rs139669564

chr1-55058631-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 4P and 9B. PM1 PM5 BP4_Strong BP6 BS2

The NM_174936.4(PCSK9):c.1487G>A(p.Arg496Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00017 in 1,611,008 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R496W) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: PCSK9 NM_174936.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:4 B:6
• Conservation: PhyloP100: 1.47

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 -5 ACMG points.

• PM1: In a strand (size 6) in uniprot entity PCSK9_HUMAN there are 5 pathogenic changes around while only 2 benign (71%) in NM_174936.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-55058630-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 201129.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=11, Pathogenic=2, not_provided=1}.
• BP4: Computational evidence support a benign effect (MetaRNN=0.01776591).
• BP6: Variant 1-55058631-G-A is Benign according to our data. Variant chr1-55058631-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 438338.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=4, Benign=2}.
• BS2: High AC in GnomAd at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCSK9	NM_174936.4	c.1487G>A	p.Arg496Gln	missense_variant	9/12	ENST00000302118.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCSK9	ENST00000302118.5	c.1487G>A	p.Arg496Gln	missense_variant	9/12	1	NM_174936.4	P2

Frequencies

GnomAD3 genomes AF: 0.0000986 AC: 15 AN: 152098 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000254 AC: 63 AN: 247982 Hom.: 0 AF XY: 0.000335 AC XY: 45 AN XY: 134504

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00138

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000179

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000178 AC: 259 AN: 1458792 Hom.: 0 Cov.: 109 AF XY: 0.000247 AC XY: 179 AN XY: 725636

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: 0.00157

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000106

Gnomad4 OTH exome AF: 0.0000997

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152216 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74412

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000114 Hom.: 0

Bravo AF: 0.0000529

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000313 AC: 38

EpiCase AF: 0.000109

EpiControl AF: 0.000238

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:4 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:1 Uncertain:2

Uncertain significance, criteria provided, single submitter	curation;literature only	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	- -
Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Robarts Research Institute, Western University	Jan 02, 2018	- -

Hypercholesterolemia, autosomal dominant, 3 Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jun 20, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 16, 2024	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 25, 2017	Variant summary: The PCSK9 c.1487G>A (p.Arg496Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. 4/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). One functional study showed that this variant was associated with amounts of cell surface LDLR and LDL internalized that were comparable to that of wild-type levels (Cameron_2006). The variant was found in the control population dataset of gnomAD in 68/240046 control chromosomes at a frequency of 0.0002833, which is approximately 14 times the estimated maximal expected allele frequency of a pathogenic PCSK9 variant (0.00002), suggesting this variant is likely a benign polymorphism. One study found this variant in a subject homozygous for apolipoprotein E-2 who presented with Type III hyperlipoproteinaemia, without strong evidence for causality. This variant was found co-occurring with the pathogenic LDLR c.1775G>A, p.Gly592Glu mutation in an internal specimen, supporting a benign impact of the variant. One clinical diagnostic laboratory classified this variant as uncertain significance. Taken together, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 03, 2020	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 08, 2020

Identified in association with hyperlipoproteinemia (Cameron et al., 2006) and hypercholesterolemia with early onset coronary artery disease (CAD) (Cao et al., 2018); In silico analysis supports that this missense variant does not alter protein structure/function; Published in vitro functional studies demonstrate no effect on autocatalytic activity and LDL-receptor surface expression and internalized LDL levels comparable to wild-type; nevertheless, it is unclear how these studies may translate to a pathogenic role in vivo (Cameron et al., 2006); Reported in ClinVar (ClinVar Variant ID#438338; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 30526649, 19191301, 16571601) -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 31, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Familial hypercholesterolemia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Dec 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	17
Dann	Uncertain	0.99
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.018	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.3	M
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.32	N
REVEL	Benign	0.16
Sift	Benign	0.42	T
Sift4G	Benign	0.28	T
Polyphen		0.91	P
Vest4		0.15
MVP		0.80
MPC		0.27
ClinPred		0.063	T
GERP RS		-1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.20
gMVP		0.62

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: rs139669564; hg19: chr1-55524304;