ClinVar Miner

Submissions for variant NM_174936.4(PCSK9):c.1756A>G (p.Asn586Asp)

gnomAD frequency: 0.00003  dbSNP: rs146035580
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Diagnostics, LLC DBA Color Health RCV001180542 SCV001345485 uncertain significance Familial hypercholesterolemia 2023-05-03 criteria provided, single submitter clinical testing This missense variant replaces asparagine with aspartic acid at codon 586 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with familial hypercholesterolemia disorders in the literature. This variant has been identified in 2/270384 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.
Ambry Genetics RCV002402538 SCV002711680 uncertain significance Cardiovascular phenotype 2024-04-19 criteria provided, single submitter clinical testing The p.N586D variant (also known as c.1756A>G), located in coding exon 11 of the PCSK9 gene, results from an A to G substitution at nucleotide position 1756. The asparagine at codon 586 is replaced by aspartic acid, an amino acid with highly similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health RCV004006670 SCV004846435 uncertain significance Hypercholesterolemia, autosomal dominant, 3 2023-11-28 criteria provided, single submitter clinical testing This missense variant replaces asparagine with aspartic acid at codon 586 of the PCSK9 protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <=0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with familial hypercholesterolemia in the literature. This variant has been identified in 2/270384 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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