ClinVar Miner

Submissions for variant NM_174936.3(PCSK9):c.94G>A (p.Glu32Lys)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000370400 SCV000358212 uncertain significance Hypobetalipoproteinemia 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina RCV000778097 SCV000358214 likely pathogenic Familial hypercholesterolemia 3 2017-04-27 criteria provided, single submitter clinical testing The PCKS9 c.94G>A (p.Glu32Lys) missense variant has been reported in at least two studies. Mabuchi et al. (2014) investigated a cohort of 1096 Japanese familial hypercholesterolemia patients and identified the p.Glu32Lys variant in two homozygotes and 62 heterozygotes, and in nine individuals who were double heterozygotes for the p.Glu32Lys variant as well as a variant in the LDLR gene. The authors also reported that the levels of LDL-cholesterol in homozygotes and double heterozygotes of the p.Glu32Lys variant were significantly higher (p<0.001) than p.Glu32Lys heterozygotes, which were in turn significantly higher (p<0.001) than in unaffected family members. In addition, the variant was shown to segregate with a phenotype of elevated LDL-cholesterol levels by Mabuchi et al. (2014) and Noguchi et al. (2010) in unrelated families, although the phenotype was milder than that of heterozygotes with a mutation in the LDLR gene. Control data are unavailable for the p.Glu32Lys variant, which is reported at a frequency of 0.00155 in the East Asian population of the Exome Aggregation Consortium but this is based on two alleles only. Based on the evidence, the p.Glu32Lys variant is classified as likely pathogenic for familial hypercholesterolemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Laboratory of Genetics and Molecular Cardiology, University of São Paulo RCV000331053 SCV000588677 uncertain significance Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Color Health, Inc RCV000775016 SCV000909113 likely pathogenic Familial hypercholesterolemia 2020-08-05 criteria provided, single submitter clinical testing This missense variant is located in the propeptide 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). Splice prediction tools suggest that this variant may impact RNA splicing. A functional study has shown that this variant result in increased levels of PCSK9 protein in plasma from hypercholesterolemia subjects and in media of transiently transfected cells in culture (PMID: 20006333). In the literature, this variant is described as a slight gain-of-function mutation causing mild hypercholesterolemia and has been reported in more than 40 individuals diagnosed with familial hypercholesterolemia, most of whom are from Japan (PMID: 17316651, 20006333, 21146822, 24859021, 25014035, 25962062, 26632531). This variant in heterozygosity is associated with a milder phenotype than other heterozygous variants associated to familial hypercholesterolemia (PMID: 25014035, 26374825). Individuals homozygous for this variant, or double heterozygous with a pathogenic LDLR mutation, tend to show a more severe phenotype than heterozygous individuals (PMID: 25014035, 26374825). This variant has been identified in 5/181812 chromosomes (4/13348 East Asian chromosomes) in the general population by the Genome Aggregation Database (gnomAD). In Japan, this variant occurs in 0.6% of the general population (14/2340 chromosomes) (PMID: 26911352) and in 6% of the individuals diagnosed with familial hypercholesterolemia (PMID: 23095242). A meta-analysis of genome-wide association studies in the Japanese population has shown that this variant is associated with higher LDL-C levels and younger age of onset for myocardial infarction than non-carriers (PMID: 29802317). Based on the available evidence and the observed frequency of this variant in the general population, this variant is classified as Likely Pathogenic with possible low penetrance.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000825628 SCV000966982 pathogenic Homozygous familial hypercholesterolemia 2020-09-16 criteria provided, single submitter clinical testing The p.Glu32Lys variant in PCSK9 has been reported in >40 Japanese and Korean individuals with hypercholesterolemia, including 2 homozygous individuals and 9 double heterozygotes who had an additional pathogenic variant in LDLR (Miyake 2008 PMID: 17316651, Mabuchi 2011 PMID: 21146822, Noguchi 2010 PMID: 20006333, Mabuchi 2014 PMID: 25014035, Han 2015 PMID: 25962062, Hopkins 2015 PMID: 26374825, ClinVar Variation ID: 297692). Homozygotes and double heterozygotes had more severe disease on average than heterozygotes, and heterozygotes for this variant had milder disease than heterozygotes for other variants associated to familial hypercholesterolemia (FH; Mabuchi 2014 PMID: 25014035, Hopkins 2015 PMID: 26374825). Additionally, this variant segregated with disease in >20 affected relatives from >5 families (Noguchi 2010 PMID: 20006333, Mabuchi 2014 PMID: 25014035). In vitro functional studies provide some evidence that the p.Glu32Lys variant may impact protein function (Noguchi 2010 PMID: 20006333). This variant has also been identified in 0.03% (4/13348) of East Asian chromosomes by gnomAD ( This frequency is low enough to be consistent with the frequency of FH in the general population. In summary, the p.Glu32Lys variant meets criteria to be classified as pathogenic for autosomal dominant FH based upon presence in multiple affected individuals and segregation with disease. The ACMG/AMP Criteria applied: PS4, PP1_Strong, PS3_Supporting, PM3.
Invitae RCV000778097 SCV001229817 pathogenic Familial hypercholesterolemia 3 2020-02-05 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 32 of the PCSK9 protein (p.Glu32Lys). The glutamic acid residue is weakly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs564427867, ExAC 0.2%). This variant has been observed to segregate with hypercholesterolemia in a family (PMID: 20006333). It has also been reported in several individuals with this disease (PMID: 25962062, 25014035, 28179607, 17316651, 26632531, 26374825). ClinVar contains an entry for this variant (Variation ID: 297692). This variant has been reported to affect PCSK9 protein function (PMID: 20006333). For these reasons, this variant has been classified as Pathogenic.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000331053 SCV000606675 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research

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