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
Consequence
NM_174936.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 32
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Hypercholesterolemia, autosomal dominant, 3 Pathogenic:1
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.