rs772677312

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM1

The NM_174936.4(PCSK9):c.1399C>G(p.Pro467Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000199 in 1,612,012 control chromosomes in the GnomAD database, with no homozygous occurrence. 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). Synonymous variant affecting the same amino acid position (i.e. P467P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

PCSK9
NM_174936.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:11

Conservation

PhyloP100: 0.496

Publications

8 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: Uncertain_significance. The variant received 2 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 12 uncertain in NM_174936.4

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCSK9	NM_174936.4 link	c.1399C>G	p.Pro467Ala	missense_variant	Exon 9 of 12	ENST00000302118.5	NP_777596.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCSK9	ENST00000302118.5 link	c.1399C>G	p.Pro467Ala	missense_variant	Exon 9 of 12	1	NM_174936.4	ENSP00000303208.5

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000278

AC:

AN:

251378

AF XY:

0.0000147

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000528

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000178

AC:

AN:

1459876

Hom.:

Cov.:

AF XY:

0.0000207

AC XY:

AN XY:

726242

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33414

American (AMR)

AF:

0.00

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:

0.0000116

AC:

AN:

86172

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53368

Middle Eastern (MID)

AF:

0.000241

AC:

AN:

4144

European-Non Finnish (NFE)

AF:

0.0000216

AC:

AN:

1111996

Other (OTH)

AF:

0.00

AC:

AN:

60224

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152136

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74308

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41452

American (AMR)

AF:

0.000262

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.433

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:11

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hypercholesterolemia, autosomal dominant, 3

Pathogenic:1Uncertain:2

Apr 28, 2017

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. -

Oct 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 467 of the PCSK9 protein (p.Pro467Ala). This variant is present in population databases (rs772677312, gnomAD 0.005%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 26541928, 32770674, 33418990, 35047021; internal data). ClinVar contains an entry for this variant (Variation ID: 265944). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt PCSK9 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects PCSK9 function (PMID: 26541928, 29259136). For these reasons, this variant has been classified as Pathogenic. -

Sep 23, 2024

All of Us Research Program, National Institutes of Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces proline with alanine at codon 467 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). One functional study has shown that this variant enhances the inhibitory function of the PCSK9 protein and results in a partially reduced LDLR expression and LDL uptake function (PMID: 26541928), while the other functional study has shown that this variant results in decreased proteolytic activity (PMID: 29259136). This variant has been reported in at least eight unrelated individuals affected with familial hypercholesterolemia (PMID: 26541928, 31893465, 32770674, 33418990, Color internal data). This variant has been identified in 8/282772 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. -

not provided

Uncertain:3

Jun 14, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a damaging effect: significantly reduced LDLR cell surface expression and lowered fluorescent LDL uptake (PMID: 26541928); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29259136, 26541928, 34426522, 36187800, 32770674, 29261184, 28587771, 32719484, 31980526, 35047021, 34074024, 38955586, 33418990, 36499307, 38122934, 37409534, 33111339) -

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PCSK9: PS4:Moderate, PM2:Supporting, PS3:Supporting, BP4 -

Sep 29, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The PCSK9 c.1399C>G (p.Pro467Ala) variant has been reported in the published literature in individuals affected with hypercholesterolemia (PMIDs: 35047021 (2021), 33418990 (2021), 31980526 (2020)). Additionally, functional evidence suggests that this variant may impact protein function (PMIDs: 29259136 (2018), 26541928 (2015)). The frequency of this variant in the general population, 0.000054 (7/129094 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

Hypercholesterolemia, familial, 1

Pathogenic:1Uncertain:1

Aug 01, 2016

CSER _CC_NCGL, University of Washington

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

Found in patient having exome sequencing for an unrelated indication. No known history of hyperlipidemia. -

Mar 01, 2016

Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

0/190 non-FH alleles (portuguese normolipidemic individuals) -

Familial hypercholesterolemia

Pathogenic:1Uncertain:1

Laboratory of Molecular Genetics, National Medical Research Center for Therapy and Preventive Medicine

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Jul 24, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces proline with alanine at codon 467 of the PCSK9 protein. Computational prediction tools indicate that this variant has a neutral impact on protein structure and function. One functional study has shown that this variant enhances the inhibitory function of the PCSK9 protein and results in a partially reduced LDLR expression and LDL uptake function (PMID: 26541928), while another functional study has shown that this variant results in decreased proteolytic activity (PMID: 29259136). This variant has been reported in several unrelated individuals affected with familial hypercholesterolemia (PMID: 26541928, 31893465, 32770674, 33418990, 38955586; Color internal data). This variant has been identified in 8/282772 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. -

not specified

Uncertain:2

Nov 16, 2020

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: PCSK9 c.1399C>G (p.Pro467Ala) results in a non-conservative amino acid change located in the proprotein convertase subtlisin/kexin type 9, C-terminal domain (IPR041254) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251378 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1399C>G has been reported in the literature in at-least one individual affected with Familial Hypercholesterolemia in whom two novel putative gain of function variants, namely, this one and p.Ala62Asp were identified (Alves_2015). This individual was reported as having no mutation in the LDL receptor (LDLR) or apolipoprotein B100 (APOB) genes. The variant was paternally inherited but the specific lipid profile was not reported. In contrast, at-least one co-occurrence with another pathogenic variant has been observed at our laboratory (LDLR c.1897C>T, p.Arg633Cys), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 56% of normal LDLR cell surface expression and reduced LDL uptake (Alves_2015). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely pathogenic, n=1; VUS, n=4). Some submitters provide overlapping evidence utilized in the context of this evaluation. Based on the equivocal evidence outlined above, the variant was classified as uncertain significance. -

May 04, 2022

Mendelics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hypobetalipoproteinemia

Uncertain:1

Apr 28, 2017

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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Cardiovascular phenotype

Uncertain:1

Nov 07, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.P467A variant (also known as c.1399C>G), located in coding exon 9 of the PCSK9 gene, results from a C to G substitution at nucleotide position 1399. The proline at codon 467 is replaced by alanine, an amino acid with highly similar properties. This alteration has been reported in familial hypercholesterolemia (FH) cohorts; however, clinical details were limited (Alves AC et al. J Am Coll Cardiol, 2015 Nov;66:2152-2154; Meshkov AN et al. J Pers Med, 2021 May;11:). Additionally, functional studies suggested a gain of function effect in transfected cells with reduced cell surface expression of LDLR and decreased LDL uptake (Alves AC et al. J Am Coll Cardiol, 2015 Nov;66:2152-2154; Chorba JS et al. J Biol Chem, 2018 02;293:1875-1886). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.10

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.57

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.69

M_CAP

Benign

0.045

MetaRNN

Uncertain

0.48

MetaSVM

Benign

-0.90

MutationAssessor

Uncertain

2.4

PhyloP100

0.50

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.90

REVEL

Benign

0.069

Sift

Benign

0.70

Sift4G

Benign

0.35

Polyphen

0.70

Vest4

0.70

MutPred

0.39

Gain of MoRF binding (P = 0.0446);

MVP

0.79

MPC

0.33

ClinPred

0.078

GERP RS

3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.9

Varity_R

0.19

gMVP

0.58

Mutation Taster

=35/65

disease causing (ClinVar)

(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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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