chr1-55039931-G-A

Position:

chr1-55039931-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PP5_Very_StrongBP4

The NM_174936.4(PCSK9):c.94G>A(p.Glu32Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000137 in 1,571,614 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00014 ( 3 hom. )

Consequence

PCSK9
NM_174936.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12U:1

Conservation

PhyloP100: 2.27

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_pathogenic. Variant got 7 ACMG points.

PP5

Variant 1-55039931-G-A is Pathogenic according to our data. Variant chr1-55039931-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 297692.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-55039931-G-A is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.27352333). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCSK9	NM_174936.4 linkuse as main transcript	c.94G>A	p.Glu32Lys	missense_variant	1/12	ENST00000302118.5	NP_777596.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCSK9	ENST00000302118.5 linkuse as main transcript	c.94G>A	p.Glu32Lys	missense_variant	1/12	1	NM_174936.4	ENSP00000303208	P2	Q8NBP7-1
PCSK9	ENST00000710286.1 linkuse as main transcript	c.451G>A	p.Glu151Lys	missense_variant	1/12			ENSP00000518176	A2
PCSK9	ENST00000673913.2 linkuse as main transcript	c.94G>A	p.Glu32Lys	missense_variant, NMD_transcript_variant	1/12			ENSP00000501161
PCSK9	ENST00000673726.1 linkuse as main transcript	c.94G>A	p.Glu32Lys	missense_variant, NMD_transcript_variant	1/6			ENSP00000501004

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152258

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:

0.00192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000275

AC:

AN:

181812

Hom.:

AF XY:

0.0000411

AC XY:

AN XY:

97290

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000300

Gnomad SAS exome

AF:

0.0000412

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000144

AC:

205

AN:

1419238

Hom.:

Cov.:

AF XY:

0.000133

AC XY:

AN XY:

701882

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00537

Gnomad4 SAS exome

AF:

0.0000248

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000340

GnomAD4 genome

AF:

0.0000656

AC:

AN:

152376

Hom.:

Cov.:

AF XY:

0.0000671

AC XY:

AN XY:

74516

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ExAC

AF:

0.0000168

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypercholesterolemia, autosomal dominant, 3

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 19, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The PCKS9 c.94G>A (p.Glu32Lys) missense variant has been reported in at least two studies. Mabuchi et al. (2014) investigated a cohort of 1096 Japanese familial hypercholesterolemia patients and identified the p.Glu32Lys variant in two homozygotes and 62 heterozygotes, and in nine individuals who were double heterozygotes for the p.Glu32Lys variant as well as a variant in the LDLR gene. The authors also reported that the levels of LDL-cholesterol in homozygotes and double heterozygotes of the p.Glu32Lys variant were significantly higher (p<0.001) than p.Glu32Lys heterozygotes, which were in turn significantly higher (p<0.001) than in unaffected family members. In addition, the variant was shown to segregate with a phenotype of elevated LDL-cholesterol levels by Mabuchi et al. (2014) and Noguchi et al. (2010) in unrelated families, although the phenotype was milder than that of heterozygotes with a mutation in the LDLR gene. Control data are unavailable for the p.Glu32Lys variant, which is reported at a frequency of 0.00155 in the East Asian population of the Exome Aggregation Consortium but this is based on two alleles only. Based on the evidence, the p.Glu32Lys variant is classified as likely pathogenic for familial hypercholesterolemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 18, 2023	This missense variant is located in the propeptide domain of the PCSK9 protein. This variant has only been identified in 5/181812 chromosomes (4/13348 East Asian chromosomes) in the general population by the Genome Aggregation Database (gnomAD). However, this variant is fairly common in the Japanese population (14/2340 chromosomes) (PMID: 26911352) and has been reported in over 60 heterozygous individuals affected with hypercholesterolemia in Japan (6% of the affected population; PMID: 17316651, 24859021, 25014035, 25962062, 26374825, 26632531, 28179607, 31491741, 33533259, 35929461; Pham et al., 2021, doi.org/10.3390/pr9020283). Individuals homozygous for this variant have shown markedly higher plasma LDL-C level than heterozygotes, but showed mild phenotype compared to individuals carrying biallelic LDLR mutations (PMID: 20006333, 21146822, 28179607). This variant has shown strong segregation with disease in multiple families (PMID: 20006333, 25014035). This variant has shown an association with an increased risk of myocardial infarction (PMID: 29802317, 33533259). Notably, this variant appears to exacerbate LDL-C levels and risk of myocardial infarction in individuals carrying LDLR mutations (PMID: 33533259). The impact of this variant on LDLR protein expression and function has not been reported in the literature, although an in vitro study has suggested that this variant may cause an increase in extracellular secretion of the mutant protein (PMID: 20006333). In summary, the available evidence indicates this variant to be a slight gain-of-function mutation that causes mild hypercholesterolemia. Based on the enrichment in affected individuals and co-segregation with disease in family studies, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 03, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 19, 2023	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 32 of the PCSK9 protein (p.Glu32Lys). This variant is present in population databases (rs564427867, gnomAD 0.03%). This missense change has been observed in individuals with hypercholesterolemia (PMID: 17316651, 20006333, 25014035, 25962062, 26374825, 26632531, 28179607). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 297692). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PCSK9 protein function. Experimental studies have shown that this missense change affects PCSK9 function (PMID: 20006333). For these reasons, this variant has been classified as Pathogenic. -

Hypercholesterolemia, familial, 1

Pathogenic:1Uncertain:1

Uncertain significance, flagged submission	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	-	- -

Homozygous familial hypercholesterolemia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 16, 2020

The p.Glu32Lys variant in PCSK9 has been reported in >40 Japanese and Korean individuals with hypercholesterolemia, including 2 homozygous individuals and 9 double heterozygotes who had an additional pathogenic variant in LDLR (Miyake 2008 PMID: 17316651, Mabuchi 2011 PMID: 21146822, Noguchi 2010 PMID: 20006333, Mabuchi 2014 PMID: 25014035, Han 2015 PMID: 25962062, Hopkins 2015 PMID: 26374825, ClinVar Variation ID: 297692). Homozygotes and double heterozygotes had more severe disease on average than heterozygotes, and heterozygotes for this variant had milder disease than heterozygotes for other variants associated to familial hypercholesterolemia (FH; Mabuchi 2014 PMID: 25014035, Hopkins 2015 PMID: 26374825). Additionally, this variant segregated with disease in >20 affected relatives from >5 families (Noguchi 2010 PMID: 20006333, Mabuchi 2014 PMID: 25014035). In vitro functional studies provide some evidence that the p.Glu32Lys variant may impact protein function (Noguchi 2010 PMID: 20006333). This variant has also been identified in 0.03% (4/13348) of East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org/). This frequency is low enough to be consistent with the frequency of FH in the general population. In summary, the p.Glu32Lys variant meets criteria to be classified as pathogenic for autosomal dominant FH based upon presence in multiple affected individuals and segregation with disease. The ACMG/AMP Criteria applied: PS4, PP1_Strong, PS3_Supporting, PM3. -

PCSK9-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 07, 2024

The PCSK9 c.94G>A variant is predicted to result in the amino acid substitution p.Glu32Lys. This variant has been reported in the heterozygous and homozygous state in individuals with familial hypercholesterolemia, primarily from Japan (see, for example, Miyake et al. 2008. PubMed ID: 17316651; Noguchi et al. 2010. PubMed ID: 20006333; Tada et al. 2016. PubMed ID: 26632531). This variant is associated with a milder phenotype than other PCSK9 variants but has been reported in patients with a more severe phenotype when homozygous or in combination with pathogenic variants in the LDLR gene (Noguchi et al. 2010. PubMed ID: 20006333; Mabuchi et al. 2014. PubMed ID: 25014035; Hopkins et al. 2015. PubMed ID: 26374825). In vitro experimental studies suggest this variant impacts protein function, and it has been described as causing a gain-of-function effect (Noguchi et al. 2010. PubMed ID: 20006333; Uribe et al. 2021. PubMed ID: 34948399). This variant is reported in 0.030% of alleles in individuals of East Asian descent in gnomAD. This variant is interpreted as likely pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 07, 2023

Published functional studies demonstrate a damaging effect: increased extracellular PCSK9 activity, increased LDLR affinity, and decreased LDLR expression and uptake (Noguchi et al., 2010; Uribe et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30241732, 17316651, 31447099, 28784313, 34652028, 22683120, 33173529, 29192238, 24859021, 29724976, 27025683, 21619378, 25399932, 27075771, 29049823, 30592178, 29292049, 34782856, 20006333, Singhal2022, 31491741, 24518357, 32719484, 34011801, 29802317, 21146822, 27206942, 34037665, 34848321, 26632531, 25014035, 28179607, 33533259, 34408116, Pham2021, 34526433, 34176852, 25962062, 26374825, 34948399, 35480308) -

Cardiovascular phenotype

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 12, 2023

The p.E32K variant (also known as c.94G>A), located in coding exon 1 of the PCSK9 gene, results from a G to A substitution at nucleotide position 94. The glutamic acid at codon 32 is replaced by lysine, an amino acid with similar properties. This alteration was detected in 62 of 1055 individuals with familial hypercholesterolemia (FH), as well as in 13 of the 41 compound heterozygous FH patients who also had an LDLR alteration (Mabuchi H et al. Atherosclerosis, 2014 Sep;236:54-61). This alteration was also shown to segregate with the disease in a few apparently unrelated families (Noguchi T et al. Atherosclerosis, 2010 May;210:166-72). In addition, alteration carriers were described to have higher levels of PCSK9 expression, LDL-C and lipoprotein (Miyake Y et al. Atherosclerosis, 2008 Jan;196:29-36; Noguchi T et al. Atherosclerosis, 2010 May;210:166-72; Tada H et al. Circ. J., 2016 Dec;80:512-8). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Familial hypercholesterolemia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Feb 28, 2023

This missense variant is located in the propeptide domain of the PCSK9 protein. This variant has only been identified in 5/181812 chromosomes (4/13348 East Asian chromosomes) in the general population by the Genome Aggregation Database (gnomAD). However, this variant is fairly common in the Japanese population (14/2340 chromosomes) (PMID: 26911352) and has been reported in over 60 heterozygous individuals affected with hypercholesterolemia in Japan (6% of the affected population; PMID: 17316651, 24859021, 25014035, 25962062, 26374825, 26632531, 28179607, 31491741, 33533259, 35929461; Pham et al., 2021, doi.org/10.3390/pr9020283). Individuals homozygous for this variant have shown markedly higher plasma LDL-C level than heterozygotes, but showed mild phenotype compared to individuals carrying biallelic LDLR mutations (PMID: 20006333, 21146822, 28179607). This variant has shown strong segregation with disease in multiple families (PMID: 20006333, 25014035). This variant has shown an association with an increased risk of myocardial infarction (PMID: 29802317, 33533259). Notably, this variant appears to exacerbate LDL-C levels and risk of myocardial infarction in individuals carrying LDLR mutations (PMID: 33533259). The impact of this variant on LDLR protein expression and function has not been reported in the literature, although an in vitro study has suggested that this variant may cause an increase in extracellular secretion of the mutant protein (PMID: 20006333). In summary, the available evidence indicates this variant to be a slight gain-of-function mutation that causes mild hypercholesterolemia. Based on the enrichment in affected individuals and co-segregation with disease in family studies, this variant is classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.090

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.16

Eigen

Benign

-0.96

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.64

LIST_S2

Benign

0.68

M_CAP

Benign

0.043

MetaRNN

Benign

0.27

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.81

MutationTaster

Benign

1.0

N;N

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-0.56

REVEL

Uncertain

0.43

Sift

Benign

0.053

Sift4G

Benign

0.061

Polyphen

0.063

Vest4

0.73

MutPred

0.72

Gain of ubiquitination at E32 (P = 0.0075);

MVP

0.72

MPC

0.28

ClinPred

0.054

GERP RS

0.33

Varity_R

0.10

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