Submissions for variant NM_174936.4(PCSK9):c.2002A>G (p.Ser668Gly)

gnomAD frequency: 0.00004  dbSNP: rs775077080

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000304492	SCV000358268	uncertain significance	Hypobetalipoproteinemia	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000417244	SCV000358269	uncertain significance	Hypercholesterolemia, autosomal dominant, 3	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	RCV000417244	SCV000503501	uncertain significance	Hypercholesterolemia, autosomal dominant, 3	2016-12-16	criteria provided, single submitter	clinical testing	subject mutated among 2600 FH index cases screened = 1, family member = 1 / Software predictions: Benign
Color Diagnostics, LLC DBA Color Health	RCV001182497	SCV001347962	uncertain significance	Familial hypercholesterolemia	2023-04-26	criteria provided, single submitter	clinical testing	This missense variant replaces serine with glycine at codon 668 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). This variant has been identified in 12/250532 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	RCV000417244	SCV001386825	uncertain significance	Hypercholesterolemia, autosomal dominant, 3	2024-01-02	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 668 of the PCSK9 protein (p.Ser668Gly). This variant is present in population databases (rs775077080, gnomAD 0.02%). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 33418990, 35913489). ClinVar contains an entry for this variant (Variation ID: 297707). 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.
Ambry Genetics	RCV002418149	SCV002724242	uncertain significance	Cardiovascular phenotype	2020-03-03	criteria provided, single submitter	clinical testing	The p.S668G variant (also known as c.2002A>G), located in coding exon 12 of the PCSK9 gene, results from an A to G substitution at nucleotide position 2002. The serine at codon 668 is replaced by glycine, an amino acid with similar properties. An alternate amino acid substitution at this codon, p.S668R, was reported in an individual from a low LDL-C cohort; however, clinical details were limited (Miyake Y et al. Atherosclerosis, 2008 Jan;196:29-36). This amino acid position is not well conserved on limited sequence alignment. 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.
Fulgent Genetics, Fulgent Genetics	RCV000417244	SCV002815511	uncertain significance	Hypercholesterolemia, autosomal dominant, 3	2021-12-09	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003477881	SCV004222373	uncertain significance	not provided	2023-04-11	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00023 (8/34564 chromosomes in Latino/Admixed American subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the variant has been reported in an individual with familial hypercholesteremia (PMID: 33418990 (2021)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
All of Us Research Program, National Institutes of Health	RCV000417244	SCV004845480	uncertain significance	Hypercholesterolemia, autosomal dominant, 3	2024-08-13	criteria provided, single submitter	clinical testing	This missense variant replaces serine with glycine at codon 668 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 one individual affected with familial hypercholesterolemia (PMID: 33418990). This variant has been identified in 12/250532 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.