Total submissions: 7
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001731276 | SCV000699995 | uncertain significance | not specified | 2021-09-24 | criteria provided, single submitter | clinical testing | Variant summary: PCSK9 c.426C>G (p.Tyr142X) 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 disease. This was confirmed by publication reports presenting experimental evidence on decreased mRNA and protein levels, implicating a loss-of-function mutation (Cohen 2005, Zhao 2006). The most pronounced variant effect results in <10% of normal activity. This variant was found in 60/277188 control chromosomes in gnomAD, predominantly observed in the African subpopulation at a frequency of 0.0024 (57/24018). However, it is unknown whether individuals were ruled out for hypocholesterolemia in gnomAD. The c.426C>G has been reported in the literature in multiple individuals affected by Hypocholesterolemia (Peloso 2014) who were predominantly of African origin. In a large case-cohort study, this variant was found to be associated with 40% reduction in plasma levels of LDL cholesterol (Cohen 2006). Although this variant is likely to confer protection against coronary artery disease due to its LDLC reducing effect (Peloso 2014), other clinical conditions including cardiovascular effects might manifest as result of the hypocholesterolemia amongst the individuals who carry this variant, e.g. recently it was found that out of 3 individuals with complete PCSK9 deficiency (each compound heterozygote for PCSK9 p.Y142X and p.C679X) two individuals had a coronary artery calcification score (CAC) greater than the 80th percentile for their age and sex, despite that they had a lower median LDL-C (64.2 mg/dL) than individuals who carry only one null mutation (85.7 mg/dL) (Peloso 2016). Hypocholesterolemia has been reported to result in other symptoms (PMID 20626336). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Benign/likely benign n=4, VUS n=1). Based on the evidence outlined above, the variant was classified as VUS. |
| Illumina Laboratory Services, |
RCV001097394 | SCV001253672 | likely benign | Hypercholesterolemia, autosomal dominant, 3 | 2018-01-23 | 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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. |
| Color Diagnostics, |
RCV001191121 | SCV001358820 | benign | Familial hypercholesterolemia | 2022-01-01 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV001097394 | SCV001685130 | likely benign | Hypercholesterolemia, autosomal dominant, 3 | 2024-01-16 | criteria provided, single submitter | clinical testing | |
| Gene |
RCV000588335 | SCV001820262 | uncertain significance | not provided | 2020-03-27 | criteria provided, single submitter | clinical testing | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is not a known mechanism of disease; This variant is associated with the following publications: (PMID: 32719484, 31589614, 30726226, 31999032, 31511398, 24507775, 29447211, 26241468, 18436227, 17215125, 17599443, 16989838, 15358785, 16909389, 16465619, 15654334, 27602404, 25525159, 22344438, 19351729, 22995991, 20031607, 24507774, 16554528, 18652535) |
| Mendelics | RCV001097394 | SCV002518768 | benign | Hypercholesterolemia, autosomal dominant, 3 | 2023-08-22 | criteria provided, single submitter | clinical testing | |
| OMIM | RCV000003010 | SCV000023168 | association | Low density lipoprotein cholesterol level quantitative trait locus 1 | 2006-03-23 | no assertion criteria provided | literature only |