rs778738291

Variant names:

• chr1-55044020-G-A
• rs778738291
• NM_174936.4:c.385G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM5 PP5 BP4

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:6 B:1
• Conservation: PhyloP100: 4.79
• Publications: 11 publications found

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 Gene-Disease associations (from GenCC):

• hypercholesterolemia, autosomal dominant, 3

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• homozygous familial hypercholesterolemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 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 submission is: [Conflicting_classifications_of_pathogenicity].
• PP5: Variant 1-55044020-G-A is Pathogenic according to our data. Variant chr1-55044020-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 375844.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
• BP4: Computational evidence support a benign effect (MetaRNN=0.39397877). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCSK9	NM_174936.4	c.385G>A	p.Asp129Asn	missense_variant	Exon 2 of 12	ENST00000302118.5	NP_777596.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCSK9	ENST00000302118.5	c.385G>A	p.Asp129Asn	missense_variant	Exon 2 of 12	1	NM_174936.4	ENSP00000303208.5

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152186 Hom.: 0 Cov.: 33

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

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251360 AF XY: 0.0000221

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461860 Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8 AN XY: 727230

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000989 AC: 11 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152186 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74352

African (AFR) AF: 0.00 AC: 0 AN: 41436

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000483 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:6 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Dec 16, 2016

Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

subjects mutated among 2600 FH index cases screened = 2, family members = 2, with co-segregation / Software predictions: Conflicting -

Jul 21, 2023

deCODE genetics, Amgen

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

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. -

May 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Dec 18, 2023

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Uncertain:3

Aug 08, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jun 27, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published in vitro studies show that this variant causes a reduction in membrane-associated LDLR while other published functional studies show PCSK9 protein with this variant is cleaved normally and secreted efficiently and binding and degradation of LDLR protein is similar to that of wild type PCSK9 activity (PMID: 26195630, 23064986, 19081568); In silico analysis suggests that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23064986, 23680767, 28994502, 34037665, 29261184, 26374825, 31491741, 33955087, 34948399, 26195630, 19081568, 34407635, 37937776, 39802654) -

Jan 23, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PCSK9 c.385G>A; p.Asp129Asn variant (rs778738291) is reported in the literature in individuals affected with familial hypercholesterolemia (Ahmad 2012, Benedek 2021, Fasano 2009, Hori 2019, Hopkins 2015, Sturm 2021, Vandrovcova 2013). This variant is also reported in ClinVar (Variation ID: 375844) and is only observed on four alleles in the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. One in vitro functional analyses demonstrates a reduction in cell surface expression of LDLR (Le 2015); however, other studies have shown no significant difference (Ahmad 2012, Fasano 2009). Additionally, computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.216). Due to conflicting information, the clinical significance of this variant is uncertain at this time. References: Ahmad Z et al. Low prevalence of mutations in known loci for autosomal dominant hypercholesterolemia in a multiethnic patient cohort. Circ Cardiovasc Genet. 2012 Dec;5(6):666-75. PMID: 23064986. Benedek P et al. Founder effects facilitate the use of a genotyping-based approach to molecular diagnosis in Swedish patients with familial hypercholesterolaemia. J Intern Med. 2021 Aug;290(2):404-415. PMID: 33955087. Fasano T et al. Degradation of LDLR protein mediated by 'gain of function' PCSK9 mutants in normal and ARH cells. Atherosclerosis. 2009 Mar;203(1):166-71. PMID: 19081568. Hopkins PN et al. Characterization of Autosomal Dominant Hypercholesterolemia Caused by PCSK9 Gain of Function Mutations and Its Specific Treatment With Alirocumab, a PCSK9 Monoclonal Antibody. Circ Cardiovasc Genet. 2015 Dec;8(6):823-31. PMID: 26374825. Hori M et al. Impact of LDLR and PCSK9 pathogenic variants in Japanese heterozygous familial hypercholesterolemia patients. Atherosclerosis. 2019 Oct;289:101-108. PMID: 31491741. Le QT et al. Plasma Membrane Tetraspanin CD81 Complexes with Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) and Low Density Lipoprotein Receptor (LDLR), and Its Levels Are Reduced by PCSK9. J Biol Chem. 2015 Sep 18;290(38):23385-400. PMID: 26195630. Sturm AC et al. Limited-Variant Screening vs Comprehensive Genetic Testing for Familial Hypercholesterolemia Diagnosis. JAMA Cardiol. 2021 Aug 1;6(8):902-909. PMID: 34037665. Vandrovcova J et al. The use of next-generation sequencing in clinical diagnosis of familial hypercholesterolemia. Genet Med. 2013 Dec;15(12):948-57. PMID: 23680767. -

Familial hypercholesterolemia Pathogenic:1 Uncertain:1

Sep 14, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jul 23, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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:1 Benign:1

-

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Mar 01, 2016

Laboratory of Genetics and Molecular Cardiology, University of São Paulo

Significance: Benign

Review Status: flagged submission

Collection Method: research

- -

Cardiovascular phenotype Uncertain:1

Dec 07, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	T
BayesDel_noAF	Benign	-0.47
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.045
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		4.8
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.91	N
REVEL	Benign	0.22
Sift	Benign	0.25	T
Sift4G	Benign	0.097	T
Polyphen		0.92	P
Vest4		0.38
MVP		0.84
MPC		0.46
ClinPred		0.85	D
GERP RS		2.5
Varity_R		0.34
gMVP		0.61
Mutation Taster		=53/47	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs778738291; hg19: chr1-55509693;