Submissions for variant NM_174936.4(PCSK9):c.1384T>C (p.Ser462Pro)

gnomAD frequency: 0.00006  dbSNP: rs746115963

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000985897	SCV001134563	uncertain significance	not provided	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001095904	SCV001252081	likely benign	Hypobetalipoproteinemia	2017-04-27	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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV001095905	SCV001252082	likely benign	Hypercholesterolemia, autosomal dominant, 3	2017-04-27	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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Color Diagnostics, LLC DBA Color Health	RCV001176799	SCV001340854	uncertain significance	Familial hypercholesterolemia	2023-02-08	criteria provided, single submitter	clinical testing	This missense variant replaces serine with proline at codon 462 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). Functional studies have suggested that this variant causes a loss of PCSK9 function (PMID: 19022446, 32058034), which is expected to be protective against hypercholesterolemia. This variant has been shown to cause a retention of the mutant PCSK9 protein the endoplasmic reticulum (PMID: 19022446, 32058034). In a mouse model, this variant has been associated with decreased levels of circulating PCSK9, increased LDLR levels in the liver and decreased LDL-C levels in the plasma (Ai 2016). This variant has been reported in an individual affected with hypercholesterolemia (PMID: 19022446) as well as in seven healthy older individuals without coronary heart disease (PMID: 34341098). This variant has also been identified in 15/251390 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001797806	SCV002041840	uncertain significance	not specified	2021-11-23	criteria provided, single submitter	clinical testing	Variant summary: PCSK9 c.1384T>C (p.Ser462Pro) results in a non-conservative amino acid change located in the C-terminal domain (IPR041254) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 251390 control chromosomes, predominantly at a frequency of 0.00012 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 3-fold of the estimated maximal expected allele frequency for a pathogenic variant in PCSK9 causing Familial Hypercholesterolemia phenotype (3.8e-05), suggesting that the variant might be a benign polymorphism. Though the variant, c.1384T>C, has been reported in the literature in individuals affected with Hypercholesterolemia associated phenotypes (examples: Cameron_2009, Pott_2018, and Gill_2021), in one of the reported families the variant was also found in an individual with normo- / hypocholesterolemia (Cameron_2009). These reports do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. Multiple publications reported experimental evidence evaluating an impact on protein function, and demonstrated in cellular models a secretion defect for this variant (examples: Cameron_2009, Chorba_2017, and Deng_2020, Ai_2016). In addition, one study reported that in a mouse model, this variant S462P resulted in reduced circulating PCSK9, which correlated well with increases in mouse liver LDLR and reductions in plasma LDL and total cholesterol (Ai 2016). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant VUS (n=2) and Likely Benign (n=1). In summary, although this variant is likely to confer protection against coronary artery disease due to its LDLC reducing effect, hypocholesterolemia has been also reported to be associated with other negative consequences (e.g. PMID 20626336). Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001095905	SCV003245156	uncertain significance	Hypercholesterolemia, autosomal dominant, 3	2022-06-20	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 462 of the PCSK9 protein (p.Ser462Pro). This variant is present in population databases (rs746115963, gnomAD 0.01%). This missense change has been observed in individual(s) with hypercholesterolemia (PMID: 19022446). ClinVar contains an entry for this variant (Variation ID: 801242). 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 expected to disrupt PCSK9 protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on PCSK9 function (PMID: 19022446, 26195630, 29259136, 32058034). 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.
All of Us Research Program, National Institutes of Health	RCV001095905	SCV004842437	uncertain significance	Hypercholesterolemia, autosomal dominant, 3	2024-09-23	criteria provided, single submitter	clinical testing	This missense variant replaces serine with proline at codon 462 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). Functional studies have suggested that this variant causes a loss of PCSK9 function (PMID: 19022446, 32058034), which is expected to be protective against hypercholesterolemia. This variant has been shown to cause a retention of the mutant PCSK9 protein the endoplasmic reticulum (PMID: 19022446, 32058034). In a mouse model, this variant has been associated with decreased levels of circulating PCSK9, increased LDLR levels in the liver and decreased LDL-C levels in the plasma (Ai 2016). This variant has been reported in an individual affected with hypercholesterolemia (PMID: 19022446) as well as in seven healthy older individuals without coronary heart disease (PMID: 34341098). This variant has also been identified in 15/251390 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	RCV004649394	SCV005147442	likely benign	Cardiovascular phenotype	2024-04-06	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.