Submissions for variant NM_174936.4(PCSK9):c.1251C>A (p.His417Gln)

gnomAD frequency: 0.00078  dbSNP: rs143275858

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Robarts Research Institute, Western University	RCV000408779	SCV000484815	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	RCV000417285	SCV000503516	likely benign	Hypercholesterolemia, autosomal dominant, 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	Hypercholesterolemia, autosomal dominant, 3	2024-01-25	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001176515	SCV001340528	likely benign	Familial hypercholesterolemia	2018-08-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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.
Ambry Genetics	RCV002411272	SCV002669583	likely benign	Cardiovascular phenotype	2019-12-12	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.
GeneDx	RCV003332164	SCV004039704	uncertain significance	not provided	2023-04-04	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Reported in association with high LDL in published literature; however, causality has not been clearly demonstrated (Kotowski et al., 2006); This variant is associated with the following publications: (PMID: 16465619, 23663650, Pham2021, 25904937, 17971861)