ClinVar Genomic variation as it relates to human health
NM_174936.4(PCSK9):c.381T>A (p.Ser127Arg)
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.381T>A (p.Ser127Arg)
Variation ID: 2873 Accession: VCV000002873.7
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p32.3 1: 55044016 (GRCh38) [ NCBI UCSC ] 1: 55509689 (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 Apr 4, 2013 Feb 14, 2024 Jun 29, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_174936.4:c.381T>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_777596.2:p.Ser127Arg missense NC_000001.11:g.55044016T>A NC_000001.10:g.55509689T>A NG_009061.1:g.9470T>A LRG_275:g.9470T>A LRG_275t1:c.381T>A LRG_275p1:p.Ser127Arg Q8NBP7:p.Ser127Arg - Protein change
- Other names
- S127R
- Canonical SPDI
- NC_000001.11:55044015:T: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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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 |
1094 | 1108 |
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
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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 (4) |
criteria provided, multiple submitters, no conflicts
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Jun 29, 2022 | RCV000003007.14 | |
Likely pathogenic (2) |
criteria provided, single submitter
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Mar 1, 2016 | RCV000505185.11 |
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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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: SCV000599421.1
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 / 125I-LDL assays; HEK transfected cells, pulse-chase [35S]Met/Cys assays / PCSK9 from transfected cells (HEK), imunoblotting and … (more)
Assay Description:Heterologous cells (HepG2), FACS and WB assays / 125I-LDL assays; HEK transfected cells, pulse-chase [35S]Met/Cys assays / PCSK9 from transfected cells (HEK), imunoblotting and FACS assays / Huh-7 cells, 125I-LDL and WB assays (less)
Result:
HepG2: Decrease ~10% LDLR activity (-10% LDLR at cell surface, -7% LDL internalization); PCSK9 autocatalytic activity 30% of normal / 5-10% LDLR at cell surface, 25-40% LDL degradation; 40-50% PCSK9 autocatalytic activity / HEK: decreased autocatalitic activity, <2% PCSK9 secretion / Huh-7: PCSK9 autocatalitic activity 20% of normal, no secreted PCSK9, 50% amount LDLR, 30% reduction in LDL binding
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Pathogenic
(Dec 16, 2016)
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criteria provided, single submitter
Method: clinical testing
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Hypercholesterolemia, autosomal dominant, 3
Affected status: yes
Allele origin:
germline
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Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix
Accession: SCV000503500.1
First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
Comment:
subjects mutated among 2600 FH index cases screened = 11, family members = 2 / Software predictions: Damaging
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Pathogenic
(Jun 29, 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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Invitae
Accession: SCV003523298.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects PCSK9 function (PMID: 15358785, 27280970). Advanced … (more)
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects PCSK9 function (PMID: 15358785, 27280970). 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. ClinVar contains an entry for this variant (Variation ID: 2873). This variant is also known as 625T>A. This missense change has been observed in individuals with autosomal dominant familial hypercholesterolemia (PMID: 12730697, 33147992). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 127 of the PCSK9 protein (p.Ser127Arg). (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: SCV000606688.1
First in ClinVar: Sep 10, 2017 Last updated: Sep 10, 2017 |
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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: SCV000023165.2
First in ClinVar: Apr 04, 2013 Last updated: Jun 23, 2019 |
Comment on evidence:
In 2 French families with autosomal dominant hypercholesterolemia-3 (FCHL3; 603776), Abifadel et al. (2003) identified a 625T-A transversion in exon 2 of the PCSK9 gene, … (more)
In 2 French families with autosomal dominant hypercholesterolemia-3 (FCHL3; 603776), Abifadel et al. (2003) identified a 625T-A transversion in exon 2 of the PCSK9 gene, resulting in a ser127-to-arg (S127R) substitution. Kwon et al. (2008) stated that PCSK9 processing and secretion were reduced in PCSK9 containing the S127R mutation, but the affinity of PCSK9 for LDLR was only modestly affected. Ouguerram et al. (2004) found that the S127R mutation in 2 related individuals with hypercholesterolemia was associated with increased production of APOB (3-fold) related to overproduction of VLDL (3-fold), intermediate density lipoprotein (IDL) (3-fold), and LDL (5-fold) compared with controls. The 2 individuals also showed a decrease in VLDL and IDL conversion (10 to 30% of controls), and their LDL fractional catabolic rate was slightly decreased (by 30%) compared with controls. (less)
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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: SCV000490153.2
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 |
Novel PCSK9 (Proprotein Convertase Subtilisin Kexin Type 9) Variants in Patients With Familial Hypercholesterolemia From Cape Town. | Huijgen R | Arteriosclerosis, thrombosis, and vascular biology | 2021 | PMID: 33147992 |
Usefulness of the genetic risk score to identify phenocopies in families with familial hypercholesterolemia? | Ghaleb Y | European journal of human genetics : EJHG | 2018 | PMID: 29374275 |
Trafficking Dynamics of PCSK9-Induced LDLR Degradation: Focus on Human PCSK9 Mutations and C-Terminal Domain. | Poirier S | PloS one | 2016 | PMID: 27280970 |
Degradation of LDLR protein mediated by 'gain of function' PCSK9 mutants in normal and ARH cells. | Fasano T | Atherosclerosis | 2009 | PMID: 19081568 |
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 |
Effect of mutations in the PCSK9 gene on the cell surface LDL receptors. | Cameron J | Human molecular genetics | 2006 | PMID: 16571601 |
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 |
Apolipoprotein B100 metabolism in autosomal-dominant hypercholesterolemia related to mutations in PCSK9. | Ouguerram K | Arteriosclerosis, thrombosis, and vascular biology | 2004 | PMID: 15166014 |
Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. | Abifadel M | Nature genetics | 2003 | PMID: 12730697 |
Text-mined citations for rs28942111 ...
HelpRecord last updated Mar 23, 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.