VCV000369876.15 - ClinVar

NM_174936.4(PCSK9):c.1537A>G (p.Asn513Asp)

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.

(7)

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.

Conflicting classifications of pathogenicity
Uncertain significance(6); Likely benign(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_174936.4(PCSK9):c.1537A>G (p.Asn513Asp)

Variation ID: 369876 Accession: VCV000369876.15

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p32.3 1: 55059519 (GRCh38) [ NCBI UCSC ] 1: 55525192 (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	Dec 18, 2016	Nov 24, 2024	May 20, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_174936.4:c.1537A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_777596.2:p.Asn513Asp	missense
NM_001407240.1:c.1660A>G	NP_001394169.1:p.Asn554Asp	missense
NM_001407241.1:c.1579A>G	NP_001394170.1:p.Asn527Asp	missense
NM_001407242.1:c.1540A>G	NP_001394171.1:p.Asn514Asp	missense
NM_001407243.1:c.1480A>G	NP_001394172.1:p.Asn494Asp	missense
NM_001407244.1:c.1363A>G	NP_001394173.1:p.Asn455Asp	missense
NM_001407245.1:c.1345A>G	NP_001394174.1:p.Asn449Asp	missense
NM_001407246.1:c.1162A>G	NP_001394175.1:p.Asn388Asp	missense
NR_110451.3:n.1818A>G
NR_176318.1:n.1511A>G
NR_176319.1:n.2096A>G
NR_176320.1:n.1950A>G
NR_176321.1:n.1775A>G
NR_176322.1:n.1730A>G
NR_176324.1:n.2037A>G
NC_000001.11:g.55059519A>G
NC_000001.10:g.55525192A>G
NG_009061.1:g.24973A>G
LRG_275:g.24973A>G
LRG_275t1:c.1537A>G	LRG_275p1:p.Asn513Asp
	NP_777596.2:p.N513D

... more HGVS ... less HGVS

Protein change

N513D, N388D, N514D, N449D, N554D, N494D, N527D, N455D

Other names

p.Asn513Asp

Canonical SPDI

NC_000001.11:55059518:A:G

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.

Trans-Omics for Precision Medicine (TOPMed) 0.00001

Links

ClinGen: CA10654837 dbSNP: rs1057516136 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.
Hypercholesterolemia, familial, 1	Uncertain significance (1)	criteria provided, single submitter	Aug 22, 2019	RCV000408784.3
Familial hypercholesterolemia	Uncertain significance (1)	criteria provided, single submitter	Nov 7, 2022	RCV000775241.6
Hypercholesterolemia, autosomal dominant, 3	Uncertain significance (3)	criteria provided, multiple submitters, no conflicts	Mar 4, 2023	RCV002502418.6
Cardiovascular phenotype	Likely benign (1)	criteria provided, single submitter	May 20, 2024	RCV004649143.1
not provided	Uncertain significance (1)	criteria provided, single submitter	May 9, 2024	RCV004791436.1

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 (Aug 22, 2019)	criteria provided, single submitter (Wang et al. (Arterioscler Thromb Vasc Biol. 2016)) Method: clinical testing	Hypercholesterolemia, familial, 1 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Robarts Research Institute, Western University Accession: SCV000484818.2 First in ClinVar: Dec 18, 2016 Last updated: Sep 11, 2019	Publications: PubMed (1) PubMed: 27765764 Number of individuals with the variant: 1
Uncertain significance (Nov 07, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial hypercholesterolemia Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV000909495.4 First in ClinVar: May 20, 2019 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 27765764‚ 36187800 Comment: This missense variant replaces asparagine with aspartic acid at codon 513 of the PCSK9 protein. Computational prediction suggests that this variant may not impact protein … (more) This missense variant replaces asparagine with aspartic acid at codon 513 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). Functional studies have shown that this variant may inhibit LDL binding (PMID: 36187800). This variant has been reported in an individual affected with hypercholesterolemia who also carried a pathogenic variant in the LDLR gene that could explain the observed phenotype (PMID: 27765764). This variant has not been identified 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)
Uncertain significance (Nov 08, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypercholesterolemia, autosomal dominant, 3 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002813447.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Uncertain significance (Oct 25, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Hypercholesterolemia, autosomal dominant, 3 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002962675.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 28, 2024	Comment: This variant is not present in population databases (gnomAD no frequency). In summary, the available evidence is currently insufficient to determine the role of this … (more) This variant is not present in population databases (gnomAD no frequency). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PCSK9 protein function. ClinVar contains an entry for this variant (Variation ID: 369876). This variant has not been reported in the literature in individuals affected with PCSK9-related conditions. This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 513 of the PCSK9 protein (p.Asn513Asp). (less)
Uncertain Significance (Mar 04, 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: SCV004845798.1 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 asparagine with aspartic acid at codon 513 of the PCSK9 protein. Computational prediction suggests that this variant may not impact protein … (more) This missense variant replaces asparagine with aspartic acid at codon 513 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 familial hypercholesterolemia in the literature. This variant has not been identified 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
Likely benign (May 20, 2024)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV005147444.1 First in ClinVar: Aug 11, 2024 Last updated: Aug 11, 2024	Publications: PubMed (1) PubMed: 27765764 Comment: This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more) This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Uncertain significance (May 09, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV005407972.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Publications: PubMed (2) PubMed: 27765764‚ 36187800 Comment: PM2, PS3_moderate Number of individuals with the variant: 1

Comment:

This missense variant replaces asparagine with aspartic acid at codon 513 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). Functional studies have shown that this variant may inhibit LDL binding (PMID: 36187800). This variant has been reported in an individual affected with hypercholesterolemia who also carried a pathogenic variant in the LDLR gene that could explain the observed phenotype (PMID: 27765764). This variant has not been identified 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:

This variant is not present in population databases (gnomAD no frequency). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PCSK9 protein function. ClinVar contains an entry for this variant (Variation ID: 369876). This variant has not been reported in the literature in individuals affected with PCSK9-related conditions. This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 513 of the PCSK9 protein (p.Asn513Asp).

Comment:

This missense variant replaces asparagine with aspartic acid at codon 513 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 familial hypercholesterolemia in the literature. This variant has not been identified 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:

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

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:

This missense variant replaces asparagine with aspartic acid at codon 513 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 familial hypercholesterolemia in the literature. This variant has not been identified 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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Pathogenic gain-of-function mutations in the prodomain and C-terminal domain of PCSK9 inhibit LDL binding.	Sarkar SK	Frontiers in physiology	2022	PMID: 36187800
Polygenic Versus Monogenic Causes of Hypercholesterolemia Ascertained Clinically.	Wang J	Arteriosclerosis, thrombosis, and vascular biology	2016	PMID: 27765764

Text-mined citations for rs1057516136 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_174936.4(PCSK9):c.1537A>G (p.Asn513Asp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1057516136 ...