Submissions for variant NM_174936.4(PCSK9):c.1399C>G (p.Pro467Ala)

gnomAD frequency: 0.00004  dbSNP: rs772677312

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000256342	SCV000323068	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research	0/190 non-FH alleles (portuguese normolipidemic individuals)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781701	SCV000919964	uncertain significance	not specified	2020-11-16	criteria provided, single submitter	clinical testing	Variant summary: PCSK9 c.1399C>G (p.Pro467Ala) results in a non-conservative amino acid change located in the proprotein convertase subtlisin/kexin type 9, C-terminal domain (IPR041254) 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 2.8e-05 in 251378 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1399C>G has been reported in the literature in at-least one individual affected with Familial Hypercholesterolemia in whom two novel putative gain of function variants, namely, this one and p.Ala62Asp were identified (Alves_2015). This individual was reported as having no mutation in the LDL receptor (LDLR) or apolipoprotein B100 (APOB) genes. The variant was paternally inherited but the specific lipid profile was not reported. In contrast, at-least one co-occurrence with another pathogenic variant has been observed at our laboratory (LDLR c.1897C>T, p.Arg633Cys), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 56% of normal LDLR cell surface expression and reduced LDL uptake (Alves_2015). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely pathogenic, n=1; VUS, n=4). Some submitters provide overlapping evidence utilized in the context of this evaluation. Based on the equivocal evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000811853	SCV000952141	pathogenic	Hypercholesterolemia, autosomal dominant, 3	2024-10-29	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 467 of the PCSK9 protein (p.Pro467Ala). This variant is present in population databases (rs772677312, gnomAD 0.005%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 26541928, 32770674, 33418990, 35047021; internal data). ClinVar contains an entry for this variant (Variation ID: 265944). 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 not expected to disrupt PCSK9 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects PCSK9 function (PMID: 26541928, 29259136). For these reasons, this variant has been classified as Pathogenic.
Illumina Laboratory Services, Illumina	RCV001095906	SCV001252083	uncertain significance	Hypobetalipoproteinemia	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV000811853	SCV001252084	uncertain significance	Hypercholesterolemia, autosomal dominant, 3	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Color Diagnostics, LLC DBA Color Health	RCV001191122	SCV001358821	uncertain significance	Familial hypercholesterolemia	2023-02-15	criteria provided, single submitter	clinical testing	This missense variant replaces proline with alanine at codon 467 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). One functional study has shown that this variant enhances the inhibitory function of the PCSK9 protein and results in a partially reduced LDLR expression and LDL uptake function (PMID: 26541928), while the other functional study has shown that this variant results in decreased proteolytic activity (PMID: 29259136). This variant has been reported in at least eight unrelated individuals affected with familial hypercholesterolemia (PMID: 26541928, 31893465, 32770674, 33418990, Color internal data). This variant has been identified in 8/282772 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.
Laboratory of Molecular Genetics, National Medical Research Center for Therapy and Preventive Medicine	RCV001191122	SCV001482450	likely pathogenic	Familial hypercholesterolemia		criteria provided, single submitter	research
Mendelics	RCV000781701	SCV002518460	uncertain significance	not specified	2022-05-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002392783	SCV002700730	uncertain significance	Cardiovascular phenotype	2023-11-07	criteria provided, single submitter	clinical testing	The p.P467A variant (also known as c.1399C>G), located in coding exon 9 of the PCSK9 gene, results from a C to G substitution at nucleotide position 1399. The proline at codon 467 is replaced by alanine, an amino acid with highly similar properties. This alteration has been reported in familial hypercholesterolemia (FH) cohorts; however, clinical details were limited (Alves AC et al. J Am Coll Cardiol, 2015 Nov;66:2152-2154; Meshkov AN et al. J Pers Med, 2021 May;11:). Additionally, functional studies suggested a gain of function effect in transfected cells with reduced cell surface expression of LDLR and decreased LDL uptake (Alves AC et al. J Am Coll Cardiol, 2015 Nov;66:2152-2154; Chorba JS et al. J Biol Chem, 2018 02;293:1875-1886). 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.
All of Us Research Program, National Institutes of Health	RCV000811853	SCV004834600	uncertain significance	Hypercholesterolemia, autosomal dominant, 3	2024-09-23	criteria provided, single submitter	clinical testing	This missense variant replaces proline with alanine at codon 467 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). One functional study has shown that this variant enhances the inhibitory function of the PCSK9 protein and results in a partially reduced LDLR expression and LDL uptake function (PMID: 26541928), while the other functional study has shown that this variant results in decreased proteolytic activity (PMID: 29259136). This variant has been reported in at least eight unrelated individuals affected with familial hypercholesterolemia (PMID: 26541928, 31893465, 32770674, 33418990, Color internal data). This variant has been identified in 8/282772 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.
CeGaT Center for Human Genetics Tuebingen	RCV004808662	SCV005432167	uncertain significance	not provided	2024-11-01	criteria provided, single submitter	clinical testing	PCSK9: PS4:Moderate, PM2:Supporting, PS3:Supporting, BP4
GeneDx	RCV004808662	SCV005439272	uncertain significance	not provided	2024-06-14	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: significantly reduced LDLR cell surface expression and lowered fluorescent LDL uptake (PMID: 26541928); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29259136, 26541928, 34426522, 36187800, 32770674, 29261184, 28587771, 32719484, 31980526, 35047021, 34074024, 38955586, 33418990, 36499307, 38122934, 37409534, 33111339)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV004808662	SCV005623406	uncertain significance	not provided	2024-09-29	criteria provided, single submitter	clinical testing	The PCSK9 c.1399C>G (p.Pro467Ala) variant has been reported in the published literature in individuals affected with hypercholesterolemia (PMIDs: 35047021 (2021), 33418990 (2021), 31980526 (2020)). Additionally, functional evidence suggests that this variant may impact protein function (PMIDs: 29259136 (2018), 26541928 (2015)). The frequency of this variant in the general population, 0.000054 (7/129094 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant.
CSER _CC_NCGL, University of Washington	RCV000256342	SCV000503526	uncertain significance	Hypercholesterolemia, familial, 1	2016-08-01	no assertion criteria provided	research	Found in patient having exome sequencing for an unrelated indication. No known history of hyperlipidemia.