VCV000375852.19 - ClinVar

NM_174936.4(PCSK9):c.1856A>C (p.Gln619Pro)

Germline

Classification

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.

(10)

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(1); Benign(6); Likely benign(2)

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.1856A>C (p.Gln619Pro)

Variation ID: 375852 Accession: VCV000375852.19

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p32.3 1: 55061549 (GRCh38) [ NCBI UCSC ] 1: 55527222 (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 8, 2017	May 1, 2024	Feb 5, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_174936.4:c.1856A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_777596.2:p.Gln619Pro	missense
NM_001407240.1:c.1979A>C	NP_001394169.1:p.Gln660Pro	missense
NM_001407241.1:c.1898A>C	NP_001394170.1:p.Gln633Pro	missense
NM_001407242.1:c.1859A>C	NP_001394171.1:p.Gln620Pro	missense
NM_001407243.1:c.1799A>C	NP_001394172.1:p.Gln600Pro	missense
NM_001407244.1:c.1682A>C	NP_001394173.1:p.Gln561Pro	missense
NM_001407245.1:c.1664A>C	NP_001394174.1:p.Gln555Pro	missense
NM_001407246.1:c.1481A>C	NP_001394175.1:p.Gln494Pro	missense
NM_001407247.1:c.1355A>C	NP_001394176.1:p.Gln452Pro	missense
NR_110451.3:n.2137A>C
NR_176318.1:n.1940A>C
NR_176319.1:n.2415A>C
NR_176320.1:n.2379A>C
NR_176321.1:n.2094A>C
NR_176322.1:n.2049A>C
NR_176323.1:n.1968A>C
NR_176324.1:n.2356A>C
NC_000001.11:g.55061549A>C
NC_000001.10:g.55527222A>C
NG_009061.1:g.27003A>C
LRG_275:g.27003A>C
LRG_275t1:c.1856A>C	LRG_275p1:p.Gln619Pro

... more HGVS ... less HGVS

Protein change

Q619P, Q452P, Q555P, Q633P, Q494P, Q561P, Q600P, Q620P, Q660P

Other names

Canonical SPDI

NC_000001.11:55061548:A:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA039163 VarSome

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
Gene	OMIM	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.
Hypercholesterolemia, autosomal dominant, 3	Benign/Likely benign (3)	criteria provided, multiple submitters, no conflicts	Feb 5, 2024	RCV000417232.15
Hypercholesterolemia, familial, 1	Uncertain significance (2)	criteria provided, single submitter	Mar 1, 2016	RCV000497196.4
not provided	Benign/Likely benign (3)	criteria provided, multiple submitters, no conflicts	May 27, 2021	RCV000590727.7
Familial hypercholesterolemia	Benign (1)	criteria provided, single submitter	Jan 24, 2018	RCV000776087.3
Cardiovascular phenotype	Benign (1)	criteria provided, single submitter	Mar 23, 2016	RCV002411284.2

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.
Likely benign (Dec 16, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypercholesterolemia, autosomal dominant, 3 Affected status: yes Allele origin: germline	Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix Accession: SCV000503518.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Comment: subject mutated among 2600 FH index cases screened = 1 / Software predictions: Benign
Uncertain significance (Mar 01, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Familial hypercholesterolemia Affected status: unknown Allele origin: germline	Laboratory of Genetics and Molecular Cardiology, University of São Paulo Study: HipercolBrasil Accession: SCV000588688.1 First in ClinVar: Aug 13, 2017 Last updated: Aug 13, 2017	Comment on evidence: %MAF(ExAC):0.1847
Benign (Apr 28, 2016)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000699988.1 First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018	Publications: PubMed (2) PubMed: 16465619‚ 19191301 Comment: Variant summary: The PCSK9 c.1856A>C variant affects a non-conserved nucleotide, resulting in amino acid change from Gln to Pro. 3/4 in-silico tools predict this variant … (more) Variant summary: The PCSK9 c.1856A>C variant affects a non-conserved nucleotide, resulting in amino acid change from Gln to Pro. 3/4 in-silico tools predict this variant to be benign (SNPs&GO not captured due to low reliability index). This variant was found in 101/54678 control chromosomes at a frequency of 0.0018472, which is about 99 times the maximal expected frequency of a pathogenic PCSK9 allele (0.0000188), suggesting this variant is benign. This variant has been found only in Africans, including African controls (101/5202 ExAC African chromosomes) and both high and low LDL African patients in the literature, at a similar allele frequency (1.5-2%). Taken together, based on the prevalence of this variant in general population, this variant was classified as Benign. (less)
Benign (Jan 24, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial hypercholesterolemias Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV000910853.1 First in ClinVar: May 20, 2019 Last updated: May 20, 2019
Likely benign (May 27, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001915167.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021	Comment: This variant is associated with the following publications: (PMID: 16465619, 17971861)
Benign (Aug 23, 2018)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV000889600.2 First in ClinVar: Mar 17, 2018 Last updated: Jan 01, 2022
Benign (Jan 25, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Hypercholesterolemia, autosomal dominant, 3 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000644865.8 First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024
Benign (Feb 05, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) 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: SCV004844476.1 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: 242
Benign (Mar 23, 2016)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002722111.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Comment: This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more) This alteration is classified as 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: SCV000606714.1 First in ClinVar: Aug 13, 2017 Last updated: Aug 13, 2017

Comment:

Variant summary: The PCSK9 c.1856A>C variant affects a non-conserved nucleotide, resulting in amino acid change from Gln to Pro. 3/4 in-silico tools predict this variant to be benign (SNPs&GO not captured due to low reliability index). This variant was found in 101/54678 control chromosomes at a frequency of 0.0018472, which is about 99 times the maximal expected frequency of a pathogenic PCSK9 allele (0.0000188), suggesting this variant is benign. This variant has been found only in Africans, including African controls (101/5202 ExAC African chromosomes) and both high and low LDL African patients in the literature, at a similar allele frequency (1.5-2%). Taken together, based on the prevalence of this variant in general population, this variant was classified as Benign.

Comment:

This alteration is classified as 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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Mutations and polymorphisms in the proprotein convertase subtilisin kexin 9 (PCSK9) gene in cholesterol metabolism and disease.	Abifadel M	Human mutation	2009	PMID: 19191301
A spectrum of PCSK9 alleles contributes to plasma levels of low-density lipoprotein cholesterol.	Kotowski IK	American journal of human genetics	2006	PMID: 16465619

Text-mined citations for this variant ...

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_174936.4(PCSK9):c.1856A>C (p.Gln619Pro)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...