rs754143671
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBS2_Supporting
The NM_174936.4(PCSK9):c.314G>A(p.Arg105Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000719 in 1,614,088 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R105W) has been classified as Uncertain significance.
Frequency
Consequence
NM_174936.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PCSK9 | NM_174936.4 | c.314G>A | p.Arg105Gln | missense_variant | 2/12 | ENST00000302118.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PCSK9 | ENST00000302118.5 | c.314G>A | p.Arg105Gln | missense_variant | 2/12 | 1 | NM_174936.4 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000526 AC: 8AN: 152218Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000358 AC: 9AN: 251354Hom.: 0 AF XY: 0.0000442 AC XY: 6AN XY: 135894
GnomAD4 exome AF: 0.0000739 AC: 108AN: 1461870Hom.: 0 Cov.: 32 AF XY: 0.0000660 AC XY: 48AN XY: 727234
GnomAD4 genome ? AF: 0.0000526 AC: 8AN: 152218Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74362
ClinVar
Submissions by phenotype
Hypercholesterolemia, autosomal dominant, 3 Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Apr 08, 2022 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 13, 2023 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Sep 22, 2021 | - - |
Hypercholesterolemia, familial, 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Robarts Research Institute, Western University | Jan 02, 2018 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Aug 03, 2023 | In the published literature, this variant has been reported in affected individuals and families with familial hypercholesterolemia (PMID: 23535506 (2013)). 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 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. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 28, 2021 | 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. - |
Familial hypercholesterolemia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 17, 2022 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at