ClinVar Miner

Submissions for variant NM_174936.4(PCSK9):c.751C>T (p.Arg251Cys)

gnomAD frequency: 0.00001  dbSNP: rs778900671
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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 RCV001179029 SCV001343603 uncertain significance Familial hypercholesterolemia 2022-10-03 criteria provided, single submitter clinical testing This missense variant replaces arginine with cysteine at codon 251 of the PCSK9 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with familial hypercholesterolemia (PMID: 30827231, 33418990) and in an individual affected with coronary artery disease (Ganesan et al, 2016). This variant has been identified in 5/248936 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.
All of Us Research Program, National Institutes of Health RCV004006527 SCV004835981 uncertain significance Hypercholesterolemia, autosomal dominant, 3 2024-04-16 criteria provided, single submitter clinical testing This missense variant replaces arginine with cysteine at codon 251 of the PCSK9 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with familial hypercholesterolemia (PMID: 30827231, 33418990) and in an individual affected with coronary artery disease (Ganesan et al, 2016). This variant has been identified in 5/248936 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 RCV004986882 SCV005472616 uncertain significance Cardiovascular phenotype 2024-09-19 criteria provided, single submitter clinical testing The p.R251C variant (also known as c.751C>T), located in coding exon 5 of the PCSK9 gene, results from a C to T substitution at nucleotide position 751. The arginine at codon 251 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been reported in individuals from familial hypercholesterolemia cohorts, but clinical details were limited (Yang Y et al. Curr Pharm Des, 2019;25:190-200; Meshkov A et al. Genes (Basel), 2021 Jan;12). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.

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