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.
ClinVar Genomic variation as it relates to human health
NM_174936.4(PCSK9):c.1487G>A (p.Arg496Gln)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(11)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Conflicting classifications of pathogenicity
Uncertain significance(4); Benign(2); Likely benign(4)
Uncertain significance(4); Benign(2); Likely benign(4)
11
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_174936.4(PCSK9):c.1487G>A (p.Arg496Gln)
Variation ID: 438338 Accession: VCV000438338.23
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 1p32.3 1: 55058631 (GRCh38) [ NCBI UCSC ] 1: 55524304 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Sep 10, 2017 May 1, 2024 Feb 5, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_174936.4:c.1487G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_777596.2:p.Arg496Gln missense NM_001407240.1:c.1610G>A NP_001394169.1:p.Arg537Gln missense NM_001407241.1:c.1487G>A NP_001394170.1:p.Arg496Gln missense NM_001407242.1:c.1490G>A NP_001394171.1:p.Arg497Gln missense NM_001407243.1:c.1430G>A NP_001394172.1:p.Arg477Gln missense NM_001407244.1:c.1313G>A NP_001394173.1:p.Arg438Gln missense NM_001407245.1:c.1295G>A NP_001394174.1:p.Arg432Gln missense NM_001407246.1:c.1112G>A NP_001394175.1:p.Arg371Gln missense NR_110451.3:n.1768G>A NR_176318.1:n.1461G>A NR_176319.1:n.2046G>A NR_176320.1:n.1900G>A NR_176321.1:n.1725G>A NR_176322.1:n.1680G>A NR_176323.1:n.1777G>A NR_176324.1:n.1987G>A NC_000001.11:g.55058631G>A NC_000001.10:g.55524304G>A NG_009061.1:g.24085G>A LRG_275:g.24085G>A LRG_275t1:c.1487G>A LRG_275p1:p.Arg496Gln - Protein change
- R496Q, R432Q, R477Q, R371Q, R537Q, R438Q, R497Q
- Other names
- -
- Canonical SPDI
- NC_000001.11:55058630:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
-
0.00020 (A)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD) 0.00005
Trans-Omics for Precision Medicine (TOPMed) 0.00005
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
The Genome Aggregation Database (gnomAD), exomes 0.00025
Exome Aggregation Consortium (ExAC) 0.00035
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| PCSK9 | Dosage sensitivity unlikely | No evidence available |
GRCh38 GRCh37 |
1275 | 1289 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
|
Jan 2, 2018 | RCV000505200.3 | |
| Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
|
Feb 5, 2024 | RCV000525584.17 | |
| Benign (2) |
criteria provided, multiple submitters, no conflicts
|
Dec 3, 2020 | RCV000780579.3 | |
| Likely benign (1) |
criteria provided, single submitter
|
Dec 1, 2018 | RCV001176519.3 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Oct 8, 2020 | RCV001564604.4 | |
| Likely benign (1) |
criteria provided, single submitter
|
Mar 31, 2022 | RCV002395216.2 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Uncertain significance
(Mar 01, 2016)
|
criteria provided, single submitter
Method: curation, literature only
|
Familial hypercholesterolemia
Affected status: unknown, not applicable
Allele origin:
germline,
not applicable
|
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge
Accession: SCV000599433.1
First in ClinVar: Sep 10, 2017 Last updated: Sep 10, 2017 |
Observation 1:
Comment on evidence:
%MAF(ExAC):0.03472
Observation 2:
Comment on evidence:
Assay Description:Heterologous cells (HepG2), FACS and WB assays
Result:
Normal LDLR activity (-5% LDLR at cell surface, -5% LDL internalization); Normal PCSK9 autocatalytic activity
|
|
|
Uncertain significance
(Jan 02, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Robarts Research Institute, Western University
Accession: SCV000782978.1
First in ClinVar: May 30, 2018 Last updated: May 30, 2018 |
|
|
|
Benign
(Sep 25, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000917975.1
First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019 |
Comment:
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 … (more)
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. (less)
|
|
|
Likely benign
(Dec 01, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV001340532.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
|
|
|
Uncertain significance
(Jun 20, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, autosomal dominant, 3
Affected status: yes
Allele origin:
germline
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001429009.1
First in ClinVar: Aug 16, 2020 Last updated: Aug 16, 2020 |
Number of individuals with the variant: 1
|
|
|
Uncertain significance
(Oct 08, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001787791.1
First in ClinVar: Aug 19, 2021 Last updated: Aug 19, 2021 |
Comment:
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 … (more)
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) (less)
|
|
|
Benign
(Dec 03, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV002046473.1
First in ClinVar: Jan 03, 2022 Last updated: Jan 03, 2022 |
|
|
|
Likely benign
(Jan 16, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, autosomal dominant, 3
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000644862.8
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
|
|
|
Likely Benign
(Feb 05, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, autosomal dominant, 3
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004834744.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
|
Number of individuals with the variant: 37
|
|
|
Likely benign
(Mar 31, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002701640.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
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 … (more)
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. (less)
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: research
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum
Accession: SCV000606712.1
First in ClinVar: Sep 10, 2017 Last updated: Sep 10, 2017 |
|
|
| click to load more click to collapse | |||||
Comment:
Comment:
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)
Comment:
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.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
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.
Comment:
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)
Comment:
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.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Application of expanded genetic analysis in the diagnosis of familial hypercholesterolemia in patients with very early-onset coronary artery disease. | Cao YX | Journal of translational medicine | 2018 | PMID: 30526649 |
| Stepwise processing analyses of the single-turnover PCSK9 protease reveal its substrate sequence specificity and link clinical genotype to lipid phenotype. | Chorba JS | The Journal of biological chemistry | 2018 | PMID: 29259136 |
| Mutations and polymorphisms in the proprotein convertase subtilisin kexin 9 (PCSK9) gene in cholesterol metabolism and disease. | Abifadel M | Human mutation | 2009 | PMID: 19191301 |
| Effect of mutations in the PCSK9 gene on the cell surface LDL receptors. | Cameron J | Human molecular genetics | 2006 | PMID: 16571601 |
Text-mined citations for rs139669564 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.