rs139669564
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 4P and 9B. PM1PM5BP4_StrongBP6BS2
The NM_174936.4(PCSK9):c.1487G>A(p.Arg496Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00017 in 1,611,008 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R496W) has been classified as Likely pathogenic.
Frequency
Consequence
NM_174936.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PCSK9 | NM_174936.4 | c.1487G>A | p.Arg496Gln | missense_variant | 9/12 | ENST00000302118.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PCSK9 | ENST00000302118.5 | c.1487G>A | p.Arg496Gln | missense_variant | 9/12 | 1 | NM_174936.4 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000986 AC: 15AN: 152098Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000254 AC: 63AN: 247982Hom.: 0 AF XY: 0.000335 AC XY: 45AN XY: 134504
GnomAD4 exome AF: 0.000178 AC: 259AN: 1458792Hom.: 0 Cov.: 109 AF XY: 0.000247 AC XY: 179AN XY: 725636
GnomAD4 genome ? AF: 0.0000985 AC: 15AN: 152216Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12AN XY: 74412
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:1Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Robarts Research Institute, Western University | Jan 02, 2018 | - - |
Uncertain significance, criteria provided, single submitter | curation;literature only | Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge | Mar 01, 2016 | - - |
Pathogenic, no assertion criteria provided | research | Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum | - | - - |
Hypercholesterolemia, autosomal dominant, 3 Uncertain:1Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 16, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jun 20, 2019 | - - |
Likely benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Feb 05, 2024 | - - |
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 25, 2017 | Variant summary: The PCSK9 c.1487G>A (p.Arg496Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. 4/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). One functional study showed that this variant was associated with amounts of cell surface LDLR and LDL internalized that were comparable to that of wild-type levels (Cameron_2006). The variant was found in the control population dataset of gnomAD in 68/240046 control chromosomes at a frequency of 0.0002833, which is approximately 14 times the estimated maximal expected allele frequency of a pathogenic PCSK9 variant (0.00002), suggesting this variant is likely a benign polymorphism. One study found this variant in a subject homozygous for apolipoprotein E-2 who presented with Type III hyperlipoproteinaemia, without strong evidence for causality. This variant was found co-occurring with the pathogenic LDLR c.1775G>A, p.Gly592Glu mutation in an internal specimen, supporting a benign impact of the variant. One clinical diagnostic laboratory classified this variant as uncertain significance. Taken together, this variant is classified as benign. - |
Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Dec 03, 2020 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 08, 2020 | Identified in association with hyperlipoproteinemia (Cameron et al., 2006) and hypercholesterolemia with early onset coronary artery disease (CAD) (Cao et al., 2018); In silico analysis supports that this missense variant does not alter protein structure/function; Published in vitro functional studies demonstrate no effect on autocatalytic activity and LDL-receptor surface expression and internalized LDL levels comparable to wild-type; nevertheless, it is unclear how these studies may translate to a pathogenic role in vivo (Cameron et al., 2006); Reported in ClinVar (ClinVar Variant ID#438338; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 30526649, 19191301, 16571601) - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 31, 2022 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Familial hypercholesterolemia Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 01, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at