chr1-55044020-G-A

Position:

chr1-55044020-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM5BP4BS2

The NM_174936.4(PCSK9):c.385G>A(p.Asp129Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000805 in 1,614,046 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. D129G) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

PCSK9
NM_174936.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:5B:1

Conservation

PhyloP100: 4.79

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-55044021-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 438332.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Likely_pathogenic=2, Uncertain_significance=1}.

BP4

Computational evidence support a benign effect (MetaRNN=0.39397877).

BS2

High AC in GnomAdExome4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCSK9	NM_174936.4 linkuse as main transcript	c.385G>A	p.Asp129Asn	missense_variant	2/12	ENST00000302118.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCSK9	ENST00000302118.5 linkuse as main transcript	c.385G>A	p.Asp129Asn	missense_variant	2/12	1	NM_174936.4	P2	Q8NBP7-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251360

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135872

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

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:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000821

AC:

AN:

1461860

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

0.00000989

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000508

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:5Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hypercholesterolemia, autosomal dominant, 3

Pathogenic:3Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	Dec 16, 2016	subjects mutated among 2600 FH index cases screened = 2, family members = 2, with co-segregation / Software predictions: Conflicting -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 18, 2023	This missense variant replaces aspartic acid with asparagine at codon 129 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 studies for this variant are conflicted as some have shown that this variant causes a reduction of the cell surface expression of LDLR and LDL uptake compared to wild type (PMID: 26195630, 34948399), while other studies have shown no significant difference (PMID: 19081568, 23064986). This variant has been reported in several unrelated individuals affected with familial hypercholesterolemia (PMID: 19081568, 23680767, 26195630, 26374825, 28994502, 31491741, 33955087, 34407635). This variant has also been reported in five individuals from a family affected with hypercholesterolemia, including three affected and two unaffected, suggesting a reduced penetrance for this variant (PMID: 23064986). This variant has been identified in 4/251360 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. -
Likely pathogenic, no assertion criteria provided	research	deCODE genetics, Amgen	Jul 21, 2023	The variant NM_174936.4:c.385G>A (chr1:55044020) in PCSK9 was detected in 1 heterozygote out of 58K WGS Icelanders (MAF= 0,001%). The variant occurred de novo (confirmed absence from parents’ WGS data) in an individual with highly elevated LDL cholesterol. This variant has been reported in ClinVar previously as benign, likely pathogenic, and as a variant of uncertain significance. Based on ACMG criteria (PS2, PM2, PM5, PP5) this variant classifies as likely pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 129 of the PCSK9 protein (p.Asp129Asn). This variant is present in population databases (rs778738291, gnomAD 0.003%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 19081568, 23064986, 23680767, 26374825, 31491741, 34037665; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 375844). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on PCSK9 function (PMID: 19081568, 23064986, 26195630, 34948399). This variant disrupts the p.Asp129 amino acid residue in PCSK9. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17765244, 26195630, 27280970, 29259136; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Familial hypercholesterolemia

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 14, 2023	This missense variant replaces aspartic acid with asparagine at codon 129 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 studies for this variant are conflicted as some have shown that this variant causes a reduction of the cell surface expression of LDLR and LDL uptake compared to wild type (PMID: 26195630, 34948399), while other studies have shown no significant difference (PMID: 19081568, 23064986). This variant has been reported in several unrelated individuals affected with familial hypercholesterolemia (PMID: 19081568, 23680767, 26195630, 26374825, 28994502, 31491741, 33955087, 34407635). This variant has also been reported in five individuals from a family affected with hypercholesterolemia, including three affected and two unaffected, suggesting a reduced penetrance for this variant (PMID: 23064986). This variant has been identified in 4/251360 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 23, 2024	Variant summary: PCSK9 c.385G>A (p.Asp129Asn) results in a conservative amino acid change located in the Peptidase S8 propeptide/proteinase inhibitor I9 domain (IPR010259) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251360 control chromosomes. c.385G>A has been reported in the literature segregating with disease in the heterozygous state in multiple individuals affected with autosomal dominant Familial Hypercholesterolemia (example, Ahmad_2012, Bjornsson_2021, Cao_2021, Fasano_2009), and was also observed de novo in at least 1 affected individual with confirmed parentage (ClinVar, deCODE entry). In at least 1 family, there was evidence to suggest incomplete penetrance. In vitro experiments carried out in HEK293 and HepG2 cell lines found this variant to have a relatively mild gain-of-function impact on the activity of PCSK9 (example, Ahmad_2012, Chorba_2018, Fasano_2009, Uribe_2021). The following publications have been ascertained in the context of this evaluation (PMID: 23064986, 34407635, 36338372, 29259136, 19081568, 34948399). ClinVar contains an entry for this variant (Variation ID: 375844). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Hypercholesterolemia, familial, 1

Pathogenic:1Benign:1

Benign, criteria provided, single submitter	research	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	Mar 01, 2016	- -
Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 08, 2023	In the published literature, this variant has been reported in affected individuals with familial hypercholesterolemia (PMIDs: 19081568 (2009), 23064986 (2012), 23680767 (2013), 26374825 (2015), 31491741 (2019), 33955087 (2021), and 34037665 (2021)). One functional study demonstrated that this variant may reduce cell surface expression of LDLR (PMID: 26195630 (2015)), while two additional functional studies found that this variant performed similar to wild type (PMIDs: 19081568 (2009) and 23064986 (2012)). The frequency of this variant in the general population, 0.000026 (3/113682 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 predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 06, 2022	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Published in vitro studies show that this variant causes a reduction in membrane-associated LDLR (Le et al., 2015) while other published functional studies show PCSK9 protein with this variant is cleaved normally and secreted efficiently (Fasano et al., 2009) and binding and degradation of LDLR protein is similar to that of wild type PCSK9 activity (Ahmad et al., 2012); This variant is associated with the following publications: (PMID: 23064986, 23680767, 28994502, 34037665, 29261184, 26374825, 31491741, 33955087, 26195630, 19081568) -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 07, 2023

The c.385G>A (p.D129N) alteration is located in exon 2 (coding exon 2) of the PCSK9 gene. This alteration results from a G to A substitution at nucleotide position 385, causing the aspartic acid (D) at amino acid position 129 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.47

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.13

Eigen

Benign

-0.045

Eigen_PC

Benign

-0.12

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.86

M_CAP

Benign

0.046

MetaRNN

Benign

0.39

MetaSVM

Benign

-0.77

MutationAssessor

Uncertain

2.2

MutationTaster

Benign

0.99

D;D;D

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.91

REVEL

Benign

0.22

Sift

Benign

0.25

Sift4G

Benign

0.097

Polyphen

0.92

Vest4

0.38

MVP

0.84

MPC

0.46

ClinPred

0.85

GERP RS

2.5

Varity_R

0.34

gMVP

0.61

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