ClinVar Miner

Submissions for variant NM_174936.3(PCSK9):c.644G>A (p.Arg215His) (rs794728683)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182575 SCV000234925 pathogenic not provided 2016-05-03 criteria provided, single submitter clinical testing The R215H mutation in the PCSK9 gene has been reported previously in two unrelated probands (Cameron et al., 2008). R215H co-segregated with hypercholesterolemia in eight relatives from one family and functional studies indicate R215H is a gain-of-function mutation (Cameron et al., 2008). Mutations in nearby residues (F216L, R218S) have been reported in association with hypercholesterolemia, further supporting the functional importance of this region of the protein. The R215H mutation was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret R215H as a disease-causing mutation. The variant is found in the PCSK9 panel(s).
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge RCV000505198 SCV000599424 uncertain significance Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter curation
Invitae RCV000412537 SCV000766233 likely pathogenic Familial hypercholesterolemia 3 2017-09-19 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 215 of the PCSK9 protein (p.Arg215His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with hypercholesterolemia in a single family (PMID: 18266662). ClinVar contains an entry for this variant (Variation ID: 201127). Experimental studies have shown that this missense change does not get cleaved by furin and therefore prevents regular PCSK9 inactivation leading to a PCSK9 protein more active than wild-type (PMID: 18266662, 18631360, 27896130). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000412537 SCV000840037 likely pathogenic Familial hypercholesterolemia 3 2017-08-21 criteria provided, single submitter clinical testing This c.644G>A (p.Arg215His) variant in the PCSK9 gene has been reported in 3 unrelated patients with hypercholesterolemia (PMID: 18266662, 28008010). In the family of one of these patients, this variant segregated with hypercholesterolemia in eight relatives (PMID: 18266662). A different amino acid substitution, arginine to lysine at residue 215 of the PCSK9 protein, has also been reported as disease-causing in 1 patient with familial hypercholesterolemia (PMID: 25962062). Functional studies have shown that the p.Arg215His mutant PSCK9 protein causes fewer low density lipoprotein receptors (LDLR) to be on the cell surface, thereby leading to increased levels of LDL cholesterol (PMID: 18266662). This variant is classified as likely pathogenic.
Color Health, Inc RCV001526127 SCV001736420 likely pathogenic Familial hypercholesterolemia 2021-02-01 criteria provided, single submitter clinical testing This missense variant replaces arginine with histidine at codon 215 in the catalytic peptidase domain of the PCSK9 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). An experimental study has shown no impact on catalytic peptidase function but reduced LDL uptake by ~14% (PMID: 18266662). A different study has shown no significant impact on the LDL uptake by the mutant protein (PMID: 27896130). Clinical significance of these experimental findings is not clear. This variant has been reported in more than 20 individuals affected with hypercholesterolemia from two Norwegian families (PMID: 18266662, 26374825), as well as in 3 unrelated individuals with hypercholesterolemia (PMID: 26633542, 28008010, 31491741). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
GeneReviews RCV000412537 SCV000490154 pathogenic Familial hypercholesterolemia 3 2016-12-08 no assertion criteria provided literature only
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000505198 SCV000606691 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research

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