ClinVar Miner

Submissions for variant NM_174936.4(PCSK9):c.1355G>A (p.Gly452Asp)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
All of Us Research Program, National Institutes of Health RCV004015114 SCV004832174 uncertain significance Hypercholesterolemia, autosomal dominant, 3 2023-08-23 criteria provided, single submitter clinical testing This missense variant replaces glycine with aspartic acid at codon 452 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). Functional studies using transfected Huh7 and HEK293 cells have shown that this variant causes increased LDLR cell surface expression and decreased PCSK9 cleavage (PMID: 26195630, 29259136). This variant has been reported in an individual identified as having circulating low LDL-C levels (PMID: 17316651). This variant has been identified in 2/251398 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV005000497 SCV005623404 uncertain significance not provided 2024-11-05 criteria provided, single submitter clinical testing The PCSK9 c.1355G>A (p.Gly452Asp) variant has been reported in the published literature in an individual with low LDL-C levels (PMID: 17316651 (2018)). Assessment of experimental evidence regarding the effect of this variant on protein function is inconclusive (PMID: 26195630 (2018), 29259136 (2018)). The frequency of this variant in the general population, 0.000008 (2/251398 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.

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