ClinVar Miner

Submissions for variant NM_174936.3(PCSK9):c.426C>G (p.Tyr142Ter) (rs67608943)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000588335 SCV000699995 pathogenic not provided 2016-05-31 criteria provided, single submitter clinical testing Variant summary: The PCSK9 c.426C>G (p.Tyr142X) variant results in a premature termination codon, predicted to cause a truncated or absent PCSK9 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Functional studies showed that it leads to the nonsense mediated decay with no detectable protein (Cohen_2005, Zhao_2006). This variant was found in 33/121362 control chromosomes from ExAC, predominantly observed in the African subpopulation at a frequency of 0.0029813 (31/10398). However, it is unknown whether the individuals in ExAC were ruled out to be hypocholesterolemic. This variant is widely known to be a causative mutation for hypocholesterolemia predominantly in Africans including cosegregation data. 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 are likely to manifest as result of the hypocholesterolemia amongst the individuals who carry this variant. Taken together, this variant is classified as Pathogenic.
OMIM RCV000003010 SCV000023168 association Low density lipoprotein cholesterol level quantitative trait locus 1 2006-03-23 no assertion criteria provided literature only

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