ClinVar Miner

Submissions for variant NM_174936.4(PCSK9):c.1486C>T (p.Arg496Trp) (rs374603772)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766559 SCV000234927 uncertain significance not provided 2017-07-10 criteria provided, single submitter clinical testing The R496W variant of uncertain significance in the PCSK9 gene has been reported several times in association with FH (Pisciotta et al., 2006; Fasano et al., 2009; Bertolini et al., 2013; Ohta et al., 2016). Pisciotta et al. (2006) originally identified R496W in a proband with homozygous FH who also harbored a second variant in the LDLR gene. In this same study, the proband's mother was found to be a heterozygous carrier of R496W and had plasma LDL-C levels similar to those of individuals with heterozygous FH (Pisciotta et al., 2006). Bertolini et al. (2013) reported R496W in an Italian female proband with severe carotid stenosis and significantly elevated LDL-C, as well as in her 2 year-old granddaughter with elevated LDL-C levels. Ohta et al. (2016) identified R476W in a Japanese individual with heterozygous FH clinical phenotype, although it is unclear whether this individual harbored any additional variants in the PCSK9 or LDLR genes. The R496W variant was observed in 5/15,790 (0.03%) alleles from individual of South Asian ancestry in the Exome Aggregation Consortium (Lek et al., 2016). R496W 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. However, this substitution occurs at a position that is not conserved, where W496 is the native amino acid residue in at least two species. Functional studies utilizing HEK293T cells demonstrated that cells transfected with the R496W variant showed slightly increased activity on cell surface LDLRs compared to wild-type, yet the confidence interval was large (Fasano et al., 2009).
Invitae RCV000231738 SCV000291597 uncertain significance Familial hypercholesterolemia 3 2019-12-13 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 496 of the PCSK9 protein (p.Arg496Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs374603772, ExAC 0.03%). This variant has been reported in the literature in an individual affected with familial hypercholesterolemia, who was also heterozygous for a pathogenic variant in the LDLR gene (PMID: 16183066). This individual's affected mother and unaffected child were heterozygous for the PCSK9 variant (PMID: 16183066, 23375686). This variant has also been observed in other individuals with familial hypercholesterolemia (PMID: 26374825, 28777095, 27206942, Invitae). ClinVar contains an entry for this variant (Variation ID: 201129). Experimental studies have shown that this missense change had a neutral effect on the cell-surface LDL receptor (PMID: 16183066, 19081568). In addition, the tryptophan amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. However, algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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.
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies,APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix RCV000231738 SCV000503508 uncertain significance Familial hypercholesterolemia 3 2016-12-16 criteria provided, single submitter clinical testing subjects mutated among 2600 FH index cases screened = 3 / Software predictions: Damaging
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000455706 SCV000539998 uncertain significance not specified 2016-10-20 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in 1 proband with "homozygous" FH who was also het for LDLR E228K. Functional study suggests activity is similar to WT.ClinVar: Path by GeneDx.
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge RCV000505260 SCV000599432 uncertain significance Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter curation
Illumina Clinical Services Laboratory,Illumina RCV000231738 SCV000914420 pathogenic Familial hypercholesterolemia 3 2018-12-04 criteria provided, single submitter clinical testing Across a selection of the available literature, the PCSK9 c.1486C>T (p.Arg496Trp) missense variant has been identified in a total of 20 individuals with familial hypercholesterolemia, including in a homozygous state in one individual, in a double heterozygous state with a pathogenic variant in the LDLR gene in one individual, and in a heterozygous state in 18 individuals, 16 of whom are unrelated (Pisciotta et al. 2006; Bertolini et al. 2013; Hopkins et al. 2015; Ohta et al. 2016; Kaya et al. (2017). Pisciotta et al. (2006) postulate an additive effect of the p.Arg496Trp variant on the pathogenic LDLR variant to account for the clinical homozygous FH phenotype in the double heterozygous proband. The p.Arg496Trp variant was absent from 110 controls and is reported at a frequency of 0.00032 in the South Asian population of the Exome Aggregation Consortium. FACS-based determination of the potency of PCSK9 mutants on cell-surface LDLR in EBV-human transformed lymphocytes revealed the p.Arg496Trp variant showed a small but significant increase in its capacity to reduce LDLR compared with WT PCSK9 (Fasano et al. 2009). Based on the collective evidence, the p.Arg496Trp variant is classified as pathogenic for familial hypercholesterolemia.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000766559 SCV001147295 uncertain significance not provided 2018-05-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001097684 SCV001253986 uncertain significance Hypobetalipoproteinemia 2017-04-27 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.
Color RCV001182214 SCV001347573 uncertain significance Familial hypercholesterolemia 2019-07-21 criteria provided, single submitter clinical testing
GeneReviews RCV000231738 SCV000490157 pathogenic Familial hypercholesterolemia 3 2016-12-08 no assertion criteria provided literature only
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000505260 SCV000606711 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research

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