Submissions for variant NM_174936.4(PCSK9):c.1070G>A (p.Arg357His)

gnomAD frequency: 0.00002  dbSNP: rs370507566

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000455200	SCV000539997	uncertain significance	not specified	2016-03-29	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Found in 1 proband with no segs
Color Diagnostics, LLC DBA Color Health	RCV001182021	SCV001347336	uncertain significance	Familial hypercholesterolemia	2023-01-03	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 357 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in three individuals affected with familial hypercholesterolemia (PMID: 16211558, 33418990, ClinVar SCV002120714.1), including one individual who also carried a pathogenic variant in the LDLR gene (PMID: 33418990). This variant has been identified in 10/251364 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	RCV000455200	SCV001363301	uncertain significance	not specified	2019-01-28	criteria provided, single submitter	clinical testing	Variant summary: The variant, PCSK9 c.1070G>A (p.Arg357His) results in a non-conservative amino acid change located in the Proteinase K-like catalytic domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.5e-05 in 246868 control chromosomes, predominantly at a frequency of 0.00018 within the 'Other' subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant c.1070G>A has been reported in the literature in an individual with the family history of cardiovascular disease and high LDL cholesterol levels (Allard_2005). However, this report does not provide unequivocal conclusions about association of the variant with Early Onset Coronary Artery Disease. At least one publication reports experimental evidence of the variant evaluating an impact on LDL receptor levels (Le_2015) but does not allow convincing conclusions about the variant effect. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001856799	SCV002120714	uncertain significance	Hypercholesterolemia, autosomal dominant, 3	2023-12-12	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 357 of the PCSK9 protein (p.Arg357His). This variant is present in population databases (rs370507566, gnomAD 0.009%). This missense change has been observed in individuals with clinical features of familial hypercholesterolemia (PMID: 16211558; Invitae). ClinVar contains an entry for this variant (Variation ID: 403288). 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 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on PCSK9 function (PMID: 26195630). 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.
Fulgent Genetics, Fulgent Genetics	RCV001856799	SCV002791815	uncertain significance	Hypercholesterolemia, autosomal dominant, 3	2021-09-22	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001856799	SCV004836463	uncertain significance	Hypercholesterolemia, autosomal dominant, 3	2024-07-20	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 357 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in three individuals affected with familial hypercholesterolemia (PMID: 16211558, 33418990, ClinVar SCV002120714.1), including one individual who also carried a pathogenic variant in the LDLR gene (PMID: 33418990). This variant has been identified in 10/251364 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	RCV004649153	SCV005147443	uncertain significance	Cardiovascular phenotype	2024-05-02	criteria provided, single submitter	clinical testing	The p.R357H variant (also known as c.1070G>A), located in coding exon 7 of the PCSK9 gene, results from a G to A substitution at nucleotide position 1070. The arginine at codon 357 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in familial hypercholesterolemia (FH) cohorts (Allard D et al. Hum Mutat, 2005 Nov;26:497; Meshkov A et al. Genes (Basel), 2021 Jan;12:[ePub ahead of print]). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.