rs141502002

Variant names:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2

The NM_174936.4(PCSK9):c.1405C>T(p.Arg469Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000481 in 1,612,150 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R469Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0025 ( 4 hom., cov: 33)

Exomes 𝑓: 0.00027 ( 3 hom. )

Consequence

PCSK9
NM_174936.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:5B:8

Conservation

PhyloP100: 0.0310

Publications

33 publications found

Variant links:

Genes affected

PCSK9 (HGNC:20001): (proprotein convertase subtilisin/kexin type 9) This gene encodes a member of the subtilisin-like proprotein convertase family, which includes proteases that process protein and peptide precursors trafficking through regulated or constitutive branches of the secretory pathway. The encoded protein undergoes an autocatalytic processing event with its prosegment in the ER and is constitutively secreted as an inactive protease into the extracellular matrix and trans-Golgi network. It is expressed in liver, intestine and kidney tissues and escorts specific receptors for lysosomal degradation. It plays a role in cholesterol and fatty acid metabolism. Mutations in this gene have been associated with autosomal dominant familial hypercholesterolemia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2014]

PCSK9 Gene-Disease associations (from GenCC):

hypercholesterolemia, autosomal dominant, 3
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
homozygous familial hypercholesterolemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

PCSK9 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 9 uncertain in NM_174936.4

BP4

Computational evidence support a benign effect (MetaRNN=0.011399835).

BP6

Variant 1-55058549-C-T is Benign according to our data. Variant chr1-55058549-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 201128.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00253 (385/152288) while in subpopulation AFR AF = 0.00883 (367/41564). AF 95% confidence interval is 0.00809. There are 4 homozygotes in GnomAd4. There are 176 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCSK9	NM_174936.4 link	c.1405C>T	p.Arg469Trp	missense_variant	Exon 9 of 12	ENST00000302118.5	NP_777596.2	Q8NBP7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCSK9	ENST00000302118.5 link	c.1405C>T	p.Arg469Trp	missense_variant	Exon 9 of 12	1	NM_174936.4	ENSP00000303208.5		Q8NBP7-1

Frequencies

GnomAD3 genomes

AF:

0.00254

AC:

386

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00888

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.000605

AC:

152

AN:

251352

AF XY:

0.000427

show subpopulations

Gnomad AFR exome

AF:

0.00837

Gnomad AMR exome

AF:

0.000231

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000268

AC:

391

AN:

1459862

Hom.:

Cov.:

AF XY:

0.000256

AC XY:

186

AN XY:

726236

show subpopulations

African (AFR)

AF:

0.00868

AC:

290

AN:

33414

American (AMR)

AF:

0.000335

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000139

AC:

AN:

86172

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53354

Middle Eastern (MID)

AF:

0.000241

AC:

AN:

4144

European-Non Finnish (NFE)

AF:

0.0000297

AC:

AN:

1111996

Other (OTH)

AF:

0.000664

AC:

AN:

60224

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

104

130

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00253

AC:

385

AN:

152288

Hom.:

Cov.:

AF XY:

0.00236

AC XY:

176

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.00883

AC:

367

AN:

41564

American (AMR)

AF:

0.000588

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68018

Other (OTH)

AF:

0.00189

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

100

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000797

Hom.:

Bravo

AF:

0.00277

ESP6500AA

AF:

0.00794

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000700

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:5Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:1Uncertain:1Benign:1

Aug 22, 2019

Robarts Research Institute, Western University

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 01, 2016

Laboratory of Genetics and Molecular Cardiology, University of São Paulo

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Hypercholesterolemia, autosomal dominant, 3

Uncertain:1Benign:2

Feb 02, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1Benign:1

Mar 21, 2017

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The R469W variant has been reported in one individual with severe hypercholesterolemia, who was also heterozygous for a variant in the LDLR gene (Allard et al., 2005). Subsequently, an individual with elevated LDL-C was found to harbor this variant in isolation (Wang et al., 2016). The R469W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Nevertheless, this substitution occurs at a position that is not conserved across species, where W469 is wild-type in at least one mammalian species. Additionally, the majority of in silico analyses (2 out of 3) predict this variant likely does not alter the protein structure/function. Though R469W was presumed to be a gain-of-function variant by Hampton et al. (2007), in vitro functional analysis showed no effect on the ability of the PCSK9-encoded protein to bind Annexin A2, a protein responsible for inhibiting PCSK9-endoded protein activity (Ly et al,. 2014). Therefore, the mechanism by which this variant may result in disease is unclear. Furthermore, the Exome Aggregation Consortium reports R469W was observed in 80/10392 (0.8%) alleles from individuals of African background, including two individuals of African background who were homozygous for the variant. Of note, this variant has been reported in individuals of African descent with high LDL, though the association was not statistically significant (Kotowski et al., 2006). It has also been identified in two individuals of African Canadian descent from the general population who also harbored other PCSK9 variants (Mayne et al., 2013). Ultimately, the possibility that this variant may have a mild clinical effect and/or function as a genetic modifier for disease can not be excluded, at this time. -

Aug 28, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: PCSK9 c.1405C>T (p.Arg469Trp) results in a non-conservative amino acid change located in the Proprotein convertase subtilisin/kexin type 9, C-terminal domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0006 in 252032 control chromosomes, predominantly at a frequency of 0.0084 within the African or African-American subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 90 fold of the estimated maximal expected allele frequency for a pathogenic variant in PCSK9 causing Familial Hypercholesterolemia phenotype (9.4e-05), suggesting that the variant may not be associated with Familial Hypercholesterolemia. c.1405C>T has been reported in the literature in sequencing studies of individuals affected with Familial Hypercholesterolemia (example, Allard_2005, Kotowski_2006, Mayne_2013, Wang_2016 and Taranto_2017). At-least one patient with tendinous xanthomata and an elevated lipid profile in whom a co-occurring LDL-R variant, c.1209delC ( p.Phe403fs) that could have explained the phenotype, has been described (Allard_2005). The authors postulated a digenic/additive role for this variant. At least one study of 57,850 individuals with African ancestry showed that this variant is associated with elevated maxLDL levels (Sun_2018). This association was not found in individuals with European or Chinese ancestry (Sun_2018, Lu_2016). Furthermore, this variant was identified among carriers who did not meet the Dutch Lipid Clinic Network (DLCN) criteria for a diagnosis of possible, probable or definite FH, thereby resulting in an estimated clinical penetrance of 0% (Abul-Husn_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. Multiple experimental showed that this variant may result in loss of function effect (Geschwindner_2015), no effect on binding activity to AnxA2 (Ly_2014), and no effect on protein processing (Chorba_2017). PCSK9 normally degrades LDL-Receptor. Defective PCSK9 results in impaired LDL-receptor degradation, resulting in an increased uptake of plasma LDL than necessary, leading to hypocholesterolemia. Therefore, a GOF mechanism has been attributed to variants in PCSK9 that are causative of FH. However, none of the ascertained functional studies provide concrete evidence supporting an association of this variant with the pathognomic mechanism of FH attributed to variants in PCSK9. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation with conflicting assessments (benign, n=1; likely benign, n=3; VUS, n=3). Based on the evidence outlined above, although some residual association as a risk factor for high LDL levels cannot be entirely ruled out, the variant was classified as likely benign in the context of an association with inherited autosomal dominant Familial Hypercholesterolemia, -

Familial hypercholesterolemia

Benign:2

Feb 15, 2018

Color Diagnostics, LLC DBA Color Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 02, 2023

GENinCode PLC

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PCSK9-related disorder

Uncertain:1

Jun 28, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The PCSK9 c.1405C>T variant is predicted to result in the amino acid substitution p.Arg469Trp. This variant has been reported in individuals with hypercholesterolemia (Allard et al. 2005. PubMed ID: 16211558; Kotowski et al. 2006. PubMed ID: 16465619; Wang et al. 2016. PubMed ID: 27765764, Table SI; Di Taranto et al. 2017. PubMed ID: 29127338). Functional studies showed that this variant has no effect on binding activity to Annexin A2 and protein processing (Ly et al. 2014. PubMed ID: 24808179; Chorba et al. 2017. PubMed ID: 29259136), but another study showed that it may affect the protein activity (Geschwindner et al. 2015. PubMed ID: 25744035). This variant is reported in 0.93% of alleles in individuals of African descent including 1 homozygous individual in gnomAD. In ClinVar, this variant has conflicting interpretations of benign, likely benign, uncertain significance and pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/201128/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Hypobetalipoproteinemia

Uncertain:1

Feb 02, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not provided

Benign:1

Jun 08, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Mar 30, 2019

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.52

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.85

M_CAP

Benign

0.035

MetaRNN

Benign

0.011

MetaSVM

Benign

-0.78

MutationAssessor

Uncertain

2.2

PhyloP100

0.031

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-1.8

REVEL

Benign

0.24

Sift

Uncertain

0.010

Sift4G

Uncertain

0.020

Polyphen

1.0

Vest4

0.71

MVP

0.84

MPC

0.24

ClinPred

0.017

GERP RS

1.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.9

Varity_R

0.38

gMVP

0.80

Mutation Taster

=86/14

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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rs141502002

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over