ClinVar Miner

Submissions for variant NM_174936.3(PCSK9):c.709C>T (p.Arg237Trp) (rs148195424)

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Total submissions: 9
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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 Familial hypercholesterolemia 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 Familial hypercholesterolemia 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 Familial hypercholesterolemia 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 RCV000771113 SCV000902818 likely benign Familial hypercholesterolemia 2019-08-23 criteria provided, single submitter clinical testing
Invitae RCV000417261 SCV001002323 likely benign Familial hypercholesterolemia 3 2019-12-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,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 Clinical Services Laboratory,Illumina RCV000417261 SCV001255679 uncertain significance Familial hypercholesterolemia 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.
Integrated Genetics/Laboratory Corporation of America RCV001194053 SCV001363300 likely benign not specified 2019-10-16 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 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 (gnomAD). The observed variant frequency is approximately 7.7 fold the estimated maximal pathogenic allele frequency for a variant in PCSK9 causing Familial Hypercholesterolemia phenotype (9.4e-05), strongly suggesting that the variant is benign. c.709C>T has been reported in the literature in individuals affected with hypercholesterolemia (e.g. Kotowski_2006, Homer_2008, Madeiros_2016) without strong evidence for causality. These reports do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. The variant has also been reported in individuals with hypocholesterolemia (e.g. Berge_2006, Cameron_2008, Leren_2008, Lange_2014, Benn_2017, Balder_2018) without strong evidence for causality. 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 laboratory 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). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
CSER _CC_NCGL, University of Washington RCV000256274 SCV000503554 uncertain significance Familial hypercholesterolemia 1 2016-08-01 no assertion criteria provided research Found in patient having exome sequencing for an unrelated indication. No known history of hyperlipidemia.

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