1-55058106-C-A
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The NM_174936.4(PCSK9):c.1251C>A(p.His417Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00015 in 1,613,692 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign 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. H417R) has been classified as Uncertain significance.
Frequency
Consequence
NM_174936.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PCSK9 | NM_174936.4 | c.1251C>A | p.His417Gln | missense_variant | 8/12 | ENST00000302118.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PCSK9 | ENST00000302118.5 | c.1251C>A | p.His417Gln | missense_variant | 8/12 | 1 | NM_174936.4 | P2 |
Frequencies
GnomAD3 genomes AF: 0.000762 AC: 116AN: 152194Hom.: 1 Cov.: 33
GnomAD3 exomes AF: 0.000215 AC: 54AN: 251248Hom.: 0 AF XY: 0.000132 AC XY: 18AN XY: 135900
GnomAD4 exome AF: 0.0000862 AC: 126AN: 1461380Hom.: 0 Cov.: 33 AF XY: 0.0000674 AC XY: 49AN XY: 726990
GnomAD4 genome AF: 0.000762 AC: 116AN: 152312Hom.: 1 Cov.: 33 AF XY: 0.000631 AC XY: 47AN XY: 74472
ClinVar
Submissions by phenotype
Hypercholesterolemia, autosomal dominant, 3 Benign:2
Likely benign, 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 = 2 / One index case is double heterozygote with moderate phenotype / Software predictions: Conflicting - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 25, 2024 | - - |
Hypercholesterolemia, familial, 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Robarts Research Institute, Western University | Aug 22, 2019 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 04, 2023 | In silico analysis supports that this missense variant does not alter protein structure/function; Reported in association with high LDL in published literature; however, causality has not been clearly demonstrated (Kotowski et al., 2006); This variant is associated with the following publications: (PMID: 16465619, 23663650, Pham2021, 25904937, 17971861) - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 10, 2019 | Variant summary: PCSK9 c.1251C>A (p.His417Gln) results in a non-conservative amino acid change located in the Peptidase S8/S53 domain (IPR000209) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00021 in 251248 control chromosomes, predominantly at a frequency of 0.0032 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 34-fold the estimated maximal allele frequency expected for a pathogenic variant in PCSK9 causing Familial Hypercholesterolemia phenotype (9.4e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.1251C>A has been reported in the literature in individuals affected with hypercholesterolemia without strong evidence for causality (Kotowski_2006, Wang_2016). In one cohort, the association between this variant and LDL-C levels was not found (Kotowski_2006). At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant to PCSK9 processing (Chorba_2018). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 12, 2019 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Familial hypercholesterolemia Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Aug 08, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at