Total submissions: 9
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000531428 | SCV000644868 | benign | Hypercholesterolemia, autosomal dominant, 3 | 2024-01-25 | criteria provided, single submitter | clinical testing | |
| Color Diagnostics, |
RCV000771132 | SCV000902915 | benign | Familial hypercholesterolemia | 2022-01-01 | criteria provided, single submitter | clinical testing | |
| Mayo Clinic Laboratories, |
RCV001508868 | SCV001715293 | pathogenic | not provided | 2022-08-11 | criteria provided, single submitter | clinical testing | |
| Gene |
RCV001508868 | SCV001766474 | uncertain significance | not provided | 2023-05-02 | criteria provided, single submitter | clinical testing | Identified at a high frequency in individuals of African ancestry and results in a significant reduction in plasma levels of LDL-C (Cohen et al., 2005; Hooper et al., 2007; Huang et al., 2009); Functional studies show that the p.(C679*) variant results in impaired PCSK9 secretion (Lakosi et al., 2009; Benjannet et al., 2012); individuals who harbor this variant have a significant reduction in plasma levels of LDL-C (Cohen et al., 2005; Hooper et al., 2007; Huang et al., 2009); Nonsense variant predicted to result in protein truncation as the last 14 amino acids are lost, although loss-of-function variants have not been reported downstream of this position in the protein; This variant is associated with the following publications: (PMID: 16989838, 30227170, 24507774, 20031607, 27602404, 22875854, 30899674, 33111339, 17461796, 35056760, 34428338, 33207932, 16912035, 35546142, 35859178, 32948841, 36196022, 34340953, 33866776, 28768753, 16465619, 16554528, 18652535, 17599443, 16909389, 30726226, 33563358, 34070931, 34376796, 34606887, 34782856, 35323658, 35323699, 33647772, Pham2021, 19351729, 15654334) |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001731277 | SCV001983711 | uncertain significance | not specified | 2021-09-22 | criteria provided, single submitter | clinical testing | Variant summary: PCSK9 c.2037C>A (p.Cys679X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for Hyporcholesterolemia. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 0.00056 in 248284 control chromosomes, predominantly at a frequency of 0.008 within the African or African-American subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 213 fold of the estimated maximal expected allele frequency for a pathogenic variant in PCSK9 causing Familial Hypercholesterolemia phenotype (3.8e-05), suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.2037C>A has been reported in the literature in individuals affected with Hyporcholesterolemia (Cohen_2005), which may associate with other symptoms (PMID 20626336). However, this variant is likely to confer protection against coronary artery disease due to its LDLC reducing effect (PMID 24507774). Four 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 (Benign n=2, Pathogenic n=1, VUS n=1). Based on the evidence outlined above, the variant was classified as VUS. |
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV001731277 | SCV002046680 | benign | not specified | 2021-02-26 | criteria provided, single submitter | clinical testing | |
| New York Genome Center | RCV000531428 | SCV003925075 | uncertain significance | Hypercholesterolemia, autosomal dominant, 3 | 2022-03-14 | criteria provided, single submitter | clinical testing | |
| OMIM | RCV000003011 | SCV000023169 | association | Low density lipoprotein cholesterol level quantitative trait locus 1 | 2006-03-23 | no assertion criteria provided | literature only | |
| Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, |
RCV000508694 | SCV000606718 | pathogenic | Hypocholesterolemia | no assertion criteria provided | research |