rs1553135971

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 7P and 1B. PM5PP3_StrongPP5BS2_Supporting

The NM_174936.4(PCSK9):ā€‹c.386A>Gā€‹(p.Asp129Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000684 in 1,461,860 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. D129N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)
Exomes š‘“: 0.0000068 ( 0 hom. )

Consequence

PCSK9
NM_174936.4 missense

Scores

2
11
6

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1

Conservation

PhyloP100: 7.15
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM5
Other missense variant is known to change same aminoacid residue: Variant chr1-55044020-G-A is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.947
PP5
Variant 1-55044021-A-G is Pathogenic according to our data. Variant chr1-55044021-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 438332.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1, Likely_pathogenic=2}.
BS2
High AC in GnomAdExome4 at 10 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PCSK9NM_174936.4 linkuse as main transcriptc.386A>G p.Asp129Gly missense_variant 2/12 ENST00000302118.5 NP_777596.2 Q8NBP7-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PCSK9ENST00000302118.5 linkuse as main transcriptc.386A>G p.Asp129Gly missense_variant 2/121 NM_174936.4 ENSP00000303208.5 Q8NBP7-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000684
AC:
10
AN:
1461860
Hom.:
0
Cov.:
32
AF XY:
0.00000688
AC XY:
5
AN XY:
727230
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:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000899
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:3Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Hypercholesterolemia, autosomal dominant, 3 Pathogenic:2
Likely pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsJun 01, 2023- -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 04, 2023ClinVar contains an entry for this variant (Variation ID: 438332). 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. Experimental studies have shown that this missense change affects PCSK9 function (PMID: 17765244, 26195630, 27280970, 29259136). This variant disrupts the p.Asp129 amino acid residue in PCSK9. Other variant(s) that disrupt this residue have been observed in individuals with PCSK9-related conditions (PMID: 19081568), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 17765244; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 129 of the PCSK9 protein (p.Asp129Gly). -
Hypercholesterolemia, familial, 1 Pathogenic:1
Likely pathogenic, criteria provided, single submittercuration;literature onlyCardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo JorgeMar 01, 2016- -
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsFeb 01, 2024The p.D129G variant (also known as c.386A>G), located in coding exon 2 of the PCSK9 gene, results from an A to G substitution at nucleotide position 386. The aspartic acid at codon 129 is replaced by glycine, an amino acid with similar properties. This alteration has been reported in a subject with familial hypercholesterolemia (FH) (Homer VM et al. Atherosclerosis, 2008 Feb;196:659-66). Functional studies for this alteration show some reduction in LDLR expression, but are not overly compelling (Homer VM et al. Atherosclerosis, 2008 Feb;196:659-66; Le QT et al. J Biol Chem, 2015 Sep;290:23385-400; Poirier S et al. PLoS One, 2016 Jun;11:e0157230; Chorba JS et al. J Biol Chem, 2018 Feb;293:1875-1886; Uribe KB et al. Int J Mol Sci, 2021 Dec;22:). This amino acid position is 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 alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.19
BayesDel_addAF
Pathogenic
0.19
D
BayesDel_noAF
Uncertain
0.040
CADD
Uncertain
23
DANN
Uncertain
1.0
DEOGEN2
Benign
0.38
T
Eigen
Uncertain
0.32
Eigen_PC
Uncertain
0.23
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Benign
0.82
T
M_CAP
Uncertain
0.14
D
MetaRNN
Pathogenic
0.95
D
MetaSVM
Uncertain
-0.26
T
MutationAssessor
Uncertain
2.3
M
PrimateAI
Benign
0.46
T
PROVEAN
Uncertain
-2.6
D
REVEL
Uncertain
0.62
Sift
Benign
0.064
T
Sift4G
Uncertain
0.020
D
Polyphen
0.99
D
Vest4
0.57
MutPred
0.82
Gain of catalytic residue at D129 (P = 0.0248);
MVP
0.88
MPC
0.64
ClinPred
0.98
D
GERP RS
4.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.61
gMVP
0.73

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.

Other links and lift over

dbSNP: rs1553135971; hg19: chr1-55509694; API