Submissions for variant NM_174936.4(PCSK9):c.94G>A (p.Glu32Lys)

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000778097	SCV000358214	likely pathogenic	Hypercholesterolemia, autosomal dominant, 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.
Color Diagnostics, LLC DBA Color Health	RCV000775016	SCV000909113	pathogenic	Familial hypercholesterolemia	2023-02-28	criteria provided, single submitter	clinical testing	This missense variant is located in the propeptide domain of the PCSK9 protein. This variant has only been identified in 5/181812 chromosomes (4/13348 East Asian chromosomes) in the general population by the Genome Aggregation Database (gnomAD). However, this variant is fairly common in the Japanese population (14/2340 chromosomes) (PMID: 26911352) and has been reported in over 60 heterozygous individuals affected with hypercholesterolemia in Japan (6% of the affected population; PMID: 17316651, 24859021, 25014035, 25962062, 26374825, 26632531, 28179607, 31491741, 33533259, 35929461; Pham et al., 2021, doi.org/10.3390/pr9020283). Individuals homozygous for this variant have shown markedly higher plasma LDL-C level than heterozygotes, but showed mild phenotype compared to individuals carrying biallelic LDLR mutations (PMID: 20006333, 21146822, 28179607). This variant has shown strong segregation with disease in multiple families (PMID: 20006333, 25014035). This variant has shown an association with an increased risk of myocardial infarction (PMID: 29802317, 33533259). Notably, this variant appears to exacerbate LDL-C levels and risk of myocardial infarction in individuals carrying LDLR mutations (PMID: 33533259). The impact of this variant on LDLR protein expression and function has not been reported in the literature, although an in vitro study has suggested that this variant may cause an increase in extracellular secretion of the mutant protein (PMID: 20006333). In summary, the available evidence indicates this variant to be a slight gain-of-function mutation that causes mild hypercholesterolemia. Based on the enrichment in affected individuals and co-segregation with disease in family studies, this variant is classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham 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 (http://gnomad.broadinstitute.org/). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000778097	SCV001229817	pathogenic	Hypercholesterolemia, autosomal dominant, 3	2024-12-15	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 32 of the PCSK9 protein (p.Glu32Lys). This variant is present in population databases (rs564427867, gnomAD 0.03%). This missense change has been observed in individuals with hypercholesterolemia (PMID: 17316651, 20006333, 25014035, 25962062, 26374825, 26632531, 28179607). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 297692). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PCSK9 protein function. Experimental studies have shown that this missense change affects PCSK9 function (PMID: 20006333). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000778097	SCV002016561	pathogenic	Hypercholesterolemia, autosomal dominant, 3	2022-10-19	criteria provided, single submitter	clinical testing
Mendelics	RCV000778097	SCV002517863	pathogenic	Hypercholesterolemia, autosomal dominant, 3	2022-05-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002374503	SCV002686984	likely pathogenic	Cardiovascular phenotype	2024-10-30	criteria provided, single submitter	clinical testing	The c.94G>A (p.E32K) alteration is located in exon 1 (coding exon 1) of the PCSK9 gene. This alteration results from a G to A substitution at nucleotide position 94, causing the glutamic acid (E) at amino acid position 32 to be replaced by a lysine (K). Based on data from gnomAD, the A allele has an overall frequency of 0.003% (5/181812) total alleles studied. The highest observed frequency was 0.03% (4/13348) of East Asian alleles. This alteration was detected in 62 of 1055 individuals with familial hypercholesterolemia (FH), as well as in 13 of the 41 compound heterozygous FH patients who also had an LDLR alteration (Mabuchi, 2014). This alteration was also shown to segregate with the disease in a few apparently unrelated families (Noguchi, 2010). In addition, alteration carriers were described to have higher levels of PCSK9 expression, LDL-C and lipoprotein (Miyake, 2008; Noguchi, 2010; Tada, 2016). This amino acid position is well conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as likely pathogenic.
Baylor Genetics	RCV000778097	SCV003835778	pathogenic	Hypercholesterolemia, autosomal dominant, 3	2022-10-03	criteria provided, single submitter	clinical testing
GeneDx	RCV003223634	SCV003919432	pathogenic	not provided	2023-04-07	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: increased extracellular PCSK9 activity, increased LDLR affinity, and decreased LDLR expression and uptake (Noguchi et al., 2010; Uribe et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30241732, 17316651, 31447099, 28784313, 34652028, 22683120, 33173529, 29192238, 24859021, 29724976, 27025683, 21619378, 25399932, 27075771, 29049823, 30592178, 29292049, 34782856, 20006333, Singhal2022, 31491741, 24518357, 32719484, 34011801, 29802317, 21146822, 27206942, 34037665, 34848321, 26632531, 25014035, 28179607, 33533259, 34408116, Pham2021, 34526433, 34176852, 25962062, 26374825, 34948399, 35480308)
All of Us Research Program, National Institutes of Health	RCV000778097	SCV004843922	pathogenic	Hypercholesterolemia, autosomal dominant, 3	2024-06-09	criteria provided, single submitter	clinical testing	This missense variant is located in the propeptide domain of the PCSK9 protein. This variant has only been identified in 5/181812 chromosomes (4/13348 East Asian chromosomes) in the general population by the Genome Aggregation Database (gnomAD). However, this variant is fairly common in the Japanese population (14/2340 chromosomes) (PMID: 26911352) and has been reported in over 60 heterozygous individuals affected with hypercholesterolemia in Japan (6% of the affected population; PMID: 17316651, 24859021, 25014035, 25962062, 26374825, 26632531, 28179607, 31491741, 33533259, 35929461; Pham et al., 2021, doi.org/10.3390/pr9020283). Individuals homozygous for this variant have shown markedly higher plasma LDL-C level than heterozygotes, but showed mild phenotype compared to individuals carrying biallelic LDLR mutations (PMID: 20006333, 21146822, 28179607). This variant has shown strong segregation with disease in multiple families (PMID: 20006333, 25014035). This variant has shown an association with an increased risk of myocardial infarction (PMID: 29802317, 33533259). Notably, this variant appears to exacerbate LDL-C levels and risk of myocardial infarction in individuals carrying LDLR mutations (PMID: 33533259). The impact of this variant on LDLR protein expression and function has not been reported in the literature, although an in vitro study has suggested that this variant may cause an increase in extracellular secretion of the mutant protein (PMID: 20006333). In summary, the available evidence indicates this variant to be a slight gain-of-function mutation that causes mild hypercholesterolemia. Based on the enrichment in affected individuals and co-segregation with disease in family studies, this variant is classified as Pathogenic.
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000778097	SCV005418496	pathogenic	Hypercholesterolemia, autosomal dominant, 3		criteria provided, single submitter	clinical testing	PS4+PS3_Supporting+PP1_Strong+PP4
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000331053	SCV000588677	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-01	flagged submission	research
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000331053	SCV000606675	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV004734956	SCV005349406	likely pathogenic	PCSK9-related disorder	2024-06-07	no assertion criteria provided	clinical testing	The PCSK9 c.94G>A variant is predicted to result in the amino acid substitution p.Glu32Lys. This variant has been reported in the heterozygous and homozygous state in individuals with familial hypercholesterolemia, primarily from Japan (see, for example, Miyake et al. 2008. PubMed ID: 17316651; Noguchi et al. 2010. PubMed ID: 20006333; Tada et al. 2016. PubMed ID: 26632531). This variant is associated with a milder phenotype than other PCSK9 variants but has been reported in patients with a more severe phenotype when homozygous or in combination with pathogenic variants in the LDLR gene (Noguchi et al. 2010. PubMed ID: 20006333; Mabuchi et al. 2014. PubMed ID: 25014035; Hopkins et al. 2015. PubMed ID: 26374825). In vitro experimental studies suggest this variant impacts protein function, and it has been described as causing a gain-of-function effect (Noguchi et al. 2010. PubMed ID: 20006333; Uribe et al. 2021. PubMed ID: 34948399). This variant is reported in 0.030% of alleles in individuals of East Asian descent in gnomAD. This variant is interpreted as likely pathogenic.