Submissions for variant NM_174936.4(PCSK9):c.314G>A (p.Arg105Gln)

gnomAD frequency: 0.00005  dbSNP: rs754143671

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Robarts Research Institute, Western University	RCV000660750	SCV000782985	uncertain significance	Hypercholesterolemia, familial, 1	2018-01-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001191371	SCV001359167	uncertain significance	Familial hypercholesterolemia	2022-11-17	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 105 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 been reported in an individual affected with premature coronary heart disease (PMID: 23535506). The proband and other heterozygous carriers from the family showed lower total cholesterol levels than non-carriers. This variant has been identified in 12/282734 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001868181	SCV002317714	uncertain significance	Hypercholesterolemia, autosomal dominant, 3	2022-04-08	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 105 of the PCSK9 protein (p.Arg105Gln). This variant is present in population databases (rs754143671, gnomAD 0.02%). 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: 548107). 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. 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.
Ambry Genetics	RCV002325334	SCV002610530	uncertain significance	Cardiovascular phenotype	2021-07-28	criteria provided, single submitter	clinical testing	The p.R105Q variant (also known as c.314G>A), located in coding exon 2 of the PCSK9 gene, results from a G to A substitution at nucleotide position 314. The arginine at codon 105 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in a familial hypercholesterolemia (FH) cohort; however, diagnostic criteria was not met for the individuals with this alteration (Ahmed W et al. Clin Chim Acta, 2013 Jun;421:219-25). This amino acid position is not well conserved in available vertebrate species, and glutamine is the reference amino acid in other 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.
Fulgent Genetics, Fulgent Genetics	RCV001868181	SCV002812871	uncertain significance	Hypercholesterolemia, autosomal dominant, 3	2021-09-22	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003478390	SCV004222379	uncertain significance	not provided	2024-07-24	criteria provided, single submitter	clinical testing	The PCSK9 c.314G>A (p.Arg105Gln) variant has been reported in the published literature, this variant has been reported in an individuals with premature coronary heart disease (PMID: 23535506 (2013)). The proband and other heterozygous carriers from the family showed lower total cholesterol levels than non-carriers. The frequency of this variant in the general population, 0.00013 (4/30614 chromosomes in South Asian subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools (i.e., MutationTaster and PolyPhen-2) for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant.
All of Us Research Program, National Institutes of Health	RCV001868181	SCV004839871	uncertain significance	Hypercholesterolemia, autosomal dominant, 3	2024-08-13	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 105 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 been reported in an individual affected with premature coronary heart disease (PMID: 23535506). The proband and other heterozygous carriers from the family showed lower total cholesterol levels than non-carriers. This variant has been identified in 12/282734 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.