ClinVar Miner

Submissions for variant NM_174936.4(PCSK9):c.1773C>G (p.His591Gln)

gnomAD frequency: 0.00014  dbSNP: rs529912877
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix RCV000417320 SCV000503514 uncertain significance Hypercholesterolemia, autosomal dominant, 3 2016-12-16 criteria provided, single submitter clinical testing subject mutated among 2600 FH index cases screened = 1 / Software predictions: Benign
Color Diagnostics, LLC DBA Color Health RCV000771326 SCV000903593 uncertain significance Familial hypercholesterolemia 2023-09-14 criteria provided, single submitter clinical testing This missense variant replaces histidine with glutamine at codon 591 of the PCSK9 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has shown that the variant causes increased PCSK9 proteolysis (PMID: 29259136). This variant has not been reported in individuals affected with PCSK9-related disorders in the literature. This variant has been identified in 33/234832 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 RCV000417320 SCV001003477 benign Hypercholesterolemia, autosomal dominant, 3 2023-11-28 criteria provided, single submitter clinical testing
Ambry Genetics RCV002402115 SCV002711862 likely benign Cardiovascular phenotype 2021-07-20 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.
All of Us Research Program, National Institutes of Health RCV000417320 SCV004846457 uncertain significance Hypercholesterolemia, autosomal dominant, 3 2023-12-13 criteria provided, single submitter clinical testing This missense variant replaces histidine with glutamine at codon 591 of the PCSK9 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has shown that the variant causes increased PCSK9 proteolysis (PMID: 29259136). This variant has not been reported in individuals affected with PCSK9-related disorders in the literature. This variant has been identified in 33/234832 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.

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