rs28942111

chr1-55044016-T-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PS1 PM2 PP3_Strong PP5_Very_Strong

The NM_174936.4(PCSK9):c.381T>A(p.Ser127Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PCSK9 NM_174936.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: 0.664

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 Pathogenic. Variant got 18 ACMG points.

• PS1: Transcript NM_174936.4 (PCSK9) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 2027927
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98
• PP5: Variant 1-55044016-T-A is Pathogenic according to our data. Variant chr1-55044016-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCSK9	NM_174936.4	c.381T>A	p.Ser127Arg	missense_variant	2/12	ENST00000302118.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCSK9	ENST00000302118.5	c.381T>A	p.Ser127Arg	missense_variant	2/12	1	NM_174936.4	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, autosomal dominant, 3 Pathogenic:4 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 12, 2008	- -
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 = 11, family members = 2 / Software predictions: Damaging -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 12, 2024	The c.381T>A (p.Ser127Arg) variant in the PCSK9 gene is located in the exon 2 of the PCSK9 gene and is predicted to replace serine with arginine at codon 127 of the PCSK9 protein. This variant has been identified in individuals with autosomal dominant familial hypercholesterolemia (PMID: 12730697, 33147992, 15166014). Experimental studies have shown that this missense change affects PCSK9 function (PMID: 15358785, 27280970, 15166014, 36187800). This variant has not been reported in the general population according to gnomAD. A different variant affecting amino acid residue Ser127 (c.381T>G, p.Ser127Leu) has been determined to be pathogenic in ClinVar according to ACMG guidelines. Therefore, the c.381 T>A (p.Ser127Arg) variant in the PCSK9 gene has been classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jun 29, 2022	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects PCSK9 function (PMID: 15358785, 27280970). 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 expected to disrupt PCSK9 protein function. ClinVar contains an entry for this variant (Variation ID: 2873). This variant is also known as 625T>A. This missense change has been observed in individuals with autosomal dominant familial hypercholesterolemia (PMID: 12730697, 33147992). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 127 of the PCSK9 protein (p.Ser127Arg). -
not provided, no classification provided	literature only	GeneReviews	-	- -

Hypercholesterolemia, familial, 1 Pathogenic:2

Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Likely pathogenic, criteria provided, single submitter	curation;literature only	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
Cadd	Benign	17
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.42	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.81	T
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Uncertain	2.8	M
MutationTaster	Benign	0.95	A;A;A
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.59
Sift	Benign	0.042	D
Sift4G	Benign	0.10	T
Polyphen		0.95	P
Vest4		0.94
MutPred		0.84		Gain of methylation at S127 (P = 0.0333);
MVP		0.81
MPC		0.81
ClinPred		0.98	D
GERP RS		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.88
gMVP		0.86

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: rs28942111; hg19: chr1-55509689;