Submissions for variant NM_174936.4(PCSK9):c.479G>A (p.Arg160Gln)

gnomAD frequency: 0.00008  dbSNP: rs367620267

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781704	SCV000919967	uncertain significance	not specified	2018-06-11	criteria provided, single submitter	clinical testing	Variant summary: PCSK9 c.479G>A (p.Arg160Gln) results in a conservative amino acid change located in the Peptidase S8/S53 domain and Proteinase K-like catalytic domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1-fold higher than the estimated maximal expected allele frequency for a pathogenic variant in PCSK9 causing Familial Hypercholesterolemia phenotype (9.4e-05). However, due to the cohort containing individuals that could have a PCSK9 phenotype, this observation needs to be cautiously considered. The variant, c.479G>A, has been reported in the literature in a GWAS study observed in one individual with low LDL-C (Lange_2014). This report does not provide an unequivocal conclusion about association of the variant with Familial Hypercholesterolemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as VUS - possibly benign.
Illumina Laboratory Services, Illumina	RCV001097395	SCV001253673	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.
Illumina Laboratory Services, Illumina	RCV001097396	SCV001253674	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.
Color Diagnostics, LLC DBA Color Health	RCV001182725	SCV001348280	uncertain significance	Familial hypercholesterolemia	2023-03-29	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 160 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). A functional study has shown that this variant may cause a moderate decrease in LDL uptake as well as moderate decrease in LDLR binding affinity (PMID: 36834740). This variant has been reported in an individual affected with familial hypercholesterolemia (PMID: 36834740) as well as in an individual with extremely low circulating LDL-C (PMID: 24507775). This variant has been identified in 19/282782 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	RCV002332571	SCV002634459	uncertain significance	Cardiovascular phenotype	2024-01-04	criteria provided, single submitter	clinical testing	The p.R160Q variant (also known as c.479G>A), located in coding exon 3 of the PCSK9 gene, results from a G to A substitution at nucleotide position 479. The arginine at codon 160 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in an individual with low LDL-C levels (Lange LA et al. Am J Hum Genet, 2014 Feb;94:233-45). Additionally, this variant has been detected in a family with hypercholesterolemia; however, in vitro studies showed this alteration may have a loss of function impact on the protein (Larrea-Sebal A et al. Int J Mol Sci, 2023 Feb;24:[ePub ahead of print]). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV001097395	SCV002797547	uncertain significance	Hypercholesterolemia, autosomal dominant, 3	2021-07-20	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001097395	SCV004842258	uncertain significance	Hypercholesterolemia, autosomal dominant, 3	2024-09-23	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 160 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). A functional study has shown that this variant may cause a moderate decrease in LDL uptake as well as moderate decrease in LDLR binding affinity (PMID: 36834740). This variant has been reported in an individual affected with familial hypercholesterolemia (PMID: 36834740) as well as in an individual with extremely low circulating LDL-C (PMID: 24507775). This variant has been identified in 19/282782 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	RCV001097395	SCV005775275	uncertain significance	Hypercholesterolemia, autosomal dominant, 3	2024-11-24	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 160 of the PCSK9 protein (p.Arg160Gln). This variant is present in population databases (rs367620267, gnomAD 0.01%). This missense change has been observed in individual(s) with PCSK9-related conditions (PMID: 24507775, 36834740). ClinVar contains an entry for this variant (Variation ID: 633347). 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 expected to disrupt PCSK9 protein function with a positive predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on PCSK9 function (PMID: 36834740). 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.