ClinVar Miner

Submissions for variant NM_174936.4(PCSK9):c.1660C>G (p.Gln554Glu)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory of Genetics and Molecular Cardiology, University of São Paulo RCV000497107 SCV000588687 uncertain significance Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter research
Labcorp Genetics (formerly Invitae), Labcorp RCV001080081 SCV001001093 likely benign Hypercholesterolemia, autosomal dominant, 3 2024-01-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000860913 SCV001134566 benign not provided 2019-05-28 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV001099463 SCV001255921 uncertain significance 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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina RCV001080081 SCV001255922 uncertain significance 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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Color Diagnostics, LLC DBA Color Health RCV001176520 SCV001340533 likely benign Familial hypercholesterolemia 2018-07-06 criteria provided, single submitter clinical testing
Ambry Genetics RCV002395199 SCV002703285 likely benign Cardiovascular phenotype 2020-11-17 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.
New York Genome Center RCV001080081 SCV002764494 uncertain significance Hypercholesterolemia, autosomal dominant, 3 2021-12-17 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004767306 SCV005381552 likely benign not specified 2024-08-02 criteria provided, single submitter clinical testing Variant summary: PCSK9 c.1660C>G (p.Gln554Glu) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 156836 control chromosomes, predominantly at a frequency of 0.0025 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 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in PCSK9 causing Familial Hypocholesterolemia phenotype (0.001). c.1660C>G has been reported in at-least two screens in ostensibly healthy populations (Kotowski_2006,Lange_2014). These report(s) do not provide unequivocal conclusions about association of the variant with Familial Hypocholesterolemia. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Le_2015). The following publications have been ascertained in the context of this evaluation (PMID: 19191301, 17971861, 16465619, 24507775, 26195630, 18280815, 24808179, 18799458, 17461796, 20172854, 26269718, 23105118, 21943799). ClinVar contains an entry for this variant (Variation ID: 431558). Based on the evidence outlined above, the variant was classified as likely benign.

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