rs1553135971
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 7P and 1B. PM5PP3_StrongPP5BS2_Supporting
The NM_174936.4(PCSK9):āc.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
Consequence
NM_174936.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PCSK9 | NM_174936.4 | c.386A>G | p.Asp129Gly | missense_variant | 2/12 | ENST00000302118.5 | NP_777596.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PCSK9 | ENST00000302118.5 | c.386A>G | p.Asp129Gly | missense_variant | 2/12 | 1 | NM_174936.4 | ENSP00000303208.5 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461860Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5AN XY: 727230
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Hypercholesterolemia, autosomal dominant, 3 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jun 01, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 04, 2023 | ClinVar 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 submitter | curation;literature only | Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge | Mar 01, 2016 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 01, 2024 | The 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at