Submissions for variant NM_174936.4(PCSK9):c.1405C>T (p.Arg469Trp)

Total submissions: 14

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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000228895	SCV000291596	benign	Hypercholesterolemia, autosomal dominant, 3	2024-01-31	criteria provided, single submitter	clinical testing
Robarts Research Institute, Western University	RCV000408878	SCV000484814	likely benign	Hypercholesterolemia, familial, 1	2019-08-22	criteria provided, single submitter	clinical testing
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000408878	SCV000588683	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Color Diagnostics, LLC DBA Color Health	RCV000776243	SCV000911494	likely benign	Familial hypercholesterolemia	2018-02-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000182576	SCV000917973	likely benign	not specified	2021-08-28	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. Seven 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=3; VUS, n=3). 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	Hypercholesterolemia, autosomal dominant, 3		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, 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 Laboratory Services, Illumina	RCV000228895	SCV001253983	likely benign	Hypercholesterolemia, autosomal dominant, 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.
Ambry Genetics	RCV002390460	SCV002697788	likely benign	Cardiovascular phenotype	2019-03-30	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003477647	SCV004222366	benign	not provided	2023-06-08	criteria provided, single submitter	clinical testing
GENinCode PLC	RCV000776243	SCV005077855	benign	Familial hypercholesterolemia	2023-05-02	criteria provided, single submitter	clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000408878	SCV000606707	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV004528959	SCV004108678	uncertain significance	PCSK9-related disorder	2024-06-28	no assertion criteria provided	clinical testing	The PCSK9 c.1405C>T variant is predicted to result in the amino acid substitution p.Arg469Trp. This variant has been reported in individuals with hypercholesterolemia (Allard et al. 2005. PubMed ID: 16211558; Kotowski et al. 2006. PubMed ID: 16465619; Wang et al. 2016. PubMed ID: 27765764, Table SI; Di Taranto et al. 2017. PubMed ID: 29127338). Functional studies showed that this variant has no effect on binding activity to Annexin A2 and protein processing (Ly et al. 2014. PubMed ID: 24808179; Chorba et al. 2017. PubMed ID: 29259136), but another study showed that it may affect the protein activity (Geschwindner et al. 2015. PubMed ID: 25744035). This variant is reported in 0.93% of alleles in individuals of African descent including 1 homozygous individual in gnomAD. In ClinVar, this variant has conflicting interpretations of benign, likely benign, uncertain significance and pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/201128/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.