1-55046643-C-T

Position:

chr1-55046643-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_174936.4(PCSK9):c.520C>T(p.Pro174Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000125 in 1,613,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P174L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

PCSK9
NM_174936.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:8

Conservation

PhyloP100: 1.99

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 links:

PCSK9 (HGNC:):

PCSK9 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.4139136).

BS2

High AC in GnomAd4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCSK9	NM_174936.4 linkuse as main transcript	c.520C>T	p.Pro174Ser	missense_variant	3/12	ENST00000302118.5	NP_777596.2	Q8NBP7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCSK9	ENST00000302118.5 linkuse as main transcript	c.520C>T	p.Pro174Ser	missense_variant	3/12	1	NM_174936.4	ENSP00000303208.5		Q8NBP7-1

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

AN:

152044

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000103

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000718

AC:

AN:

250796

Hom.:

AF XY:

0.0000811

AC XY:

AN XY:

135680

show subpopulations

Gnomad AFR exome

AF:

0.000124

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000794

Gnomad OTH exome

AF:

0.000817

GnomAD4 exome

AF:

0.000130

AC:

190

AN:

1461684

Hom.:

Cov.:

AF XY:

0.000132

AC XY:

AN XY:

727138

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000155

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.0000789

AC:

AN:

152162

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74382

show subpopulations

Gnomad4 AFR

AF:

0.0000963

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000170

Hom.:

Bravo

AF:

0.000102

ExAC

AF:

0.0000577

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypercholesterolemia, autosomal dominant, 3

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 27, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 06, 2022	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Aug 30, 2024	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. -

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 06, 2016	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 04, 2024	Identified in a family with FH who also harbored a homozygous variant in the LDLR gene; most family members who were homozygous for both variants showed an attenuated phenotype, suggesting that this PCSK9 variant may reduce the severity of FH by acting as a loss-of-function variant (PMID: 22417841); Functional studies have shown a loss of function effect, which is inconsistent with the known gain of function mechanism of disease (PMID: 31386798); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30218657, 25985138, 28521186, 33418990, 23997648, 34341098, 25911074, 22417841, 30415195, 31386798) -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 28, 2024

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 this variant, 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)). 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. -

Familial hypercholesterolemia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Feb 27, 2023

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.074

BayesDel_noAF

Benign

-0.11

CADD

Benign

7.5

DANN

Uncertain

1.0

DEOGEN2

Benign

0.13

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.57

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.50

M_CAP

Benign

0.040

MetaRNN

Benign

0.41

MetaSVM

Benign

-0.63

MutationAssessor

Benign

0.72

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.4

REVEL

Uncertain

0.46

Sift

Benign

0.13

Sift4G

Pathogenic

0.0

Polyphen

0.38

Vest4

0.71

MutPred

0.39

Loss of solvent accessibility (P = 0.0635);

MVP

0.84

MPC

0.28

ClinPred

0.031

GERP RS

2.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.16

gMVP

0.56

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over