rs772677312

chr1-55058543-C-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM1 PP5 BS2

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. 12/20 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:8
• Conservation: PhyloP100: 0.496

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 -1 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 6 benign, 11 uncertain in NM_174936.4
• PP5: Variant 1-55058543-C-G is Pathogenic according to our data. Variant chr1-55058543-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 265944.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=7, Likely_pathogenic=3}. Variant chr1-55058543-C-G is described in Lovd as [Pathogenic].
• BS2: High AC in GnomAd at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCSK9	NM_174936.4	c.1399C>G	p.Pro467Ala	missense_variant	9/12	ENST00000302118.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCSK9	ENST00000302118.5	c.1399C>G	p.Pro467Ala	missense_variant	9/12	1	NM_174936.4	P2

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152136 Hom.: 0 Cov.: 33

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

GnomAD3 exomes AF: 0.0000278 AC: 7 AN: 251378 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135894

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 SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000178 AC: 26 AN: 1459876 Hom.: 0 Cov.: 86 AF XY: 0.0000207 AC XY: 15 AN XY: 726242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000216

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152136 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74308

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000412 AC: 5

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypercholesterolemia, autosomal dominant, 3 Pathogenic:1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 13, 2023	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 19, 2023	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, 33418990, 35047021; Invitae). ClinVar contains an entry for this variant (Variation ID: 265944). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Hypercholesterolemia, familial, 1 Pathogenic:1 Uncertain:1

Uncertain significance, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Aug 01, 2016	Found in patient having exome sequencing for an unrelated indication. No known history of hyperlipidemia. -
Likely pathogenic, criteria provided, single submitter	research	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	0/190 non-FH alleles (portuguese normolipidemic individuals) -

Familial hypercholesterolemia Pathogenic:1 Uncertain:1

Likely pathogenic, criteria provided, single submitter	research	Laboratory of Molecular Genetics, National Medical Research Center for Therapy and Preventive Medicine	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 15, 2023	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 specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 16, 2020	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. -

Hypobetalipoproteinemia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 07, 2023

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	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	11
Dann	Benign	0.82
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.045	D
MetaRNN	Uncertain	0.48	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.90	N
REVEL	Benign	0.069
Sift	Benign	0.70	T
Sift4G	Benign	0.35	T
Polyphen		0.70	P
Vest4		0.70
MutPred		0.39		Gain of MoRF binding (P = 0.0446);
MVP		0.79
MPC		0.33
ClinPred		0.078	T
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.19
gMVP		0.58

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: rs772677312; hg19: chr1-55524216;