Submissions for variant NM_174936.4(PCSK9):c.1658A>G (p.His553Arg)

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000234453	SCV000291598	benign	Hypercholesterolemia, autosomal dominant, 3	2024-01-27	criteria provided, single submitter	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000234453	SCV000297395	likely benign	Hypercholesterolemia, autosomal dominant, 3	2015-10-30	criteria provided, single submitter	clinical testing
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000497017	SCV000588686	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Color Diagnostics, LLC DBA Color Health	RCV000776244	SCV000911495	likely benign	Familial hypercholesterolemia	2017-07-10	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000858409	SCV001134565	likely benign	not provided	2022-10-17	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000234453	SCV001255920	likely benign	Hypercholesterolemia, autosomal dominant, 3	2019-03-11	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.
GeneDx	RCV000858409	SCV001886493	benign	not provided	2020-01-13	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 33147992, 16465619)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002265707	SCV002547732	benign	not specified	2022-05-09	criteria provided, single submitter	clinical testing	Variant summary: PCSK9 c.1658A>G (p.His553Arg) results in a non-conservative amino acid change located in the Proprotein convertase subtilisin/kexin type 9, C-terminal domain 2 (IPR041052) 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 0.00073 in 156996 control chromosomes, predominantly at a frequency of 0.011 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 293 fold of the estimated maximal expected allele frequency for a pathogenic variant in PCSK9 causing Familial Hypercholesterolemia phenotype (3.8e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. Although c.1658A>G has been reported in the literature, to our knolwedge, no penetrant association of the variant with Familial Hypercholesterolemia have been confirmed (example, Anderson_2014, Rodriguez_2013). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with a majority consensus as benign/likely benign (n=6). Based on the evidence outlined above, the variant was classified as benign.
Ambry Genetics	RCV002401913	SCV002704738	likely benign	Cardiovascular phenotype	2019-01-04	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.
GENinCode PLC	RCV000776244	SCV005077859	benign	Familial hypercholesterolemia	2023-02-28	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004734889	SCV005357757	likely benign	PCSK9-related disorder	2024-05-20	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).