ClinVar Miner

Submissions for variant NM_174936.3(PCSK9):c.1405C>T (p.Arg469Trp)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182576 SCV000234926 uncertain significance not specified 2017-03-21 criteria provided, single submitter clinical testing The R469W variant has been reported in one individual with severe hypercholesterolemia, who was also heterozygous for a variant in the LDLR gene (Allard et al., 2005). Subsequently, an individual with elevated LDL-C was found to harbor this variant in isolation (Wang et al., 2016). The R469W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Nevertheless, this substitution occurs at a position that is not conserved across species, where W469 is wild-type in at least one mammalian species. Additionally, the majority of in silico analyses (2 out of 3) predict this variant likely does not alter the protein structure/function. Though R469W was presumed to be a gain-of-function variant by Hampton et al. (2007), in vitro functional analysis showed no effect on the ability of the PCSK9-encoded protein to bind Annexin A2, a protein responsible for inhibiting PCSK9-endoded protein activity (Ly et al,. 2014). Therefore, the mechanism by which this variant may result in disease is unclear. Furthermore, the Exome Aggregation Consortium reports R469W was observed in 80/10392 (0.8%) alleles from individuals of African background, including two individuals of African background who were homozygous for the variant. Of note, this variant has been reported in individuals of African descent with high LDL, though the association was not statistically significant (Kotowski et al., 2006). It has also been identified in two individuals of African Canadian descent from the general population who also harbored other PCSK9 variants (Mayne et al., 2013). Ultimately, the possibility that this variant may have a mild clinical effect and/or function as a genetic modifier for disease can not be excluded, at this time.
Invitae RCV000228895 SCV000291596 benign Familial hypercholesterolemia 3 2019-12-31 criteria provided, single submitter clinical testing
Robarts Research Institute,Western University RCV000408878 SCV000484814 likely benign Familial hypercholesterolemia 1 2019-08-22 criteria provided, single submitter clinical testing
Laboratory of Genetics and Molecular Cardiology, University of São Paulo RCV000408878 SCV000588683 uncertain significance Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Color RCV000776243 SCV000911494 likely benign Familial hypercholesterolemia 2018-02-15 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000182576 SCV000917973 likely benign not specified 2020-02-25 criteria provided, single submitter clinical testing Variant summary: PCSK9 c.1405C>T (p.Arg469Trp) results in a non-conservative amino acid change located in the Proprotein convertase subtilisin/kexin type 9, C-terminal domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0006 in 252032 control chromosomes, predominantly at a frequency of 0.0084 within the African or African-American subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 90 fold of the estimated maximal expected allele frequency for a pathogenic variant in PCSK9 causing Familial Hypercholesterolemia phenotype (9.4e-05), suggesting that the variant may not be associated with Familial Hypercholesterolemia. c.1405C>T has been reported in the literature in sequencing studies of individuals affected with Familial Hypercholesterolemia (example, Allard_2005, Kotowski_2006, Mayne_2013, Wang_2016 and Taranto_2017). At-least one patient with tendinous xanthomata and an elevated lipid profile in whom a co-occurring LDL-R variant, c.1209delC ( p.Phe403fs) that could have explained the phenotype, has been described (Allard_2005). The authors postulated a digenic/additive role for this variant. At least one study of 57,850 individuals with African ancestry showed that this variant is associated with elevated maxLDL levels (Sun_2018). This association was not found in individuals with European or Chinese ancestry (Sun_2018, Lu_2016). Furthermore, this variant was identified among carriers who did not meet the Dutch Lipid Clinic Network (DLCN) criteria for a diagnosis of possible, probable or definite FH, thereby resulting in an estimated clinical penetrance of 0% (Abul-Husn_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. Multiple experimental showed that this variant may result in loss of function effect (Geschwindner_2015), no effect on binding activity to AnxA2 (Ly_2014), and no effect on protein processing (Chorba_2017). PCSK9 normally degrades LDL-Receptor. Defective PCSK9 results in impaired LDL-receptor degradation, resulting in an increased uptake of plasma LDL than necessary, leading to hypocholesterolemia. Therefore, a GOF mechanism has been attributed to variants in PCSK9 that are causative of FH. However, none of the ascertained functional studies provide concrete evidence supporting an association of this variant with the pathognomic mechanism of FH attributed to variants in PCSK9. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation with conflicting assessments (benign, n=1; likely benign, n=2; VUS, n=2). Based on the evidence outlined above, although some residual association as a risk factor for high LDL levels cannot be entirely ruled out, the variant was classified as likely benign in the context of an association with inherited autosomal dominant Familial Hypercholesterolemia.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000228895 SCV000987631 uncertain significance Familial hypercholesterolemia 3 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001095907 SCV001252085 uncertain significance Hypobetalipoproteinemia 2018-02-02 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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina RCV000228895 SCV001253983 likely benign Familial hypercholesterolemia 3 2018-02-02 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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000408878 SCV000606707 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research

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