ClinVar Miner

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

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Total submissions: 13
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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 2020-03-15 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 RCV000505260 SCV000539998 likely pathogenic Familial hypercholesterolemia 1 2020-03-03 criteria provided, single submitter clinical testing The p.Arg496Trp variant in PCSK9 has been reported in the heterozygous state in >25 individuals with hypercholesterolemia or primary dyslipidemia, the majority of whom were from Turkey or the Netherlands, and segregated with disease in 1 affected individual (Bertolini 2013 PMID: 23375686, Hopkins 2015 PMID: 26374825, Ohta 2016 PMID: 27206942, Kaya 2017 PMID: 28777095, Martin-Campos 2018 PMID: 30293936, Eroglu 2018 PMID: 29724976, Invitae pers. comm., GeneDx pers. comm.). In addition, it was identified in an individual with a severe presentation who also carried a pathogenic variant in LDLR. His affected mother also carried the PCSK9 variant (Pisciotta 2006 PMID: 16183066). It has been seen in the homozygous state in 2 individuals with hypercholesterolemia (Kaya 2017 PMID: 28777095, Eroglu 2018 PMID: 29724976, Invitae pers. comm.). A case control study of Turkish individuals showed that individuals harboring this variant were statistically more likely to be affected with primary dyslipidemia compared to controls and had a 12.8-fold higher triglyceride levels compared to controls (Eroglu 2018 PMID: 29724976). This variant has also been identified in 0.026% (8/30508) of South Asian chromosomes and 0.003% (4/126638) of European chromosomes by gnomAD ( and has been reported in ClinVar (Variation ID 201129). An in vitro functional studies showed a modest gain of function impact (Fasano 2009 PMID: 19081568) and 2 additional studies did not demonstrate a significant functional change (Pisciotta 2006 PMID: 16183066, Ly 2014 PMID: 24808179); however, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein and 1 mammal carries Tryptophan (Trp) at this position with high nearby conservation. In summary, although additional studies are required to fully establish its clinical significance particularly because the allele frequency of this variant in the South Asian population of gnomAD is relatively high and functional studies are unclear, this variant meets criteria to be classified as likely pathogenic for autosomal dominant familial hypercholesterolemia. ACMG/AMP Criteria applied: PS4, PM3.
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 Health, Inc RCV001182214 SCV001347573 uncertain significance Familial hypercholesterolemia 2021-01-21 criteria provided, single submitter clinical testing This missense variant replaces arginine with tryptophan at codon 496 in the C-terminal region of the PCSK9 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Evolutionary conservation analysis indicates that arginine at this position is not well conserved and the variant tryptophan amino acid is tolerated in multiple mammalian species, suggesting that this variant is unlikely to adversely affect protein function. Functional studies have shown that this variant does not disrupt PCSK9 secretion (PMID: 27280970) or LDLR expression, uptake or degradation (PMID: 16183066, 19081568, 27280970, 31949048, 32058034). The mutant protein has shown normal ability to bind annexin A2, an extracellular endogenous inhibitor of PCSK9 activity on cell-surface LDLR degradation (PMID: 24808179). Unlike the wild type protein, the mutant protein has shown inability to bind LDL particles in vitro (PMID: 31949048), and the physiological significance of this observation is not clear. This variant has been reported in over ten individuals affected with familial hypercholesterolemia (PMID: 26374825, 27206942, 28777095, 32044282, 33147992). In a study of 80 Turkish individuals affected with hypercholesterolemia (PMID: 28777095), LDL-C levels of one homozygous individual (197-378 mg/dl) overlapped the LDL-C levels observed in six heterozygous individuals (92-378 mg/dl). A follow-up study of 200 Turkish individuals with primary dyslipidemia and 201 healthy controls has shown that individuals who carry both PCS9 p.Arg496Trp and p.Asp374Tyr show increased LDL-C levels, when compared to individuals who do not carry these variants (p=0.028) (PMID: 29724976). This study did not provide data specific for the p.Arg496Trp variant. This variant has also been observed in three related, heterozygous individuals affected with hypercholesterolemia (PMID: 16183066, 23375686), one of whom also carried a pathogenic LDLR variant and showed a severe phenotype (PMID: 16183066). This p.Arg496Trp variant has been identified in 12/273982 chromosomes in the general population by the Genome Aggregation Database (gnomAD). In summary, this variant has been observed in affected individuals, as well as in unaffected individuals (Color internal data, PMID: 29724976) and in the general population. Multiple functional studies have shown no significant deficit in the mutant protein function. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000455706 SCV001572417 uncertain significance not specified 2021-04-08 criteria provided, single submitter clinical testing Variant summary: PCSK9 c.1486C>T (p.Arg496Trp) results in a non-conservative amino acid change located in the Proprotein convertase subtilisin/kexin type 9, C-terminal domain (IPR041254) 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 4.4e-05 in 247944 control chromosomes. The observed variant frequency is approximately 1.2 fold of the estimated maximal expected allele frequency for a pathogenic variant in PCSK9 causing Familial Hypercholesterolemia phenotype (3.8e-05), suggesting that the variant is benign. c.1486C>T has been reported in the literature in individuals affected with Familial Hypercholesterolemia, however without strong evidence for pathogenicity such as co-segregation (Hopkins_2015, Ohta_2016, Abul-Husn_2016, Kaya_2017, Martn-Campos__2018, Hori_2019, Huijgen_2020, Miroshnikova_2020, Gill_2020). Additionally, in one family, the variant has been reported in one FH proband also carried another pathogenic LDLR variant (E228K, c.682G>A), affected probands mother and unaffected child (Pisciotta_2006, Bertolini_2013). Functional studies showed this variant had a neutral effect on the cell-surface LDL receptor in FACS assay and did not affect the ability of PCSK9 to bind AnxA2 (Fasano_2009, Ly_2014). However, one in-vitro study showed this variant disrupts LDL binding completely (Sarkar_2020). Ten ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=8) and pathogenic (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance until additional information becomes available.
Mayo Clinic Laboratories, Mayo Clinic RCV000766559 SCV001715292 uncertain significance not provided 2019-04-21 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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