ClinVar Genomic variation as it relates to human health

Variant summary: PCSK9 c.286C>T (p.Arg96Cys) results in a non-conservative amino acid change located in the Peptidase S8 propeptide/proteinase inhibitor I9 of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.2e-05 in 277054 control chromosomes (gnomAD). c.286C>T has been reported in the literature in three members of a family with Familial Hypercholesterolemia (Hopkins_2015), and was reported along with a pathogenic APOB variant in a severly affected patient (Elbitar_2018). These data indicate that the variant is likely to be associated with disease. Functional studies proved that the p.Arg96Cys mutation leads to increased LDL receptor degradation (Elbitar_2018). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.

This missense variant replaces arginine with cysteine at codon 96 of the PCSK9 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has shown that this variant causes a partial reduction in LDLR levels and LDL uptake (PMID: 29386597). This variant has been observed three individuals affected with familial hypercholesterolemia (PMID: 35910211), in three individuals from one family affected with familial hypercholesterolemia (PMID: 34407635), and has been observed in a few individuals showing elevated levels of LDL-C (PMID: 26374825). It has also been reported in a family affected with familial hypercholesterolemia, where high LDL-C appeared to segregate with a APOB variant (PMID: 29386597). This variant has been identified in 6/282616 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

This missense variant replaces arginine with cysteine at codon 96 of the PCSK9 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has shown that this variant causes a partial reduction in LDLR levels and LDL uptake (PMID: 29386597). This variant has been observed three individuals affected with familial hypercholesterolemia (PMID: 35910211), in three individuals from one family affected with familial hypercholesterolemia (PMID: 34407635), and has been observed in a few individuals showing elevated levels of LDL-C (PMID: 26374825). It has also been reported in a family affected with familial hypercholesterolemia, where high LDL-C appeared to segregate with a APOB variant (PMID: 29386597). This variant has been identified in 6/282616 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

The p.R96C variant (also known as c.286C>T), located in coding exon 2 of the PCSK9 gene, results from a C to T substitution at nucleotide position 286. The arginine at codon 96 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration was reported in three individuals from one Dutch family with familial hypercholesterolemia (FH); however, limited clinical information was provided (Hopkins PN et al. Circ Cardiovasc Genet, 2015 Dec;8:823-31). This alteration was also detected in one affected member of another FH family, who also had an alteration in APOB that segregated with the disease in the family. In addition, in vitro assays suggested that this alteration might lead to reduced LDLR level and thus was an gain-of-function mutation (Elbitar S et al. Sci Rep, 2018 Jan;8:1943). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

In vitro functional studies demonstrated increased LDLR degradation consistent with a gain-of-function mechanism (PMID: 29386597); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33519890, 32719484, 34407635, 30779729, 34426522, 29386597, 35913489, 35910211, 36499307, 26374825, 37937776, 35130036)

PCSK9: PM5, PS3:Supporting, BP4