ClinVar Genomic variation as it relates to human health

Variant summary: PCSK9 c.643C>T (p.Arg215Cys) 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. The variant allele was found at a frequency of 1.6e-05 in 121658 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in PCSK9 causing Familial Hypercholesterolemia (1.6e-05 vs 9.4e-05), allowing no conclusion about variant significance. c.643C>T has been reported in the literature in one individual affected with Familial Hypercholesterolemia and had family history of this disease (Han_2015). Although, to our knowledge, no experimental evidence demonstrating an impact of this variant on protein function has been reported, Arg215 has been shown to be a furin cleavage site and Arg215His affects PCSK9 function (PMID 23135270). Arg215His has also been reported in FH patients (HGMD). 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 VUS-Possibly Pathogenic.

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 215 of the PCSK9 protein (p.Arg215Cys). This variant is present in population databases (rs753505066, gnomAD 0.003%). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 25962062). ClinVar contains an entry for this variant (Variation ID: 633346). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PCSK9 protein function with a positive predictive value of 95%. This variant disrupts the Arg215 amino acid residue in PCSK9. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18266662, 18631360, 27896130). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

This missense variant replaces arginine with cysteine at codon 215 of the PCSK9 protein. Computational prediction suggests that this variant may have a 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 five individuals affected with familial hypercholesterolemia (PMID: 25962062, 34456200, 35137788). This variant has been identified in 4/251138 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Arg215His, is considered to be disease-causing (ClinVar variation ID: 201127), suggesting that arginine at this position is important for the protein function. 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 variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.83). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with PCSK9 related disorder (ClinVar ID: VCV000633346 / PMID: 25962062). A different missense change at the same codon (p.Arg215His) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000201127 / PMID: 18266662). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.

This missense variant replaces arginine with cysteine at codon 215 of the PCSK9 protein. Computational prediction suggests that this variant may have a 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 five individuals affected with familial hypercholesterolemia (PMID: 25962062, 34456200, 35137788). This variant has been identified in 4/251138 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Arg215His, is considered to be disease-causing (ClinVar variation ID: 201127), suggesting that arginine at this position is important for the protein function. 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.