rs778738291

Positions:

• chr1-55044020-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM5 BP4 BS2

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:4 U:5 B:1
• Conservation: PhyloP100: 4.79

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 -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: {Uncertain_significance=1, Likely_pathogenic=2, Pathogenic=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	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	c.385G>A	p.Asp129Asn	missense_variant	2/12	1	NM_174936.4	P2

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

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251360 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135872

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

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

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.: 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:4 Uncertain:5 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	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. -
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, 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 -
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. -

Hypercholesterolemia, familial, 1 Pathogenic:1 Benign: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. -

Familial hypercholesterolemia Uncertain: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. -

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
MutationTaster	Benign	0.99	D;D;D
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

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: rs778738291; hg19: chr1-55509693;