ClinVar Miner

Submissions for variant NM_174936.4(PCSK9):c.658G>A (p.Ala220Thr)

gnomAD frequency: 0.00001  dbSNP: rs768795323
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Diagnostics, LLC DBA Color Health RCV000775268 SCV000909527 uncertain significance Familial hypercholesterolemia 2023-07-11 criteria provided, single submitter clinical testing This missense variant replaces alanine with threonine at codon 220 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 not been reported in two related individuals affected with familial hypercholesterolemia (PMID: 30795984) and in an individual affected with hypercholesterolemia (PMID: 34573395). This variant has been identified in 4/280576 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 RCV001857286 SCV002195532 uncertain significance Hypercholesterolemia, autosomal dominant, 3 2024-09-23 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 220 of the PCSK9 protein (p.Ala220Thr). This variant is present in population databases (rs768795323, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of familial hypercholesterolemia (PMID: 30795984, 34573395, 35913489, 36752612). ClinVar contains an entry for this variant (Variation ID: 440718). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV003478085 SCV004222385 uncertain significance not provided 2023-04-11 criteria provided, single submitter clinical testing The frequency of this variant in the general population, 0.00015 (3/19922 chromosomes in East Asian subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the variant has been reported in individuals and families affected by hypercholesterolemia (PMID: 30795984 (2019), 34573395 (2021), 36752612 (2023)). 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 deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant.
All of Us Research Program, National Institutes of Health RCV001857286 SCV004840658 uncertain significance Hypercholesterolemia, autosomal dominant, 3 2023-08-28 criteria provided, single submitter clinical testing This missense variant replaces alanine with threonine at codon 220 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 been reported in two individuals affected with familial hypercholesterolemia (PMID: 30795984). This variant has also been identified in 4/280576 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 RCV004023450 SCV005001975 uncertain significance Cardiovascular phenotype 2023-12-28 criteria provided, single submitter clinical testing Occurs in the first base pair of the exon Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum RCV000508945 SCV000606695 pathogenic Hypercholesterolemia, familial, 1 no assertion criteria provided research

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