ClinVar Genomic variation as it relates to human health
NM_174936.4(PCSK9):c.1120G>T (p.Asp374Tyr)
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.1120G>T (p.Asp374Tyr)
Variation ID: 2875 Accession: VCV000002875.9
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p32.3 1: 55057454 (GRCh38) [ NCBI UCSC ] 1: 55523127 (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 Jul 26, 2013 Apr 20, 2024 Jan 18, 2024 - HGVS
- ... more HGVS ... less HGVS
- Protein change
- D249Y, D355Y, D375Y, D415Y, D310Y
- Other names
- D374Y
- Canonical SPDI
- NC_000001.11:55057453:G:T
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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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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
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. |
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PCSK9 | Dosage sensitivity unlikely | No evidence available |
GRCh38 GRCh37 |
1255 | 1268 |
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
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
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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 (5) |
criteria provided, multiple submitters, no conflicts
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Jan 18, 2024 | RCV000003009.18 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jan 2, 2018 | RCV000505195.11 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 18, 2019 | RCV004017221.1 |
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
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. |
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Pathogenic
(Jan 02, 2018)
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criteria provided, single submitter
Method: clinical testing
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Hypercholesterolemia, familial, 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Robarts Research Institute, Western University
Accession: SCV000782972.1
First in ClinVar: May 30, 2018 Last updated: May 30, 2018 |
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Pathogenic
(Apr 18, 2019)
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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: SCV004847635.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The p.Asp374Tyr variant in PCSK9 has been reported in at least 12 individuals with hypercholesterolemia and segregated with disease in at least 9 affected individuals … (more)
The p.Asp374Tyr variant in PCSK9 has been reported in at least 12 individuals with hypercholesterolemia and segregated with disease in at least 9 affected individuals from 1 family (Timms 2004, Humphries 2009, Kaya 2017). It was absent from large population studies, but has been reported in ClinVar (Variation ID: 2875). Computational prediction tools and conservation analysis are consistent with pathogenicity. In vitro functional studies support an impact on protein function (Benjannet 2004, Bottomley 2009, Al-Mashhadi 2013). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hypercholesterolemia. ACMG/AMP Criteria applied: PP1_Strong, PM2, PS4_Moderate, PP3, PS3_Supporting. (less)
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Likely pathogenic
(Mar 01, 2016)
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criteria provided, single submitter
Method: curation, literature only
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Familial hypercholesterolemia
(Autosomal dominant inheritance)
Affected status: unknown, not applicable
Allele origin:
germline,
not applicable
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Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge
Accession: SCV000599430.1
First in ClinVar: Sep 10, 2017 Last updated: Sep 10, 2017 |
Observation 1: Observation 2:
Comment on evidence:
Assay Description:Heterologous cells (HepG2), FACS and WB assays
Result:
Decrease 36% LDLR at cell surface, decrease 68% LDL internalization; Normal PCSK9 autocatalytic activity
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Pathogenic
(Jan 22, 2020)
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criteria provided, single submitter
Method: curation
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Hypercholesterolemia, autosomal dominant, 3
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001422592.2
First in ClinVar: Jul 19, 2020 Last updated: Feb 05, 2022 |
Comment:
The p.Asp374Tyr variant in PCSK9 has been reported in at least 10 families with hypercholesterolemia, segregated with disease in 20 affected relatives from 5 families, … (more)
The p.Asp374Tyr variant in PCSK9 has been reported in at least 10 families with hypercholesterolemia, segregated with disease in 20 affected relatives from 5 families, and was absent from large population studies. This variant has also been reported in ClinVar (VariationID: 2875) as likely pathogenic by the Instituto Nacional de Saude Doutor Ricardo Jorge and as pathogenic by Roberts Research Institute, Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, OMIM, and GeneReviews. In vitro functional studies demonstrating that cells transfected with the variant result in a near complete disappearance of LDLR protein provide some evidence that the p.Asp374Tyr variant may impact protein function (PMID: 19081568, 15772090). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. One additional likely pathogenic variant, resulting in a different amino acid change at the same position, p.Asp374His, has been reported in association with disease in the literature and ClinVar, slightly supporting that a change at this position may not be tolerated (PMID: 19081568, 26374825/Variation ID: 265939). The p.Asp374Tyr variant is located in a region of PCSK9 that is essential to protein folding and stability, suggesting that this variant is in a functional domain and slightly supports pathogenicity (PMID: 19081568). In summary, this variant meets criteria to be classified as pathogenic for hypercholesterolemia in an autosomal dominant manner based on the increased prevalence and cosegregation of the variant in affected individuals compared to controls, in vitro functional studies, and computational evidence. ACMG/AMP Criteria applied: PP1_strong, PM2, PS4_moderate, PP3, PM5_supporting, PS3_supporting, PM1_supporting (Richards 2015). (less)
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Pathogenic
(Feb 02, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hypercholesterolemia, autosomal dominant, 3
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002768238.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with hypercholesterolemia, familial, 3 (MIM#603776) (PMID: 33173529). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from aspartic acid to tyrosine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (20 heterozygotes, 0 homozygotes). (SP) 0600 - Variant is located in the annotated Peptidase S8 domain (Pfam). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been submitted as pathogenic in the ClinVar database, and has been reported in multiple families with familial hypercholesterolaemia (PMID: 14727179, 15099351, 16224054, 28777095). (SP) 0901 - This variant has strong evidence for segregation with disease. This variant has been shown to segregate with disease in multiple families (PMID: 14727179, 15099351, 16224054). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. In vitro functional studies show that this variant results in increased binding affinity to LDLR and reduced LDLR protein levels (PMID: 17435765, 19081568). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(Jan 18, 2024)
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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: SCV004292328.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 374 of the PCSK9 protein … (more)
This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 374 of the PCSK9 protein (p.Asp374Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 14727179, 19797716, 28777095, 33740630). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2875). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PCSK9 function (PMID: 15358785, 16912035, 18197702, 19081568, 23283366, 27280970). This variant disrupts the p.Asp374 amino acid residue in PCSK9. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17765246, 26374825; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Feb 12, 2008)
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no assertion criteria provided
Method: literature only
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HYPERCHOLESTEROLEMIA, FAMILIAL, 3
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000023167.3
First in ClinVar: Apr 04, 2013 Last updated: Jun 23, 2019 |
Comment on evidence:
In a large Utah pedigree (K1173) segregating hypercholesterolemia (FHCL3; 603776), originally described by Haddad et al. (1999), Hunt et al. (2000) found linkage of the … (more)
In a large Utah pedigree (K1173) segregating hypercholesterolemia (FHCL3; 603776), originally described by Haddad et al. (1999), Hunt et al. (2000) found linkage of the disorder to chromosome 1p32. By mutation screening of genes in this region, Timms et al. (2004) identified a G-to-T transversion in the PCSK9 gene, resulting in an asp374-to-tyr (D374Y) substitution. Sun et al. (2005) identified the D374Y mutation in 3 families of English origin with hypercholesterolemia; all 12 affected individuals had unusually severe hypercholesterolaemia and required more stringent treatment than FH patients with heterozygous LDLR mutations. In stably transfected rat hepatoma cells, both mutant and wildtype PCSK9 colocalized with protein disulfide isomerase in the ER. Expression of D374Y-mutant PCSK9 increased secretion of apolipoprotein B100 (107730)-containing lipoproteins by 2- to 4-fold compared to wildtype, but no significant difference in LDLR content was observed in any transfected cell line. Sun et al. (2005) suggested that pathogenic variants of PCSK9 found in FH influence the secretion of apoB-containing lipoproteins, providing an explanation for the marked increase in circulating LDL in heterozygous carriers. Kwon et al. (2008) found that the D374Y mutation increased the affinity of mutant PCSK9 for LDLR compared with wildtype PCSK9. (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: SCV000606699.1
First in ClinVar: Sep 10, 2017 Last updated: Sep 10, 2017 |
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not provided
(-)
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no classification provided
Method: literature only
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Hypercholesterolemia, autosomal dominant, 3
Affected status: yes
Allele origin:
germline
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GeneReviews
Accession: SCV000490156.2
First in ClinVar: Oct 11, 2015 Last updated: Oct 01, 2022 |
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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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Familial Hypercholesterolemia. | Adam MP | - | 2022 | PMID: 24404629 |
Molecular genetic testing for autosomal dominant hypercholesterolemia in 29,449 Norwegian index patients and 14,230 relatives during the years 1993-2020. | Leren TP | Atherosclerosis | 2021 | PMID: 33740630 |
PCSK9 Variants in Familial Hypercholesterolemia: A Comprehensive Synopsis. | Guo Q | Frontiers in genetics | 2020 | PMID: 33173529 |
PCSK 9 gain-of-function mutations (R496W and D374Y) and clinical cardiovascular characteristics in a cohort of Turkish patients with familial hypercholesterolemia. | Kaya E | Anatolian journal of cardiology | 2017 | PMID: 28777095 |
Trafficking Dynamics of PCSK9-Induced LDLR Degradation: Focus on Human PCSK9 Mutations and C-Terminal Domain. | Poirier S | PloS one | 2016 | PMID: 27280970 |
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 |
Familial hypercholesterolemia and atherosclerosis in cloned minipigs created by DNA transposition of a human PCSK9 gain-of-function mutant. | Al-Mashhadi RH | Science translational medicine | 2013 | PMID: 23283366 |
Healthy individuals carrying the PCSK9 p.R46L variant and familial hypercholesterolemia patients carrying PCSK9 p.D374Y exhibit lower plasma concentrations of PCSK9. | Humphries SE | Clinical chemistry | 2009 | PMID: 19797716 |
Degradation of LDLR protein mediated by 'gain of function' PCSK9 mutants in normal and ARH cells. | Fasano T | Atherosclerosis | 2009 | PMID: 19081568 |
Structural and biochemical characterization of the wild type PCSK9-EGF(AB) complex and natural familial hypercholesterolemia mutants. | Bottomley MJ | The Journal of biological chemistry | 2009 | PMID: 19001363 |
Molecular basis for LDL receptor recognition by PCSK9. | Kwon HJ | Proceedings of the National Academy of Sciences of the United States of America | 2008 | PMID: 18250299 |
Self-association of human PCSK9 correlates with its LDLR-degrading activity. | Fan D | Biochemistry | 2008 | PMID: 18197702 |
Familial hypercholesterolaemia in Portugal. | Bourbon M | Atherosclerosis | 2008 | PMID: 17765246 |
Structural and biophysical studies of PCSK9 and its mutants linked to familial hypercholesterolemia. | Cunningham D | Nature structural & molecular biology | 2007 | PMID: 17435765 |
The proprotein convertase (PC) PCSK9 is inactivated by furin and/or PC5/6A: functional consequences of natural mutations and post-translational modifications. | Benjannet S | The Journal of biological chemistry | 2006 | PMID: 16912035 |
Low-density lipoprotein receptor activity in Epstein-Barr virus-transformed lymphocytes from heterozygotes for the D374Y mutation in the PCSK9 gene. | Holla ØL | Scandinavian journal of clinical and laboratory investigation | 2006 | PMID: 16777760 |
Effect of mutations in the PCSK9 gene on the cell surface LDL receptors. | Cameron J | Human molecular genetics | 2006 | PMID: 16571601 |
Evidence for effect of mutant PCSK9 on apolipoprotein B secretion as the cause of unusually severe dominant hypercholesterolaemia. | Sun XM | Human molecular genetics | 2005 | PMID: 15772090 |
NARC-1/PCSK9 and its natural mutants: zymogen cleavage and effects on the low density lipoprotein (LDL) receptor and LDL cholesterol. | Benjannet S | The Journal of biological chemistry | 2004 | PMID: 15358785 |
Mutations in the PCSK9 gene in Norwegian subjects with autosomal dominant hypercholesterolemia. | Leren TP | Clinical genetics | 2004 | PMID: 15099351 |
A mutation in PCSK9 causing autosomal-dominant hypercholesterolemia in a Utah pedigree. | Timms KM | Human genetics | 2004 | PMID: 14727179 |
Genetic localization to chromosome 1p32 of the third locus for familial hypercholesterolemia in a Utah kindred. | Hunt SC | Arteriosclerosis, thrombosis, and vascular biology | 2000 | PMID: 10764678 |
Evidence for a third genetic locus causing familial hypercholesterolemia. A non-LDLR, non-APOB kindred. | Haddad L | Journal of lipid research | 1999 | PMID: 10357843 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/91a85a05-1acc-49d4-94d6-f64b591cfa6b | - | - | - | - |
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Text-mined citations for rs137852912 ...
HelpRecord last updated Apr 20, 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.