rs148195424

Positions:

• chr1-55052701-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4 BP6 BS2

The NM_174936.4(PCSK9):​c.709C>T​(p.Arg237Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00107 in 1,613,120 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).

• Frequency:
  • Genomes: 𝑓 0.00065 (0 hom., cov: 35)
  • Exomes 𝑓: 0.0011 (0 hom.)
• Consequence: PCSK9 NM_174936.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11 B:7
• Conservation: PhyloP100: 1.33

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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.27151805).
• BP6: Variant 1-55052701-C-T is Benign according to our data. Variant chr1-55052701-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 265933.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Uncertain_significance=9}.
• BS2: High AC in GnomAd4 at 99 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCSK9	NM_174936.4	c.709C>T	p.Arg237Trp	missense_variant	5/12	ENST00000302118.5	NP_777596.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCSK9	ENST00000302118.5	c.709C>T	p.Arg237Trp	missense_variant	5/12	1	NM_174936.4	ENSP00000303208	P2

Frequencies

GnomAD3 genomes AF: 0.000650 AC: 99 AN: 152224 Hom.: 0 Cov.: 35

Gnomad AFR AF: 0.000289

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000999

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000719 AC: 179 AN: 249096 Hom.: 0 AF XY: 0.000666 AC XY: 90 AN XY: 135140

Gnomad AFR exome AF: 0.000187

Gnomad AMR exome AF: 0.00130

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000981

Gnomad FIN exome AF: 0.000509

Gnomad NFE exome AF: 0.000974

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00111 AC: 1620 AN: 1460778 Hom.: 0 Cov.: 81 AF XY: 0.00104 AC XY: 757 AN XY: 726698

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.00123

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.000514

Gnomad4 NFE exome AF: 0.00131

Gnomad4 OTH exome AF: 0.00106

GnomAD4 genome AF: 0.000650 AC: 99 AN: 152342 Hom.: 0 Cov.: 35 AF XY: 0.000618 AC XY: 46 AN XY: 74492

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.000784

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000999

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.000853 Hom.: 0

Bravo AF: 0.000880

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00163 AC: 14

ExAC AF: 0.000593 AC: 72

EpiCase AF: 0.00104

EpiControl AF: 0.00119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:11 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Uncertain significance, 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 member = 1 / Software predictions: Damaging -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	Oct 26, 2021	The c.709C>T (p.Arg237Trp) variant identified in the PCSK9 gene substitutes a conserved Arginine for Tryptophan at amino acid 237/693 (exon5/12). This variant is found in 99 heterozygotes in gnomAD(v3.1.1) (0 homozygotes; allele frequency:6.5e-4), which is slightly higher than expected for a pathogenic Familial Hypercholesterolemia associated variant (ClinGen Familial Hypercholesterolemia Expert Panel Specifications, Version 1.1). In silico algorithms predict this variant to be Pathogenic (REVEL; score:0.615) and Damaging (SIFT; score:0.001) to the function of the canonical transcript. This variant is reported in ClinVar as both a Variant of Uncertain Significance and Likely Benign (VarID:265933). The p.Arg237Trp variant has been reported in individuals in the literature with hypercholesterolemia [PMID:26020417, 18262190, 16465619, 33418990], but has also been identified in many individuals with hypocholesterolemia [PMID:29459468,24507775, 20623344, 16424354, others]. Functional studies on the role of this variant to PCSK9 function are conflicting, with some studies suggesting no damaging effect on PCSK9 [PMID:15358785, 29259136], and another suggesting mild increase in LDL receptor and higher LDL internalization possibly due to failure to undergo autocatalytic cleavage [PMID:16571601]. The p.Arg237 residue is within the Peptidase S8 domain of PCSK9 (UniProtKB:Q8NBP7). Given the conflicting informationregarding the c.709C>T (p.Arg237Trp) variant identified in the PCSK9 gene, it is reported as a Variant of Uncertain Significance. -

not provided Uncertain:2 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	PCSK9: BS1 -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 28, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 26, 2022	Also identified in patients with hypercholesterolemia in published literature (de Paiva Silvino et al., 2020; Gill et al., 2021; Meshkov et al., 2021); at least one patient also harbored a pathogenic variant in the LDLR gene (Wang et al., 2016); Published functional studies demonstrate loss-of-function with a modest effect, resulting in a 16% increased level of cell surface LDL-receptors and a 35% increase in the internalization of LDL when compared to wild-type PCSK9 (Cameron et al., 2006); This variant is associated with the following publications: (PMID: 18300938, 25046268, 16424354, 16465619, 17765244, 21943799, 28157721, 17435765, 16912035, 15358785, 24507775, 27535533, 16571601, 26582918, 27765764, 33418990, 33231818, 33303402) -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 09, 2019	- -

Hypercholesterolemia, familial, 1 Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Robarts Research Institute, Western University	Aug 22, 2019	- -
Uncertain significance, criteria provided, single submitter	research	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	0/190 non-FH alleles (portuguese normolipidemic individuals); 0/100 normolipidemic individuals -
Uncertain significance, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Aug 01, 2016	Found in patient having exome sequencing for an unrelated indication. No known history of hyperlipidemia. -

not specified Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 16, 2021	Variant summary: PCSK9 c.709C>T (p.Arg237Trp) results in a non-conservative amino acid change located in the Peptidase S8/S53 domain (IPR000209) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00072 in 249096 control chromosomes. The observed variant frequency is approximately 19 fold of the estimated maximal expected allele frequency for a pathogenic variant in PCSK9 causing Familial Hypercholesterolemia phenotype (3.8e-05), strongly suggesting that the variant is benign. c.709C>T has been reported in the literature in sequencing studies of individuals affected with hypercholesterolemia (e.g. Kotowski_2006, Homer_2008, Madeiros_2016, Berge_2006, Cameron_2008, Leren_2008, Lange_2014, Benn_2017, Balder_2018) without strong evidence for causality. These reports do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. At-least one co-occurrence with another pathogenic variant causative of Familial Hypercholesterolemia has been observed at our laboratory (LDLR c.2043C>A, p.Cys681*), providing supporting evidence for a benign role. Several publications report experimental evidence evaluating an impact on protein function. One group reports little to no damaging effects for the variant in the processing and secretion of PCSK9 protein (Benjannet_2004, Benjannet_2006). Another study reports a very mild increase in the expression of LDL receptor on the cell surface and slightly higher levels of LDL internalization in cells with the variant (Cameron_2006). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=2; VUS, n=6). Based on the evidence outlined above, the variant was classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -

Short fetal femur length Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Phenosystems SA

-

- -

Hypobetalipoproteinemia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

PCSK9-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 02, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 30, 2021

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

Aug 23, 2019

This variant has been identified in 0.2200% (62/28178) of Color clients and in 0.1327% (47/35392) of Latino population in the Genome Aggregation Database (gnomAD). This variant allele frequency is greater than expected for PCSK9-related disorders based on prevalence, penetrance, and genetic heterogeneity. Therefore, this variant is classified as Likely Benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.074
FATHMM_MKL	Benign	0.56	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.27	T
MetaSVM	Uncertain	0.71	D
MutationAssessor	Uncertain	2.2	M
MutationTaster	Benign	0.67	D;D;D
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Uncertain	0.61
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.53
MVP		0.91
MPC		0.86
ClinPred		0.069	T
GERP RS		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.84
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: rs148195424; hg19: chr1-55518374;