Submissions for variant NM_174936.4(PCSK9):c.1646G>T (p.Arg549Leu)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002394985	SCV002703434	uncertain significance	Cardiovascular phenotype	2022-08-22	criteria provided, single submitter	clinical testing	The p.R549L variant (also known as c.1646G>T), located in coding exon 10 of the PCSK9 gene, results from a G to T substitution at nucleotide position 1646. The arginine at codon 549 is replaced by leucine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003605840	SCV004540076	uncertain significance	Hypercholesterolemia, autosomal dominant, 3	2023-08-25	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in individuals affected with PCSK9-related conditions. 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. 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. ClinVar contains an entry for this variant (Variation ID: 1777160). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 549 of the PCSK9 protein (p.Arg549Leu).
All of Us Research Program, National Institutes of Health	RCV003605840	SCV004830609	uncertain significance	Hypercholesterolemia, autosomal dominant, 3	2023-10-02	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with leucine at codon 549 of the PCSK9 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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 not been identified 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.