Submissions for variant NM_174936.4(PCSK9):c.142G>A (p.Glu48Lys)

gnomAD frequency: 0.00001  dbSNP: rs1278890129

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000644533	SCV000766232	uncertain significance	Hypercholesterolemia, autosomal dominant, 3	2024-01-20	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 48 of the PCSK9 protein (p.Glu48Lys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with hypercholesterolemia (PMID: 26374825). ClinVar contains an entry for this variant (Variation ID: 440707). 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 with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Diagnostics, LLC DBA Color Health	RCV001183221	SCV001348896	uncertain significance	Familial hypercholesterolemia	2023-04-18	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 48 of the PCSK9 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with familial hypercholesterolemia (PMID: 33418990) and in an individual affected with hypercholesterolemia (PMID: 26374825). This variant has been identified in 5/228356 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics	RCV000644533	SCV002786970	uncertain significance	Hypercholesterolemia, autosomal dominant, 3	2021-07-27	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000644533	SCV004843988	uncertain significance	Hypercholesterolemia, autosomal dominant, 3	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 48 of the PCSK9 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with familial hypercholesterolemia (PMID: 33418990) and in an individual affected with hypercholesterolemia (PMID: 26374825). This variant has been identified in 5/228356 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV004023449	SCV005030924	uncertain significance	Cardiovascular phenotype	2023-10-17	criteria provided, single submitter	clinical testing	The p.E48K variant (also known as c.142G>A), located in coding exon 1 of the PCSK9 gene, results from a G to A substitution at nucleotide position 142. The glutamic acid at codon 48 is replaced by lysine, an amino acid with similar properties. This alteration has been reported in a cohort of subjects with PCSK9 alterations and in a cohort of subjects with familial hypercholesterolemia (FH) (Hopkins PN et al. Circ Cardiovasc Genet, 2015 Dec;8:823-31; Meshkov A et al. Genes (Basel), 2021 Jan;12:). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000786382	SCV005325442	uncertain significance	not provided	2023-11-02	criteria provided, single submitter	clinical testing	Has been reported in individuals with familial hypercholesterolemia (PMID: 26374825, 33418990); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 37331523, 26374825, 33418990)
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000508707	SCV000606678	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000786382	SCV000925190	uncertain significance	not provided	2018-01-17	no assertion criteria provided	provider interpretation	Variant p.Glu48Lys in PCSK9 c.142G>A in exon 1 of 12 NM_174936.3, hg19, chr1-55505652-G-A SCICD classification Variant of uncertain significance We do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The rationale for this assessment is: the lack of case data pertaining to this variant. The lack of functional studies that demonstrates gain-of-function. Gene-level evidence PCSK9 encodes proprotein convertase, subtilisin/kexin-type 9, a protein that is responsible for recycling LDL receptors. Gain-of-function variants in PCSK9 are an uncommon cause (<3%) of familial hypercholesterolemia. Individuals with loss-of-function variants in PCSK9 have very low levels of circulating LDL (Cohen et al 2005). It is the target of a new class of drugs named PCSK9-inhibitors, the role of which is to inhibit the removal of LDL receptors. Case data summary At least 1 unrelated individual with FH (not including our patient) Not reported in the literature. Present in ClinVar by Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum, but no clinical assertions provided. No segregation data Predicted Consequence Per the test report, "This sequence change replaces glutamic acid with lysine at codon 48 of the PCSK9 protein (p.Glu48Lys)." Experimental Data None reported In silico data Per the test report, "Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The lysine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain." Conservation Per the test report, "The glutamic acid residue is weakly conserved and there is a small physicochemical difference between glutamic acid and lysine." The amino acid at codon 48 is weakly conserved n the UCSC genome browser. Many species have a lysine at codon 48. Nearby pathogenic variation None at this codon Per ClinVar, at neighboring codons p.Ser47Cys and p.Ala53Gly (no assertion critiera, also submitted by Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum and classified as pathogenic) Population Data Highest MAF in European population: 0.006% Note that this variant was initially detected in 3 other samples but these failed various filtering methods. Please see below for details. Case data for p.Glu48Lys (does not include this patient): Total cases: 1 Segregation: none ClinVar: present, but no clinical assertions provided Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum Cases in the literature: none reported Population data for p.Glu48Lys: Highest MAF in European population: 0.006%. The variant was reported online in 1 of 15,483 total individuals (MAF: 0.006%) in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, and Latino descent. Note that this variant was initially detected in 3 other samples but these failed various filtering methods. Specifically, the variant was observed in: 1 of 7,504 individuals of non-Finnish European descent (MAF=0.006%) The phenotype of those individuals is not publicly available. The dataset is composed of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in datasets like this so this does not necessarily rule out pathogenicity (Pan et al 2012). As of January 17, 2018 the average coverage at that site in gnomAD for exomes is: Mean coverage 57.5x, Median coverage 75x, and 60% of samples over 20x coverage. The average coverage at that site in gnomAD for genomes is: Mean coverage 35.9x, Median coverage 35x, and 97% of samples over 20x coverage.