Submissions for variant NM_174936.4(PCSK9):c.1426C>T (p.Arg476Cys)

gnomAD frequency: 0.00001  dbSNP: rs761767572

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Revvity Omics, Revvity	RCV003133293	SCV003814780	uncertain significance	Hypercholesterolemia, autosomal dominant, 3	2020-12-09	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003159649	SCV003858513	uncertain significance	Cardiovascular phenotype	2022-12-15	criteria provided, single submitter	clinical testing	The p.R476C variant (also known as c.1426C>T), located in coding exon 9 of the PCSK9 gene, results from a C to T substitution at nucleotide position 1426. The arginine at codon 476 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant co-occurred with a pathogenic mutation in the LDLR gene in a family with hypercholesterolemia (Sjouke B et al. J Clin Lipidol, 2016 Sep;10:1462-1469). This variant has also been detected in cohorts not selected for the presence of hypercholesterolemia; however, clinical details were limited (Grzymski JJ et al. Nat Med, 2020 Aug;26:1235-1239; Capalbo A et al. PLoS Genet, 2019 Oct;15:e1008409). This amino acid position is not 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003133293	SCV004277863	uncertain significance	Hypercholesterolemia, autosomal dominant, 3	2023-09-26	criteria provided, single submitter	clinical testing	This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 32719484). ClinVar contains an entry for this variant (Variation ID: 440723). 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. 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. This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 476 of the PCSK9 protein (p.Arg476Cys). This variant is present in population databases (rs761767572, gnomAD 0.006%).
Color Diagnostics, LLC DBA Color Health	RCV003581681	SCV004358815	uncertain significance	Familial hypercholesterolemia	2023-05-09	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 476 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 individuals affected with familial hypercholesterolemia; these individuals also carried a pathogenic splice variant in LDLR (PMID: 27919364). This variant has been identified in 3/251214 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.
All of Us Research Program, National Institutes of Health	RCV003133293	SCV004831739	uncertain significance	Hypercholesterolemia, autosomal dominant, 3	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 476 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 individuals affected with familial hypercholesterolemia; these individuals also carried a pathogenic splice variant in LDLR (PMID: 27919364). This variant has been identified in 3/251214 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.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000508733	SCV000606710	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research