3 2024-02-05 criteria provided, single submitter clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum RCV000505200 SCV000606712 pathogenic Hypercholesterolemia, familial, 1 no assertion criteria provided research

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