Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Cardiovascular Research Group, |
RCV000256310 | SCV000323033 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-01 | criteria provided, single submitter | research | 0/190 non-FH alleles (portuguese normolipidemic individuals) |
| Ambry Genetics | RCV002411136 | SCV002724077 | uncertain significance | Cardiovascular phenotype | 2021-07-16 | criteria provided, single submitter | clinical testing | The p.A62D variant (also known as c.185C>A), located in coding exon 1 of the PCSK9 gene, results from a C to A substitution at nucleotide position 185. The alanine at codon 62 is replaced by aspartic acid, an amino acid with dissimilar properties. This variant co-occurred with a second PCSK9 variant in an individual with familial hypercholesterolemia. Functional assays from the same group suggested this variant may lead to reduced LDLR cell surface expression (Alves AC et al. J Am Coll Cardiol, 2015 Nov;66:2152-2154). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Labcorp Genetics |
RCV002521862 | SCV003522754 | uncertain significance | Hypercholesterolemia, autosomal dominant, 3 | 2022-02-20 | criteria provided, single submitter | clinical testing | This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 62 of the PCSK9 protein (p.Ala62Asp). This missense change has been observed in individual(s) with clinical features of familial hypercholesterolemia (PMID: 26541928; Invitae). 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. Experimental studies have shown that this missense change affects PCSK9 function (PMID: 26541928). 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. ClinVar contains an entry for this variant (Variation ID: 265918). |