chr1-55052398-G-A
Variant names:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM5PP3_ModeratePP5_Very_Strong
The NM_174936.4(PCSK9):c.644G>A(p.Arg215His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,560 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R215C) has been classified as Likely pathogenic.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000041 ( 0 hom. )
Consequence
PCSK9
NM_174936.4 missense
NM_174936.4 missense
Scores
3
6
10
Clinical Significance
Conservation
PhyloP100: 2.39
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 uncertain in NM_174936.4
PM5
Other missense variant is known to change same aminoacid residue: Variant chr1-55052397-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 633346.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=4, Likely_pathogenic=3}.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.932
PP5
Variant 1-55052398-G-A is Pathogenic according to our data. Variant chr1-55052398-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 201127.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-55052398-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000411 AC: 6AN: 1461560Hom.: 0 Cov.: 35 AF XY: 0.00000550 AC XY: 4AN XY: 727086
GnomAD4 exome
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AC:
6
AN:
1461560
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Cov.:
35
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4
AN XY:
727086
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GnomAD4 genome
GnomAD4 genome
Cov.:
32
Bravo
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:9Uncertain:1Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hypercholesterolemia, autosomal dominant, 3 Pathogenic:4Other:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | Aug 21, 2017 | This c.644G>A (p.Arg215His) variant in the PCSK9 gene has been reported in 3 unrelated patients with hypercholesterolemia (PMID: 18266662, 28008010). In the family of one of these patients, this variant segregated with hypercholesterolemia in eight relatives (PMID: 18266662). A different amino acid substitution, arginine to lysine at residue 215 of the PCSK9 protein, has also been reported as disease-causing in 1 patient with familial hypercholesterolemia (PMID: 25962062). Functional studies have shown that the p.Arg215His mutant PSCK9 protein causes fewer low density lipoprotein receptors (LDLR) to be on the cell surface, thereby leading to increased levels of LDL cholesterol (PMID: 18266662). This variant is classified as likely pathogenic. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Juno Genomics, Hangzhou Juno Genomics, Inc | - | PS4_Supporting+PP1_Strong+PM2_Supporting - |
| not provided, no classification provided | literature only | GeneReviews | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 30, 2024 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 215 of the PCSK9 protein (p.Arg215His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of familial hypercholesterolemia (PMID: 18266662, 30526649). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 201127). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt PCSK9 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PCSK9 function (PMID: 18266662, 18631360, 27896130). For these reasons, this variant has been classified as Pathogenic. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jan 08, 2024 | This missense variant replaces arginine with histidine at codon 215 in the catalytic peptidase domain of the PCSK9 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). An experimental study has shown no impact on catalytic peptidase function but reduced LDL uptake by ~14% (PMID: 18266662, 21147780). A different study has shown no significant impact on the LDL uptake by the mutant protein (PMID: 27896130). The clinical relevance of this observation is not known. This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 18266662, 18266662, 26633542, 28008010, 34037665, 36980993). It has been shown that this variant segregates with disease in more than 20 individuals affected with hypercholesterolemia from two Norwegian families (PMID: 18266662, 26374825). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. - |
not provided Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 03, 2016 | The R215H mutation in the PCSK9 gene has been reported previously in two unrelated probands (Cameron et al., 2008). R215H co-segregated with hypercholesterolemia in eight relatives from one family and functional studies indicate R215H is a gain-of-function mutation (Cameron et al., 2008). Mutations in nearby residues (F216L, R218S) have been reported in association with hypercholesterolemia, further supporting the functional importance of this region of the protein. The R215H mutation was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret R215H as a disease-causing mutation. The variant is found in the PCSK9 panel(s). - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 28, 2024 | The PCSK9 c.644G>A; p.Arg215His variant (rs794728683, ClinVar Variation ID: 201127) is reported in the literature in multiple individuals affected with familial hypercholesterolemia and was found to segregate with disease in multiple families (Abdul Murad 2023, Abul-Husn 2016, Cameron 2008, Hopkins 2015, Strum 2021). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.612). Based on available information, this variant is considered to be likely pathogenic. References: Abdul Murad NA et al. Hypercholesterolemia in the Malaysian Cohort Participants: Genetic and Non-Genetic Risk Factors. Genes (Basel). 2023 Mar 15;14(3):721. PMID: 36980993. Abul-Husn NS et al. Genetic identification of familial hypercholesterolemia within a single U.S. health care system. Science. 2016 Dec 23;354(6319):aaf7000. PMID: 28008010. Cameron J et al. Characterization of novel mutations in the catalytic domain of the PCSK9 gene. J Intern Med. 2008 Apr;263(4):420-31. PMID: 18266662. Hopkins PN et al. Characterization of Autosomal Dominant Hypercholesterolemia Caused by PCSK9 Gain of Function Mutations and Its Specific Treatment With Alirocumab, a PCSK9 Monoclonal Antibody. Circ Cardiovasc Genet. 2015 Dec;8(6):823-31. PMID: 26374825. Sturm AC et al. Limited-Variant Screening vs Comprehensive Genetic Testing for Familial Hypercholesterolemia Diagnosis. JAMA Cardiol. 2021 Aug 1;6(8):902-909. PMID: 34037665. - |
Hypercholesterolemia, familial, 1 Pathogenic:1Uncertain:1
| Pathogenic, no assertion criteria provided | research | Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum | - | - - |
| Uncertain significance, flagged submission | curation;literature only | Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge | Mar 01, 2016 | - - |
Homozygous familial hypercholesterolemia Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 08, 2018 | The p.Arg215His variant in PCSK9 has been reported in at least 5 individuals with hypercholesterolemia, segregated with disease in at least 20 affected relatives from 2 families (Cameron 2008, Hopkins 2015, Retterer 2015, Abul-Husn 2016), and was absent from large population studies. In vitro functional studies provide conflicting evidence as to whether the p.Arg215His variant may impact protein function (Cameron 2008, Wierod 2016). However, these types of assays may not accurately represent biological function. This variant is reported in ClinVar (Variation ID: 201127). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, although additional studies are required to fully establish its clinical significance, the p.Arg215His variant is likely pathogenic. ACMG/AMP Criteria applied: PP1_Strong, PM2, PS4_Supporting. - |
Familial hypercholesterolemia Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Aug 03, 2023 | This missense variant replaces arginine with histidine at codon 215 in the catalytic peptidase domain of the PCSK9 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). An experimental study has shown no impact on catalytic peptidase function but reduced LDL uptake by ~14% (PMID: 18266662, 21147780). A different study has shown no significant impact on the LDL uptake by the mutant protein (PMID: 27896130). The clinical relevance of this observation is not known. This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 18266662, 18266662, 26633542, 28008010, 34037665, 36980993). It has been shown that this variant segregates with disease in more than 20 individuals affected with hypercholesterolemia from two Norwegian families (PMID: 18266662, 26374825). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Pathogenic
DEOGEN2
Benign
T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
M_CAP
Benign
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
T
MutationAssessor
Benign
L
PrimateAI
Benign
T
PROVEAN
Benign
N
REVEL
Uncertain
Sift
Benign
T
Sift4G
Uncertain
D
Polyphen
D
Vest4
MutPred
Loss of catalytic residue at R215 (P = 0.0247);
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at