ClinVar Miner

Submissions for variant NM_174936.4(PCSK9):c.1850C>A (p.Ala617Asp)

gnomAD frequency: 0.00001  dbSNP: rs754936553
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Iberoamerican FH Network RCV000627171 SCV000748071 uncertain significance Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter research
Color Diagnostics, LLC DBA Color Health RCV001185960 SCV001352278 uncertain significance Familial hypercholesterolemia 2023-04-27 criteria provided, single submitter clinical testing This missense variant replaces alanine with aspartic acid at codon 617 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 been reported in at least one individual affected with familial hypercholesterolemia (PMID: 21722902). This variant has not been identified 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 RCV002413780 SCV002716490 uncertain significance Cardiovascular phenotype 2018-06-19 criteria provided, single submitter clinical testing The p.A617D variant (also known as c.1850C>A), located in coding exon 11 of the PCSK9 gene, results from a C to A substitution at nucleotide position 1850. The alanine at codon 617 is replaced by aspartic acid, an amino acid with dissimilar properties. This variant has been detected in a hypercholesterolemia cohort; however, clinical details were limited (Vaca G et al. Atherosclerosis, 2011 Oct;218:391-6). This amino acid position is poorly conserved in available vertebrate species, and aspartic acid is the reference amino acid in other 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 RCV004002762 SCV004846546 uncertain significance Hypercholesterolemia, autosomal dominant, 3 2023-12-18 criteria provided, single submitter clinical testing This missense variant replaces alanine with aspartic acid at codon 617 of the PCSK9 protein in the C-terminal CM3 domain 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 been reported in an individual affected with hypercholesterolemia in the literature (PMID: 21722902). This variant has not been identified 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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