ClinVar Genomic variation as it relates to human health
NM_174936.4(PCSK9):c.520C>T (p.Pro174Ser)
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
-
NM_174936.4(PCSK9):c.520C>T (p.Pro174Ser)
Variation ID: 496561 Accession: VCV000496561.13
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 1p32.3 1: 55046643 (GRCh38) [ NCBI UCSC ] 1: 55512316 (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 Mar 17, 2018 May 1, 2024 Feb 5, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_174936.4:c.520C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_777596.2:p.Pro174Ser missense NC_000001.11:g.55046643C>T NC_000001.10:g.55512316C>T NG_009061.1:g.12097C>T LRG_275:g.12097C>T LRG_275t1:c.520C>T LRG_275p1:p.Pro174Ser - Protein change
- P174S
- Other names
- -
- Canonical SPDI
- NC_000001.11:55046642:C:T
-
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 (T)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00006
The Genome Aggregation Database (gnomAD), exomes 0.00007
The Genome Aggregation Database (gnomAD) 0.00008
Trans-Omics for Precision Medicine (TOPMed) 0.00010
1000 Genomes Project 0.00020
1000 Genomes Project 30x 0.00031
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 |
1264 | 1277 |
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 (1) |
criteria provided, single submitter
|
Apr 6, 2016 | RCV000586165.1 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
|
Feb 5, 2024 | RCV000644534.6 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Feb 27, 2023 | RCV000771583.5 | |
Uncertain significance (1) |
criteria provided, single submitter
|
May 26, 2022 | RCV002341510.2 |
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
(Apr 06, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000699997.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Comment:
Variant summary: The c.520C>T variant affects a non-conserved nucleotide, resulting in amino acid change from Pro to Ser. 2/4 in-silico tools predict this variant to … (more)
Variant summary: The c.520C>T variant affects a non-conserved nucleotide, resulting in amino acid change from Pro to Ser. 2/4 in-silico tools predict this variant to be damaging. This variant was found in 7/120144 control chromosomes including the broad and large populations of ExAC at a frequency of 0.0000583, which is more than 2 times greater than the maximal expected frequency of a pathogenic allele (0.0000188) based on the disease prevalence of FH, suggesting this variant may be benign with respect to FH. However, the same population frequency may not indicate benign outcome for recessive hypocholesterolemia. From a family study, this variant was found to reduce the severity of FH, acting as a putative loss-of-function variant (Slimani_2012). Although it may not be causing FH, its role in hypocholesterolemia (as evidenced by its lowering effect on LDL-C from the family study) needs to be further evaluated so as to clarify its pathogenicity. Taken together, this variant has been classified as VUS until more information becomes available. (less)
|
|
Uncertain significance
(Aug 27, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, autosomal dominant, 3
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002787928.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
Uncertain significance
(May 06, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, autosomal dominant, 3
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000766234.3
First in ClinVar: May 28, 2018 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 174 of the PCSK9 protein (p.Pro174Ser). … (more)
This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 174 of the PCSK9 protein (p.Pro174Ser). This variant is present in population databases (rs533273863, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with PCSK9-related conditions. ClinVar contains an entry for this variant (Variation ID: 496561). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change affects PCSK9 function (PMID: 31386798). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
|
|
Uncertain significance
(Feb 27, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000904167.4
First in ClinVar: May 20, 2019 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces proline with serine at codon 174 of the PCSK9 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces proline with serine at codon 174 of the PCSK9 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has shown the mutant protein to exhibit loss of function phenotype both extracellularly and intracellularly, which is likely due to a weaker binding to the LDLR protein (PMID: 31386798). This variant has been observed in individuals with lower than expected cholesterol (PMID: 22417841, 23997648), as well as in an individual affected with hypercholesterolemia (PMID: 33418990). This variant has also been observed in healthy individuals over age 70 without coronary heart disease, where the mean LDL level of carriers (127.6 mg/dl) was slightly higher than that of non-carriers (119.9 mg/dl) (PMID: 34341098). This variant has been identified in 20/282112 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
|
|
Uncertain Significance
(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: SCV004842348.1
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)
|
Comment:
This missense variant replaces proline with serine at codon 174 of the PCSK9 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces proline with serine at codon 174 of the PCSK9 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has shown the mutant protein to exhibit loss of function phenotype both extracellularly and intracellularly, which is likely due to a weaker binding to the LDLR protein (PMID: 31386798). This variant has been observed in individuals with lower than expected cholesterol (PMID: 22417841, 23997648), as well as in an individual affected with hypercholesterolemia (PMID: 33418990). This variant has also been observed in healthy individuals over age 70 without coronary heart disease, where the mean LDL level of carriers (127.6 mg/dl) was slightly higher than that of non-carriers (119.9 mg/dl) (PMID: 34341098). This variant has been identified in 20/282112 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Number of individuals with the variant: 17
|
|
Uncertain significance
(May 26, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002642001.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.P174S variant (also known as c.520C>T), located in coding exon 3 of the PCSK9 gene, results from a C to T substitution at nucleotide … (more)
The p.P174S variant (also known as c.520C>T), located in coding exon 3 of the PCSK9 gene, results from a C to T substitution at nucleotide position 520. The proline at codon 174 is replaced by serine, an amino acid with some similar properties. This variant was previously observed in conjunction with a mutation in the LDLR gene in a family with familial hypercholesterolemia (FH). The proband, who was homozygous for both the LDLR mutation and p.P174S, presented with what was considered an attenuated homozygous FH phenotype. In addition, five relatives with both alterations had lower than expected LDL levels for heterozygous FH. However, one relative with both alterations had LDL levels consistent with heterozygous FH (Slimani A et al. Atherosclerosis. 2012;222(1):158-66). This variant also co-occurred with an APOB mutation in an individual from a FH cohort and co-occurred with two mutations in ABCG8 in a proband with hypercholesterolemia and sitosterolemia without xanthomas whose mother had this variant and one ABCG8 mutation and normal cholesterol levels (Buonuomo PS et al. Atherosclerosis. 2017 07;262:71-77; Meshkov A et al. Genes (Basel). 2021 01;12(1)). This variant has also been detected in a cohort free of coronary heart disease where the mean LDL level of carriers was slightly higher than that of non-carriers (Lacaze P et al. Open Heart. 2021 07;8(2)). One in vitro functional study has indicated that this variant may result in loss of function and weaker binding to LDLR protein (Mikaeeli S et al. FEBS J. 2020 02;287(3):515-528). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
|
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 |
---|---|---|---|---|
Protective lipid-lowering variants in healthy older individuals without coronary heart disease. | Lacaze P | Open heart | 2021 | PMID: 34341098 |
The LDLR, APOB, and PCSK9 Variants of Index Patients with Familial Hypercholesterolemia in Russia. | Meshkov A | Genes | 2021 | PMID: 33418990 |
Functional analysis of natural PCSK9 mutants in modern and archaic humans. | Mikaeeli S | The FEBS journal | 2020 | PMID: 31386798 |
Timely diagnosis of sitosterolemia by next generation sequencing in two children with severe hypercholesterolemia. | Buonuomo PS | Atherosclerosis | 2017 | PMID: 28521186 |
Factors influencing success of clinical genome sequencing across a broad spectrum of disorders. | Taylor JC | Nature genetics | 2015 | PMID: 25985138 |
Autosomal dominant hypercholesterolemia: needs for early diagnosis and cascade screening in the tunisian population. | Jelassi A | Current genomics | 2013 | PMID: 23997648 |
Effect of mutations in LDLR and PCSK9 genes on phenotypic variability in Tunisian familial hypercholesterolemia patients. | Slimani A | Atherosclerosis | 2012 | PMID: 22417841 |
Text-mined citations for rs533273863 ...
HelpRecord last updated May 08, 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.