ClinVar Miner

Submissions for variant NM_174936.3(PCSK9):c.1251C>A (p.His417Gln) (rs143275858)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Robarts Research Institute,Western University RCV000408779 SCV000484815 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 RCV000417285 SCV000503516 likely benign Familial hypercholesterolemia 3 2016-12-16 criteria provided, single submitter clinical testing subjects mutated among 2600 FH index cases screened = 2 / One index case is double heterozygote with moderate phenotype / Software predictions: Conflicting
Invitae RCV000417285 SCV001004200 likely benign Familial hypercholesterolemia 3 2019-12-31 criteria provided, single submitter clinical testing
Color RCV001176515 SCV001340528 likely benign Familial hypercholesterolemia 2018-08-08 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001194054 SCV001363302 likely benign not specified 2019-09-10 criteria provided, single submitter clinical testing Variant summary: PCSK9 c.1251C>A (p.His417Gln) results in a non-conservative amino acid change located in the Peptidase S8/S53 domain (IPR000209) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00021 in 251248 control chromosomes, predominantly at a frequency of 0.0032 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 34-fold the estimated maximal allele frequency expected for a pathogenic variant in PCSK9 causing Familial Hypercholesterolemia phenotype (9.4e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.1251C>A has been reported in the literature in individuals affected with hypercholesterolemia without strong evidence for causality (Kotowski_2006, Wang_2016). In one cohort, the association between this variant and LDL-C levels was not found (Kotowski_2006). At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant to PCSK9 processing (Chorba_2018). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.

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