ClinVar Miner

Submissions for variant NM_174936.3(PCSK9):c.1274A>G (p.Asn425Ser) (rs28362261)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge RCV000336569 SCV000599431 uncertain significance Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter curation
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies,APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix RCV000417326 SCV000503511 uncertain significance Hypercholesterolemia, autosomal dominant, 3 2016-12-16 criteria provided, single submitter clinical testing subjects mutated among 2600 FH index cases screened = 2 / Software predictions: Benign
Color RCV000776105 SCV000910948 benign Familial hypercholesterolemias 2018-03-23 criteria provided, single submitter clinical testing
GeneDx RCV000454567 SCV000730631 likely benign not specified 2017-10-27 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Illumina Clinical Services Laboratory,Illumina RCV000297926 SCV000358248 likely benign Familial hypobetalipoproteinemia 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000336569 SCV000358249 likely benign Familial hypercholesterolemia 2016-06-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000590512 SCV000699985 likely benign not provided 2016-02-10 criteria provided, single submitter clinical testing Variant summary: PCSK9 c.1274A>G variant affects a conserved nucleotide, resulting in amino acid change from Asn to Ser. 4/4 in-silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). Functional studies show that N425S is secreted normally, and has similar to wild-type ability in reducing cell-surface LDLR (Fasano_Atherosclerosis_2009). This variant is found in 186/120674 control chromosomes at a frequency of 0.0015413, which is about 82 times of maximal expected frequency of a pathogenic PCSK9 allele (0.0000188), suggesting this variant is benign. Additionally, this variant is mainly found in Africans (173/10272; 0.01684) at an allele frequency >895-fold greater than the maximal expected frequency of a pathogenic PCSK9 allele, highly suggesting that this variant is a benign polymorphism found in Africans. Additionally, association studies have shown that this variant is not associated with low or high cholesterol (Kotowski et al 2006). Pisciotta et al 2006 suggested that this variant plays a role in a digenic form of hypercholesterolemia, where by PCSK9 and LDLR mutations have additive effects on LDL metabolism. Aside from this one publication which presented only one family, there is no additional evidence in support of this claim (eg carriers of N425S in isolation showing hypercholesterolemia). Taken together, this variant was classified as likely benign until additional evidence is available.
Invitae RCV000417326 SCV000555875 benign Hypercholesterolemia, autosomal dominant, 3 2018-01-17 criteria provided, single submitter clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000336569 SCV000606702 pathogenic Familial hypercholesterolemia no assertion criteria provided research
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000454567 SCV000539996 benign 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: ExAC: 1.7% (173/10272) African chromosomes

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