1-55044016-T-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PS1_Very_StrongPM2PP3_StrongPP5_Moderate

The NM_174936.4(PCSK9):​c.381T>G​(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 Pathogenic (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S127N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

PCSK9
NM_174936.4 missense

Scores

3
7
9

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 0.664
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PS1
Transcript NM_174936.4 (PCSK9) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 2873
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.979
PP5
Variant 1-55044016-T-G is Pathogenic according to our data. Variant chr1-55044016-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 2027927.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PCSK9NM_174936.4 linkc.381T>G p.Ser127Arg 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
PCSK9ENST00000302118.5 linkc.381T>G p.Ser127Arg missense_variant Exon 2 of 12 1 NM_174936.4 ENSP00000303208.5 Q8NBP7-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Hypercholesterolemia, autosomal dominant, 3 Pathogenic:1
Nov 05, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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). This variant is not present in population databases (gnomAD no frequency). 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 also known as nucleotide position 625. 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. Experimental studies have shown that this missense change affects PCSK9 function (PMID: 15358785, 27280970). For these reasons, this variant has been classified as Pathogenic. -

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
18
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.42
T
Eigen
Benign
-0.21
Eigen_PC
Benign
-0.32
FATHMM_MKL
Benign
0.66
D
LIST_S2
Benign
0.81
T
M_CAP
Benign
0.069
D
MetaRNN
Pathogenic
0.98
D
MetaSVM
Benign
-0.46
T
MutationAssessor
Uncertain
2.8
M
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
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-55509689; API