VCV002454168.3 - ClinVar

NM_174936.4(PCSK9):c.147G>C (p.Glu49Asp)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(2)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_174936.4(PCSK9):c.147G>C (p.Glu49Asp)

Variation ID: 2454168 Accession: VCV002454168.3

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p32.3 1: 55039984 (GRCh38) [ NCBI UCSC ] 1: 55505657 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 15, 2023	May 1, 2024	Oct 6, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_174936.4:c.147G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_777596.2:p.Glu49Asp	missense
NM_001407240.1:c.147G>C	NP_001394169.1:p.Glu49Asp	missense
NM_001407241.1:c.147G>C	NP_001394170.1:p.Glu49Asp	missense
NM_001407242.1:c.147G>C	NP_001394171.1:p.Glu49Asp	missense
NM_001407243.1:c.147G>C	NP_001394172.1:p.Glu49Asp	missense
NM_001407244.1:c.147G>C	NP_001394173.1:p.Glu49Asp	missense
NM_001407245.1:c.147G>C	NP_001394174.1:p.Glu49Asp	missense
NM_001407246.1:c.-588G>C		5 prime UTR
NM_001407247.1:c.147G>C	NP_001394176.1:p.Glu49Asp	missense
NR_110451.3:n.437G>C		non-coding transcript variant
NR_176318.1:n.437G>C		non-coding transcript variant
NR_176319.1:n.437G>C		non-coding transcript variant
NR_176320.1:n.437G>C		non-coding transcript variant
NR_176321.1:n.437G>C		non-coding transcript variant
NR_176322.1:n.437G>C		non-coding transcript variant
NR_176323.1:n.437G>C		non-coding transcript variant
NR_176324.1:n.437G>C		non-coding transcript variant
NC_000001.11:g.55039984G>C
NC_000001.10:g.55505657G>C
NG_009061.1:g.5438G>C
LRG_275:g.5438G>C
LRG_275t1:c.147G>C	LRG_275p1:p.Glu49Asp

... more HGVS ... less HGVS

Protein change

E49D

Other names

Canonical SPDI

NC_000001.11:55039983:G:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
PCSK9		Dosage sensitivity unlikely	No evidence available	GRCh38 GRCh37	1275	1289

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Cardiovascular phenotype	Uncertain significance (1)	criteria provided, single submitter	Mar 14, 2023	RCV003172700.2
Hypercholesterolemia, autosomal dominant, 3	Uncertain significance (1)	criteria provided, single submitter	Oct 6, 2023	RCV004009667.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain Significance (Oct 06, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypercholesterolemia, autosomal dominant, 3 (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	All of Us Research Program, National Institutes of Health Accession: SCV004837582.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 Comment: This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more) This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)	Comment: This missense variant replaces glutamic acid with aspartic acid at codon 49 of the PCSK9 protein. Computational prediction suggests that this variant may not impact … (more) This missense variant replaces glutamic acid with aspartic acid at codon 49 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 has not been reported in individuals affected with PCSK9-related disorders in the literature. This variant has been identified in 1/196466 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. (less) Number of individuals with the variant: 1
Uncertain significance (Mar 14, 2023)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV003867157.2 First in ClinVar: Apr 15, 2023 Last updated: May 01, 2024	Publications: PubMed (1) PubMed: 18498363 Comment: The p.E49D variant (also known as c.147G>C), located in coding exon 1 of the PCSK9 gene, results from a G to C substitution at nucleotide … (more) The p.E49D variant (also known as c.147G>C), located in coding exon 1 of the PCSK9 gene, results from a G to C substitution at nucleotide position 147. The glutamic acid at codon 49 is replaced by aspartic acid, an amino acid with highly similar properties. One study suggested this variant may impact propeptide phosphorylation; however, the physiological relevance of this finding is unclear (Dewpura T et al. FEBS J, 2008 Jul;275:3480-93). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)

Comment:

This missense variant replaces glutamic acid with aspartic acid at codon 49 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 has not been reported in individuals affected with PCSK9-related disorders in the literature. This variant has been identified in 1/196466 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.

Comment:

The p.E49D variant (also known as c.147G>C), located in coding exon 1 of the PCSK9 gene, results from a G to C substitution at nucleotide position 147. The glutamic acid at codon 49 is replaced by aspartic acid, an amino acid with highly similar properties. One study suggested this variant may impact propeptide phosphorylation; however, the physiological relevance of this finding is unclear (Dewpura T et al. FEBS J, 2008 Jul;275:3480-93). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
PCSK9 is phosphorylated by a Golgi casein kinase-like kinase ex vivo and circulates as a phosphoprotein in humans.	Dewpura T	The FEBS journal	2008	PMID: 18498363

Text-mined citations for this variant ...

Record last updated May 08, 2024

ClinVar Genomic variation as it relates to human health

NM_174936.4(PCSK9):c.147G>C (p.Glu49Asp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...