Submissions for variant NM_174936.4(PCSK9):c.709C>T (p.Arg237Trp)

gnomAD frequency: 0.00066  dbSNP: rs148195424

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000256274	SCV000323052	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research	0/190 non-FH alleles (portuguese normolipidemic individuals); 0/100 normolipidemic individuals
Robarts Research Institute, Western University	RCV000256274	SCV000484816	uncertain significance	Hypercholesterolemia, familial, 1	2019-08-22	criteria provided, single submitter	clinical testing
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	RCV000417261	SCV000503510	uncertain significance	Hypercholesterolemia, autosomal dominant, 3	2016-12-16	criteria provided, single submitter	clinical testing	subjects mutated among 2600 FH index cases screened = 2, family member = 1 / Software predictions: Damaging
Color Diagnostics, LLC DBA Color Health	RCV000771113	SCV000902818	likely benign	Familial hypercholesterolemia	2019-08-23	criteria provided, single submitter	clinical testing	This variant has been identified in 0.2200% (62/28178) of Color clients and in 0.1327% (47/35392) of Latino population in the Genome Aggregation Database (gnomAD). This variant allele frequency is greater than expected for PCSK9-related disorders based on prevalence, penetrance, and genetic heterogeneity. Therefore, this variant is classified as Likely Benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000417261	SCV001002323	likely benign	Hypercholesterolemia, autosomal dominant, 3	2024-02-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001099242	SCV001255678	uncertain significance	Hypobetalipoproteinemia	2017-04-28	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	RCV000417261	SCV001255679	uncertain significance	Hypercholesterolemia, autosomal dominant, 3	2017-04-28	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001194053	SCV001363300	likely benign	not specified	2021-05-16	criteria provided, single submitter	clinical testing	Variant summary: PCSK9 c.709C>T (p.Arg237Trp) results in a non-conservative amino acid change located in the Peptidase S8/S53 domain (IPR000209) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00072 in 249096 control chromosomes. The observed variant frequency is approximately 19 fold of the estimated maximal expected allele frequency for a pathogenic variant in PCSK9 causing Familial Hypercholesterolemia phenotype (3.8e-05), strongly suggesting that the variant is benign. c.709C>T has been reported in the literature in sequencing studies of individuals affected with hypercholesterolemia (e.g. Kotowski_2006, Homer_2008, Madeiros_2016, Berge_2006, Cameron_2008, Leren_2008, Lange_2014, Benn_2017, Balder_2018) without strong evidence for causality. These reports do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. At-least one co-occurrence with another pathogenic variant causative of Familial Hypercholesterolemia has been observed at our laboratory (LDLR c.2043C>A, p.Cys681*), providing supporting evidence for a benign role. Several publications report experimental evidence evaluating an impact on protein function. One group reports little to no damaging effects for the variant in the processing and secretion of PCSK9 protein (Benjannet_2004, Benjannet_2006). Another study reports a very mild increase in the expression of LDL receptor on the cell surface and slightly higher levels of LDL internalization in cells with the variant (Cameron_2006). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=2; VUS, n=6). Based on the evidence outlined above, the variant was classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001284675	SCV001470596	likely benign	not provided	2022-12-28	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV001284675	SCV001715291	uncertain significance	not provided	2019-06-09	criteria provided, single submitter	clinical testing
GeneDx	RCV001284675	SCV001874182	uncertain significance	not provided	2022-05-26	criteria provided, single submitter	clinical testing	Also identified in patients with hypercholesterolemia in published literature (de Paiva Silvino et al., 2020; Gill et al., 2021; Meshkov et al., 2021); at least one patient also harbored a pathogenic variant in the LDLR gene (Wang et al., 2016); Published functional studies demonstrate loss-of-function with a modest effect, resulting in a 16% increased level of cell surface LDL-receptors and a 35% increase in the internalization of LDL when compared to wild-type PCSK9 (Cameron et al., 2006); This variant is associated with the following publications: (PMID: 18300938, 25046268, 16424354, 16465619, 17765244, 21943799, 28157721, 17435765, 16912035, 15358785, 24507775, 27535533, 16571601, 26582918, 27765764, 33418990, 33231818, 33303402)
Mendelics	RCV001194053	SCV002518457	uncertain significance	not specified	2022-05-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002365275	SCV002663096	likely benign	Cardiovascular phenotype	2021-06-30	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.
New York Genome Center	RCV000417261	SCV002764436	uncertain significance	Hypercholesterolemia, autosomal dominant, 3	2021-10-26	criteria provided, single submitter	clinical testing	The c.709C>T (p.Arg237Trp) variant identified in the PCSK9 gene substitutes a conserved Arginine for Tryptophan at amino acid 237/693 (exon5/12). This variant is found in 99 heterozygotes in gnomAD(v3.1.1) (0 homozygotes; allele frequency:6.5e-4), which is slightly higher than expected for a pathogenic Familial Hypercholesterolemia associated variant (ClinGen Familial Hypercholesterolemia Expert Panel Specifications, Version 1.1). In silico algorithms predict this variant to be Pathogenic (REVEL; score:0.615) and Damaging (SIFT; score:0.001) to the function of the canonical transcript. This variant is reported in ClinVar as both a Variant of Uncertain Significance and Likely Benign (VarID:265933). The p.Arg237Trp variant has been reported in individuals in the literature with hypercholesterolemia [PMID:26020417, 18262190, 16465619, 33418990], but has also been identified in many individuals with hypocholesterolemia [PMID:29459468,24507775, 20623344, 16424354, others]. Functional studies on the role of this variant to PCSK9 function are conflicting, with some studies suggesting no damaging effect on PCSK9 [PMID:15358785, 29259136], and another suggesting mild increase in LDL receptor and higher LDL internalization possibly due to failure to undergo autocatalytic cleavage [PMID:16571601]. The p.Arg237 residue is within the Peptidase S8 domain of PCSK9 (UniProtKB:Q8NBP7). Given the conflicting informationregarding the c.709C>T (p.Arg237Trp) variant identified in the PCSK9 gene, it is reported as a Variant of Uncertain Significance.
CeGaT Center for Human Genetics Tuebingen	RCV001284675	SCV004042432	likely benign	not provided	2023-09-01	criteria provided, single submitter	clinical testing	PCSK9: BS1
CSER _CC_NCGL, University of Washington	RCV000256274	SCV000503554	uncertain significance	Hypercholesterolemia, familial, 1	2016-08-01	no assertion criteria provided	research	Found in patient having exome sequencing for an unrelated indication. No known history of hyperlipidemia.
Phenosystems SA	RCV002463441	SCV002757888	uncertain significance	Short fetal femur length		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004535242	SCV004743984	likely benign	PCSK9-related disorder	2024-02-02	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).