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NM_174936.4(PCSK9):c.94G>A (p.Glu32Lys) AND Cardiovascular phenotype

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Oct 30, 2024
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV002374503.10

Allele description [Variation Report for NM_174936.4(PCSK9):c.94G>A (p.Glu32Lys)]

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

Gene:
PCSK9:proprotein convertase subtilisin/kexin type 9 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
1p32.3
Genomic location:
Preferred name:
NM_174936.4(PCSK9):c.94G>A (p.Glu32Lys)
HGVS:
  • NC_000001.11:g.55039931G>A
  • NG_009061.1:g.5385G>A
  • NM_174936.4:c.94G>AMANE SELECT
  • NP_777596.2:p.Glu32Lys
  • NP_777596.2:p.Glu32Lys
  • LRG_275t1:c.94G>A
  • LRG_275:g.5385G>A
  • LRG_275p1:p.Glu32Lys
  • NC_000001.10:g.55505604G>A
  • NM_174936.3:c.94G>A
  • NM_174936.4:c.94G>A
  • p.Glu32Lys
Protein change:
E32K
Links:
Molecular consequence:
  • NM_174936.4:c.94G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Cardiovascular phenotype
Identifiers:
MedGen: CN230736

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Assertion and evidence details

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Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002686984Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Likely pathogenic
(Oct 30, 2024) 		germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link

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Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Genetic variants in PCSK9 in the Japanese population: rare genetic variants in PCSK9 might collectively contribute to plasma LDL cholesterol levels in the general population.

Miyake Y, Kimura R, Kokubo Y, Okayama A, Tomoike H, Yamamura T, Miyata T.

Atherosclerosis. 2008 Jan;196(1):29-36. doi: 10.1016/j.atherosclerosis.2006.12.035. Epub 2007 Feb 21.

PubMed [citation]
PMID:
17316651

The E32K variant of PCSK9 exacerbates the phenotype of familial hypercholesterolaemia by increasing PCSK9 function and concentration in the circulation.

Noguchi T, Katsuda S, Kawashiri MA, Tada H, Nohara A, Inazu A, Yamagishi M, Kobayashi J, Mabuchi H.

Atherosclerosis. 2010 May;210(1):166-72. doi: 10.1016/j.atherosclerosis.2009.11.018. Epub 2009 Nov 20.

PubMed [citation]
PMID:
20006333
See all PubMed Citations (5)

Details of each submission

From Ambry Genetics, SCV002686984.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Apr 20, 2025