chr1-55043958-T-G

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PM5PP3_ModeratePP5

The NM_174936.4(PCSK9):c.323T>G(p.Leu108Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. L108P) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PCSK9
NM_174936.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:2

Conservation

PhyloP100: 1.88

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-55043958-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 440715.Status of the report is no_assertion_criteria_provided, 0 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.889

PP5

Variant 1-55043958-T-G is Pathogenic according to our data. Variant chr1-55043958-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 375849.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2, Pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCSK9	NM_174936.4 link	c.323T>G	p.Leu108Arg	missense_variant	Exon 2 of 12	ENST00000302118.5	NP_777596.2	Q8NBP7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCSK9	ENST00000302118.5 link	c.323T>G	p.Leu108Arg	missense_variant	Exon 2 of 12	1	NM_174936.4	ENSP00000303208.5		Q8NBP7-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461880

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hypercholesterolemia, autosomal dominant, 3

Pathogenic:2

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: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

subject mutated among 2600 FH index cases screened = 1, family member = 1 / functionnal testing (PMID:22683120) / Software predictions: Benign -

Aug 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 108 of the PCSK9 protein (p.Leu108Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 22683120; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 375849). 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 have shown that this missense change affects PCSK9 function (PMID: 22683120, 26195630, 29259136, 34948399). For these reasons, this variant has been classified as Pathogenic. -

Familial hypercholesterolemia

Pathogenic:1Uncertain:1

Jan 22, 2020

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

The p.Leu108Arg variant in PCSK9 has been reported in 5 individuals with familial hypercholesterolemia, segregated with disease in 4 affected relatives from 1 family (PMID: 26374825, 22683120), and was absent from large population studies. This variant has also been reported in ClinVar as likely pathogenic and pathogenic (Variation ID: 375849). In vitro functional studies provide some evidence that the p.Leu108Arg variant may slightly impact protein function (PMID: 22683120). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PP1, PS4_supporting, PS3_supporting (Richards 2015). -

Feb 23, 2017

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: The PCSK9 c.323T>G (p.Leu108Arg) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant. This variant is absent in 121160 control chromosomes. This variant has been reported in one FH family with unequivocal co-segregation evidence (found in 4 affected members, not found in 3 unaffected members). In vitro study showed that p.L108R had a clear and significant gain-of-function effect. Taken together, this variant is classified as likely pathogenic until additional FH families are reported to carry this variant. -

Cardiovascular phenotype

Uncertain:1

Jan 30, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L108R variant (also known as c.323T>G), located in coding exon 2 of the PCSK9 gene, results from a T to G substitution at nucleotide position 323. The leucine at codon 108 is replaced by arginine, an amino acid with dissimilar properties. This variant was identified in one or more individuals with features consistent with familial hypercholesterolemia (FH) and segregated with disease in at least one family (Abifadel M et al. Atherosclerosis, 2012 Aug;223:394-400; Rimbert A et al. Front Genet, 2021 Jan;12:809256; Razman AZ et al. Int J Mol Sci, 2022 Nov;23:[ePub ahead of print]). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.0

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

Eigen

Benign

0.048

Eigen_PC

Benign

-0.049

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.62

M_CAP

Benign

0.053

MetaRNN

Pathogenic

0.89

MetaSVM

Benign

-0.56

MutationAssessor

Uncertain

2.5

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.3

REVEL

Uncertain

0.45

Sift

Benign

0.067

Sift4G

Uncertain

0.035

Polyphen

0.97

Vest4

0.77

MutPred

0.71

Gain of MoRF binding (P = 0.0091);

MVP

0.78

MPC

0.98

ClinPred

0.91

GERP RS

3.3

Varity_R

0.66

gMVP

0.71

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