Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Color Diagnostics, |
RCV001175644 | SCV001339323 | uncertain significance | Familial hypercholesterolemia | 2023-03-29 | criteria provided, single submitter | clinical testing | This missense variant replaces arginine with cysteine at codon 248 of the PCSK9 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with PCSK9-related disorders in the literature. This variant has been identified in 11/248854 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. |
| Ambry Genetics | RCV002379675 | SCV002671320 | uncertain significance | Cardiovascular phenotype | 2019-09-20 | criteria provided, single submitter | clinical testing | The p.R248C variant (also known as c.742C>T), located in coding exon 5 of the PCSK9 gene, results from a C to T substitution at nucleotide position 742. The arginine at codon 248 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is not well 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 |
RCV002555445 | SCV003513986 | uncertain significance | Hypercholesterolemia, autosomal dominant, 3 | 2021-09-01 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine with cysteine at codon 248 of the PCSK9 protein (p.Arg248Cys). The arginine residue is weakly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs779824389, ExAC 0.01%). This variant has not been reported in the literature in individuals affected with PCSK9-related conditions. ClinVar contains an entry for this variant (Variation ID: 918181). 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 not expected to disrupt PCSK9 protein function. 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. |
| All of Us Research Program, |
RCV002555445 | SCV004842890 | uncertain significance | Hypercholesterolemia, autosomal dominant, 3 | 2023-12-13 | criteria provided, single submitter | clinical testing | This missense variant replaces arginine with cysteine at codon 248 of the PCSK9 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with familial hypercholesterolemia in the literature. This variant has been identified in 11/248854 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. |