rs28942111
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PS1PM2PP3_StrongPP5_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
Consequence
NM_174936.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
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
Submissions by phenotype
Hypercholesterolemia, autosomal dominant, 3 Pathogenic:4Other:1
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). - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 12, 2008 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
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. - |
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at