Submissions for variant NM_174936.4(PCSK9):c.1492G>A (p.Glu498Lys)

gnomAD frequency: 0.00007  dbSNP: rs145468572

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000775286	SCV000909545	uncertain significance	Familial hypercholesterolemia	2023-11-22	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 498 of the PCSK9 protein. Computational prediction tools indicate that this variant has a neutral impact on protein structure and function. A functional study has shown that this variant interferes with PCSK9 protein secretion (PMID: 22875854), while the other study has shown a similar secretion efficiency as the wild-type PCSK9 (PMID: 32058034). This variant has been observed in one individual affected with familial hypobetalipoproteinemia (PMID: 21502677) and has not been reported in individuals affected with familial hypercholesterolemia in the literature. This variant has been identified in 13/277010 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000814950	SCV000955388	uncertain significance	Hypercholesterolemia, autosomal dominant, 3	2024-06-24	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 498 of the PCSK9 protein (p.Glu498Lys). This variant is present in population databases (rs145468572, gnomAD 0.01%). This missense change has been observed in individual(s) with low lipid levels (PMID: 21502677, 24507775). ClinVar contains an entry for this variant (Variation ID: 630163). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PCSK9 protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on PCSK9 function (PMID: 22875854, 32058034). This variant disrupts the p.Glu498 amino acid residue in PCSK9. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 36499307). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Ambry Genetics	RCV002388399	SCV002700466	uncertain significance	Cardiovascular phenotype	2024-06-20	criteria provided, single submitter	clinical testing	The p.E498K variant (also known as c.1492G>A), located in coding exon 9 of the PCSK9 gene, results from a G to A substitution at nucleotide position 1492. The glutamic acid at codon 498 is replaced by lysine, an amino acid with similar properties. This variant has been detected in an individual with familial hypobetalipoproteinemia who also had variants in other cholesterol-related genes, and in individuals from a low LDL-C (low-density lipoprotein cholesterol) cohort; however, details were limited (Gutiérrez-Cirlos C et al. Ann Hepatol;10:155-64; Lange LA et al. Am J Hum Genet. 2014 Feb;94(2):233-45). This variant has also been detected in a cohort with personal or family history of cancer (Maxwell KN et al. Am J Hum Genet, 2016 May;98:801-817). In one functional study, this variant was shown to result in significantly reduced protein secretion, a loss of function effect expected to be associated with low levels of LDL-C (Benjannet S et al. J Biol Chem, 2012 Sep;287:33745-55). This amino acid position is not well conserved in available vertebrate species, and lysine is the reference amino acid in other 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.
All of Us Research Program, National Institutes of Health	RCV000814950	SCV004834767	uncertain significance	Hypercholesterolemia, autosomal dominant, 3	2024-09-23	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 498 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). A functional study has shown that this variant interferes with PCSK9 protein secretion (PMID: 22875854), while the other study has shown a similar secretion efficiency as the wild-type PCSK9 (PMID: 32058034). This variant has been observed in an individual with familial hypobetalipoproteinemia (PMID: 21502677) and has not been reported in individuals affected with familial hypercholesterolemia in the literature. This variant has been identified in 13/277010 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.