ClinVar Genomic variation as it relates to human health

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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

The PCSK9 promoter variant c.-331C>A is present at a very low frequency in the gnomAD v3.1.2 population database (global: 37/152,224 alleles; European: 30/68,038 alleles) and is of uncertain significance for familial hypercholesterolaemia (FH). This variant is located close to the core sterol regulatory element (SRE) in the promoter region of PCSK9 inside a specificity protein-1 transcription factor (SP1) site (PMID:17921436). The PCSK9 c.-331C>A variant has been previously reported (as PCSK9 c.-332C>A) in a Spanish FH patient. In vitro studies indicated that this variant caused a 2.5-fold increase in PCSK9 promoter activity compared to wild-type, and could be a possible cause of hypercholesterolaemia (PMID:18559913).

This variant occurs in a non-coding region of the PCSK9 gene. It does not change the encoded amino acid sequence of the PCSK9 protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This variant has been observed in individual(s) with hypercholesterolemia (PMID: 18559913, 28965616). ClinVar contains an entry for this variant (Variation ID: 438331). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects PCSK9 protein function (PMID: 18559913). 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.

Variant summary: PCSK9 c.-331C>A is located in the untranscribed region upstream of the PCSK9 gene region. The variant allele was found at a frequency of 0.00025 in 443046 control chromosomes. The observed variant frequency is approximately 6.62 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 benign. c.-331C>A has been reported in the literature in individuals affected with autosomal dominant hypercholesterolemia and definite or probable FH (Blesa_2008, Pirillo_2017). These reports do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. Experimental studies have shown the variant caused a 2.5-fold increase in PCSK9 promoter activity relative to wild-type construction activity when transfected in HepG2 and 3T3 cells. Additionally, treatment of cells with statins (lovastatin) caused an even stronger activation in c.-332C>A mutant, maintaining the 2.5-fold of overexpression in relation to the normal sequence. However, due to technical limitations, expression studies in patients could not be considered not conclusive (Blesa_2008). The following publications have been ascertained in the context of this evaluation (PMID: 18559913, 28965616). ClinVar contains an entry for this variant (Variation ID: 438331). Based on the evidence outlined above, the variant was classified as uncertain significance.