ClinVar Genomic variation as it relates to human health

Identified in normolipidemic, hypocholesterolemic, and hypercholesterolemic individuals in published literature (Huijgen et al., 2012; Lange et al., 2014); Reported as a variant of uncertain significance by several other clinical laboratories in ClinVar (ClinVar Variant ID# 431556; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 33303402, 24507775, 22095935)

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 394 of the PCSK9 protein (p.Gly394Ser). This variant is present in population databases (rs368257906, gnomAD 0.02%). This missense change has been observed in individual(s) with hypercholesterolemia (PMID: 22095935, 33303402). ClinVar contains an entry for this variant (Variation ID: 431556). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

This missense variant replaces glycine with serine at codon 394 of the PCSK9 protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with hypercholesterolemia (PMID: 22095935, 33303402). This variant has also been identified in 26/241576 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.

Variant summary: PCSK9 c.1180G>A (p.Gly394Ser) results in a non-conservative amino acid change located in the Proteinase K-like catalytic domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Three predict the variant weakens a 5' donor site. One predict the variant no significant impact on splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00011 in 241576 control chromosomes, predominantly at a frequency of 0.00023 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 6 fold of the estimated maximal expected allele frequency for a pathogenic variant in PCSK9 causing Familial Hypercholesterolemia phenotype (3.8e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.1180G>A has been reported in the literature in individuals affected with Hypercholesterolemia without strong evidence of causality (Huijgen_2011, Lange_2014, Gill_2021). These reports do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22095935, 24507775, 33303402, 31353810). ClinVar contains an entry for this variant (Variation ID: 431556). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

This missense variant replaces glycine with serine at codon 394 of the PCSK9 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with hypercholesterolemia (PMID: 22095935). This variant has also been identified in 26/241576 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.G394S variant (also known as c.1180G>A), located in coding exon 7 of the PCSK9 gene, results from a G to A substitution at nucleotide position 1180. The amino acid change results in glycine to serine at codon 394, an amino acid with similar properties. This alteration has been reported in a familial hypercholesterolemia (FH) cohort and in a subject with low cholesterol (Huijgen R et al. Hum Mutat, 2012 Feb;33:448-55; Lange LA et al. Am J Hum Genet, 2014 Feb;94:233-45). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear.