rs533273863

chr1-55046643-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

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
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 1.99

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.4139136).
• BS2: High AC in GnomAd at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCSK9	NM_174936.4	c.520C>T	p.Pro174Ser	missense_variant	3/12	ENST00000302118.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCSK9	ENST00000302118.5	c.520C>T	p.Pro174Ser	missense_variant	3/12	1	NM_174936.4	P2

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152044 Hom.: 0 Cov.: 31

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: 18 AN: 250796 Hom.: 0 AF XY: 0.0000811 AC XY: 11 AN XY: 135680

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.: 0 Cov.: 32 AF XY: 0.000132 AC XY: 96 AN XY: 727138

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: 12 AN: 152162 Hom.: 0 Cov.: 31 AF XY: 0.000108 AC XY: 8 AN XY: 74382

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.: 0

Bravo AF: 0.000102

ExAC AF: 0.0000577 AC: 7

EpiCase AF: 0.000273

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

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	All of Us Research Program, National Institutes of Health	Feb 05, 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	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. -

not provided Uncertain:1

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. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 26, 2022

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. -

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	T
BayesDel_noAF	Benign	-0.11
Cadd	Benign	7.5
Dann	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.57
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.50	T
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.41	T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	0.72	N
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.46
Sift	Benign	0.13	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.38	B
Vest4		0.71
MutPred		0.39		Loss of solvent accessibility (P = 0.0635);
MVP		0.84
MPC		0.28
ClinPred		0.031	T
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

Other links and lift over

dbSNP: rs533273863; hg19: chr1-55512316;