ClinVar Genomic variation as it relates to human health
NM_174936.4(PCSK9):c.94G>A (p.Glu32Lys)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_174936.4(PCSK9):c.94G>A (p.Glu32Lys)
Variation ID: 297692 Accession: VCV000297692.27
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p32.3 1: 55039931 (GRCh38) [ NCBI UCSC ] 1: 55505604 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Dec 6, 2016 Feb 28, 2024 Oct 19, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_174936.4:c.94G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_777596.2:p.Glu32Lys missense NC_000001.11:g.55039931G>A NC_000001.10:g.55505604G>A NG_009061.1:g.5385G>A LRG_275:g.5385G>A LRG_275t1:c.94G>A LRG_275p1:p.Glu32Lys - Protein change
- E32K
- Other names
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- Canonical SPDI
- NC_000001.11:55039930:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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- Links
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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PCSK9 | Dosage sensitivity unlikely | No evidence available |
GRCh38 GRCh37 |
- | 1104 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (2) |
no assertion criteria provided
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- | RCV000331053.12 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 16, 2020 | RCV000825628.12 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 28, 2023 | RCV000775016.13 | |
Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Oct 19, 2023 | RCV000778097.20 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Feb 19, 2018 | RCV002374503.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 7, 2023 | RCV003223634.8 |
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
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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
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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
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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. |
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Likely pathogenic
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Hypercholesterolemia, autosomal dominant, 3
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000358214.3
First in ClinVar: Dec 06, 2016 Last updated: May 24, 2019 |
Comment:
The PCKS9 c.94G>A (p.Glu32Lys) missense variant has been reported in at least two studies. Mabuchi et al. (2014) investigated a cohort of 1096 Japanese familial … (more)
The PCKS9 c.94G>A (p.Glu32Lys) missense variant has been reported in at least two studies. Mabuchi et al. (2014) investigated a cohort of 1096 Japanese familial hypercholesterolemia patients and identified the p.Glu32Lys variant in two homozygotes and 62 heterozygotes, and in nine individuals who were double heterozygotes for the p.Glu32Lys variant as well as a variant in the LDLR gene. The authors also reported that the levels of LDL-cholesterol in homozygotes and double heterozygotes of the p.Glu32Lys variant were significantly higher (p<0.001) than p.Glu32Lys heterozygotes, which were in turn significantly higher (p<0.001) than in unaffected family members. In addition, the variant was shown to segregate with a phenotype of elevated LDL-cholesterol levels by Mabuchi et al. (2014) and Noguchi et al. (2010) in unrelated families, although the phenotype was milder than that of heterozygotes with a mutation in the LDLR gene. Control data are unavailable for the p.Glu32Lys variant, which is reported at a frequency of 0.00155 in the East Asian population of the Exome Aggregation Consortium but this is based on two alleles only. Based on the evidence, the p.Glu32Lys variant is classified as likely pathogenic for familial hypercholesterolemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Pathogenic
(Sep 16, 2020)
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criteria provided, single submitter
Method: clinical testing
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Homozygous familial hypercholesterolemia
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000966982.2
First in ClinVar: Aug 26, 2019 Last updated: May 29, 2021 |
Comment:
The p.Glu32Lys variant in PCSK9 has been reported in >40 Japanese and Korean individuals with hypercholesterolemia, including 2 homozygous individuals and 9 double heterozygotes who … (more)
The p.Glu32Lys variant in PCSK9 has been reported in >40 Japanese and Korean individuals with hypercholesterolemia, including 2 homozygous individuals and 9 double heterozygotes who had an additional pathogenic variant in LDLR (Miyake 2008 PMID: 17316651, Mabuchi 2011 PMID: 21146822, Noguchi 2010 PMID: 20006333, Mabuchi 2014 PMID: 25014035, Han 2015 PMID: 25962062, Hopkins 2015 PMID: 26374825, ClinVar Variation ID: 297692). Homozygotes and double heterozygotes had more severe disease on average than heterozygotes, and heterozygotes for this variant had milder disease than heterozygotes for other variants associated to familial hypercholesterolemia (FH; Mabuchi 2014 PMID: 25014035, Hopkins 2015 PMID: 26374825). Additionally, this variant segregated with disease in >20 affected relatives from >5 families (Noguchi 2010 PMID: 20006333, Mabuchi 2014 PMID: 25014035). In vitro functional studies provide some evidence that the p.Glu32Lys variant may impact protein function (Noguchi 2010 PMID: 20006333). This variant has also been identified in 0.03% (4/13348) of East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org/). This frequency is low enough to be consistent with the frequency of FH in the general population. In summary, the p.Glu32Lys variant meets criteria to be classified as pathogenic for autosomal dominant FH based upon presence in multiple affected individuals and segregation with disease. The ACMG/AMP Criteria applied: PS4, PP1_Strong, PS3_Supporting, PM3. (less)
Number of individuals with the variant: 4
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Pathogenic
(May 04, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hypercholesterolemia, autosomal dominant, 3
Affected status: unknown
Allele origin:
germline
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Mendelics
Accession: SCV002517863.1
First in ClinVar: May 28, 2022 Last updated: May 28, 2022 |
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Likely pathogenic
(Feb 19, 2018)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002686984.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.E32K variant (also known as c.94G>A), located in coding exon 1 of the PCSK9 gene, results from a G to A substitution at nucleotide … (more)
The p.E32K variant (also known as c.94G>A), located in coding exon 1 of the PCSK9 gene, results from a G to A substitution at nucleotide position 94. The glutamic acid at codon 32 is replaced by lysine, an amino acid with similar properties. This alteration was detected in 62 of 1055 individuals with familial hypercholesterolemia (FH), as well as in 13 of the 41 compound heterozygous FH patients who also had an LDLR alteration (Mabuchi H et al. Atherosclerosis, 2014 Sep;236:54-61). This alteration was also shown to segregate with the disease in a few apparently unrelated families (Noguchi T et al. Atherosclerosis, 2010 May;210:166-72). In addition, alteration carriers were described to have higher levels of PCSK9 expression, LDL-C and lipoprotein (Miyake Y et al. Atherosclerosis, 2008 Jan;196:29-36; Noguchi T et al. Atherosclerosis, 2010 May;210:166-72; Tada H et al. Circ. J., 2016 Dec;80:512-8). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
Number of individuals with the variant: 1
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Pathogenic
(Oct 03, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hypercholesterolemia, autosomal dominant, 3
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV003835778.1
First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023 |
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Pathogenic
(Apr 07, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV003919432.1
First in ClinVar: Apr 30, 2023 Last updated: Apr 30, 2023 |
Comment:
Published functional studies demonstrate a damaging effect: increased extracellular PCSK9 activity, increased LDLR affinity, and decreased LDLR expression and uptake (Noguchi et al., 2010; Uribe … (more)
Published functional studies demonstrate a damaging effect: increased extracellular PCSK9 activity, increased LDLR affinity, and decreased LDLR expression and uptake (Noguchi et al., 2010; Uribe et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30241732, 17316651, 31447099, 28784313, 34652028, 22683120, 33173529, 29192238, 24859021, 29724976, 27025683, 21619378, 25399932, 27075771, 29049823, 30592178, 29292049, 34782856, 20006333, Singhal2022, 31491741, 24518357, 32719484, 34011801, 29802317, 21146822, 27206942, 34037665, 34848321, 26632531, 25014035, 28179607, 33533259, 34408116, Pham2021, 34526433, 34176852, 25962062, 26374825, 34948399, 35480308) (less)
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Pathogenic
(Oct 19, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hypercholesterolemia, autosomal dominant, 3
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002016561.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Feb 28, 2023)
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criteria provided, single submitter
Method: clinical testing
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Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV000909113.5
First in ClinVar: May 20, 2019 Last updated: Feb 14, 2024 |
Comment:
This missense variant is located in the propeptide domain of the PCSK9 protein. This variant has only been identified in 5/181812 chromosomes (4/13348 East Asian … (more)
This missense variant is located in the propeptide domain of the PCSK9 protein. This variant has only been identified in 5/181812 chromosomes (4/13348 East Asian chromosomes) in the general population by the Genome Aggregation Database (gnomAD). However, this variant is fairly common in the Japanese population (14/2340 chromosomes) (PMID: 26911352) and has been reported in over 60 heterozygous individuals affected with hypercholesterolemia in Japan (6% of the affected population; PMID: 17316651, 24859021, 25014035, 25962062, 26374825, 26632531, 28179607, 31491741, 33533259, 35929461; Pham et al., 2021, doi.org/10.3390/pr9020283). Individuals homozygous for this variant have shown markedly higher plasma LDL-C level than heterozygotes, but showed mild phenotype compared to individuals carrying biallelic LDLR mutations (PMID: 20006333, 21146822, 28179607). This variant has shown strong segregation with disease in multiple families (PMID: 20006333, 25014035). This variant has shown an association with an increased risk of myocardial infarction (PMID: 29802317, 33533259). Notably, this variant appears to exacerbate LDL-C levels and risk of myocardial infarction in individuals carrying LDLR mutations (PMID: 33533259). The impact of this variant on LDLR protein expression and function has not been reported in the literature, although an in vitro study has suggested that this variant may cause an increase in extracellular secretion of the mutant protein (PMID: 20006333). In summary, the available evidence indicates this variant to be a slight gain-of-function mutation that causes mild hypercholesterolemia. Based on the enrichment in affected individuals and co-segregation with disease in family studies, this variant is classified as Pathogenic. (less)
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Pathogenic
(Oct 19, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hypercholesterolemia, autosomal dominant, 3
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001229817.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 32 of the PCSK9 protein … (more)
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 32 of the PCSK9 protein (p.Glu32Lys). This variant is present in population databases (rs564427867, gnomAD 0.03%). This missense change has been observed in individuals with hypercholesterolemia (PMID: 17316651, 20006333, 25014035, 25962062, 26374825, 26632531, 28179607). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 297692). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PCSK9 protein function. Experimental studies have shown that this missense change affects PCSK9 function (PMID: 20006333). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: research
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Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
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Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum
Accession: SCV000606675.1
First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017 |
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Uncertain significance
(Mar 01, 2016)
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Flagged submission
flagged submission
Method: research
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
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Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
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Laboratory of Genetics and Molecular Cardiology, University of São Paulo
Study: HipercolBrasil
Accession: SCV000588677.1 First in ClinVar: Aug 13, 2017 Last updated: Aug 13, 2017 |
Comment on evidence:
%MAF(ExAC):0.007694
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Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more |
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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Patients With LDLR and PCSK9 Gene Variants Experienced Higher Incidence of Cardiovascular Outcomes in Heterozygous Familial Hypercholesterolemia. | Doi T | Journal of the American Heart Association | 2021 | PMID: 33533259 |
Oligogenic familial hypercholesterolemia, LDL cholesterol, and coronary artery disease. | Tada H | Journal of clinical lipidology | 2018 | PMID: 30241732 |
Blood lipid-related low-frequency variants in LDLR and PCSK9 are associated with onset age and risk of myocardial infarction in Japanese. | Tajima T | Scientific reports | 2018 | PMID: 29802317 |
PCSK9 inhibition in the management of familial hypercholesterolemia. | Ogura M | Journal of cardiology | 2018 | PMID: 28784313 |
Half a Century Tales of Familial Hypercholesterolemia (FH) in Japan. | Mabuchi H | Journal of atherosclerosis and thrombosis | 2017 | PMID: 28179607 |
Human genetic variation database, a reference database of genetic variations in the Japanese population. | Higasa K | Journal of human genetics | 2016 | PMID: 26911352 |
Lipoprotein(a) in Familial Hypercholesterolemia With Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Gain-of-Function Mutations. | Tada H | Circulation journal : official journal of the Japanese Circulation Society | 2016 | PMID: 26632531 |
Characterization of Autosomal Dominant Hypercholesterolemia Caused by PCSK9 Gain of Function Mutations and Its Specific Treatment With Alirocumab, a PCSK9 Monoclonal Antibody. | Hopkins PN | Circulation. Cardiovascular genetics | 2015 | PMID: 26374825 |
Genetic testing of Korean familial hypercholesterolemia using whole-exome sequencing. | Han SM | PloS one | 2015 | PMID: 25962062 |
Genotypic and phenotypic features in homozygous familial hypercholesterolemia caused by proprotein convertase subtilisin/kexin type 9 (PCSK9) gain-of-function mutation. | Mabuchi H | Atherosclerosis | 2014 | PMID: 25014035 |
Clinical significance of measuring soluble LR11, a circulating marker of atherosclerosis and HbA1c in familial hypercholesterolemia. | Nohara A | Clinical biochemistry | 2014 | PMID: 24859021 |
Guidelines for the management of familial hypercholesterolemia. | Harada-Shiba M | Journal of atherosclerosis and thrombosis | 2012 | PMID: 23095242 |
Molecular genetic epidemiology of homozygous familial hypercholesterolemia in the Hokuriku district of Japan. | Mabuchi H | Atherosclerosis | 2011 | PMID: 21146822 |
The E32K variant of PCSK9 exacerbates the phenotype of familial hypercholesterolaemia by increasing PCSK9 function and concentration in the circulation. | Noguchi T | Atherosclerosis | 2010 | PMID: 20006333 |
Genetic variants in PCSK9 in the Japanese population: rare genetic variants in PCSK9 might collectively contribute to plasma LDL cholesterol levels in the general population. | Miyake Y | Atherosclerosis | 2008 | PMID: 17316651 |
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Text-mined citations for this variant ...
HelpRecord last updated Apr 15, 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.