chr1-55058538-C-T

Position:

chr1-55058538-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 5P and 4B. PM1PM5PP3BS2

The NM_174936.4(PCSK9):c.1394C>T(p.Ser465Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000753 in 1,459,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. S465W) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

PCSK9
NM_174936.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:6

Conservation

PhyloP100: 3.73

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. 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 4 benign, 10 uncertain in NM_174936.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-55058538-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2418130.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.77

BS2

High AC in GnomAdExome4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCSK9	NM_174936.4 linkuse as main transcript	c.1394C>T	p.Ser465Leu	missense_variant	9/12	ENST00000302118.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCSK9	ENST00000302118.5 linkuse as main transcript	c.1394C>T	p.Ser465Leu	missense_variant	9/12	1	NM_174936.4	P2	Q8NBP7-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251370

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135888

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.00000753

AC:

AN:

1459884

Hom.:

Cov.:

AF XY:

0.00000826

AC XY:

AN XY:

726246

show subpopulations

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000899

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000675

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:2Uncertain:1

Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 29, 2023	Published functional studies demonstrate a damaging effect through defective PCSK9-LDL binding (Sarkar et al., 2022); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in association with FH in published literature (Sturm et al., 2021; Hopkins et al., 2015; Di Taranto et al., 2017; Ruotolo et al., 2014); This variant is associated with the following publications: (PMID: 29259136, 32058034, 26165249, 26374825, 29127338, 24607922, 31653860, 34037665, 36187800) -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Hypercholesterolemia, autosomal dominant, 3

Pathogenic:1Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 03, 2024	This missense variant replaces serine with leucine at codon 465 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). Functional studies have shown that this variant may cause a decrease in PCSK9 secretion and noted that this finding is not consistent with reported high LDL-C levels (PMID: 29259136, 32058034). Another functional study in transfected HEK293 cells has shown that this variant significantly decreased LDL binding (PMID: 36187800). This variant has been reported in two related individuals affected with hypercholesterolemia (PMID: 24607922). Cells from these carriers showed partially reduced LDLR activity but no change in the amount of LDLR protein at the cell surface. This variant has been reported in over ten unrelated individuals affected with hypercholesterolemia who showed mildly elevated LDL-C levels (PMID: 29127338, 26374825, 34037665; Color internal data). This variant has also been identified in 6/251370 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion that this variant may be associated with disease, the role of this variant cannot be determined conclusively, due to the unclear impact of this variant on the LDLR function and the observation of this variant in the general population. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 10, 2023	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 465 of the PCSK9 protein (p.Ser465Leu). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individuals with hypercholesterolemia (PMID: 24607922, 26374825). ClinVar contains an entry for this variant (Variation ID: 403292). 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 expected to disrupt PCSK9 protein function. For these reasons, this variant has been classified as Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	May 03, 2023	Criteria applied: PS4_SUP -

Familial hypercholesterolemia

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 18, 2023	This missense variant replaces serine with leucine at codon 465 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). Functional studies have shown that this variant may cause a decrease in PCSK9 secretion and noted that this finding is not consistent with reported high LDL-C levels (PMID: 29259136, 32058034). Another functional study in transfected HEK293 cells has shown that this variant significantly decreased LDL binding (PMID: 36187800). This variant has been reported in two related individuals affected with hypercholesterolemia (PMID: 24607922). Cells from these carriers showed partially reduced LDLR activity but no change in the amount of LDLR protein at the cell surface. This variant has been reported in over ten unrelated individuals affected with hypercholesterolemia who showed mildly elevated LDL-C levels (PMID: 29127338, 26374825, 34037665; Color internal data). This variant has also been identified in 6/251370 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion that this variant may be associated with disease, the role of this variant cannot be determined conclusively, due to the unclear impact of this variant on the LDLR function and the observation of this variant in the general population. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Ser465Leu variant in PCSK9 has been reported in 13 individuals with familial hypercholesterolemia, segregated with disease in 2 affected relatives from 1 family (PMID: 24607922, 26374825, 29127338), and has been identified in 0.005% (1/18392) of East Asian chromosomes and 0.004% (4/113662) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs778849441). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported in ClinVar as a VUS, likely pathogenic, and pathogenic (Variation ID#: 403292). Computational prediction tools, including splice predictors, and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Ser465Leu variant is uncertain. ACMG/AMP Criteria applied: PS4_moderate, BP4 (Richards 2015). -

Hypercholesterolemia, familial, 1

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 31, 2017

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 2 papers, not sig diff LDLR -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.28

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.44

Eigen

Benign

0.079

Eigen_PC

Benign

-0.10

FATHMM_MKL

Benign

0.63

LIST_S2

Uncertain

0.86

M_CAP

Benign

0.026

MetaRNN

Pathogenic

0.77

MetaSVM

Benign

-0.42

MutationAssessor

Uncertain

2.6

MutationTaster

Benign

0.74

N;N

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-3.6

REVEL

Uncertain

0.32

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.010

Polyphen

1.0

Vest4

0.73

MutPred

0.50

Loss of glycosylation at S465 (P = 0.0374);

MVP

0.85

MPC

0.29

ClinPred

0.74

GERP RS

1.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.3

Varity_R

0.61

gMVP

0.87

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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