NM_174936.4(PCSK9):c.1547G>T (p.Gly516Val) AND not specified

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: May 8, 2023
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:: RCV003235253.1

Allele description [Variation Report for NM_174936.4(PCSK9):c.1547G>T (p.Gly516Val)]

NM_174936.4(PCSK9):c.1547G>T (p.Gly516Val)

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.1547G>T (p.Gly516Val)

HGVS:

NC_000001.11:g.55059529G>T
NG_009061.1:g.24983G>T
NM_001407240.1:c.1670G>T
NM_001407241.1:c.1589G>T
NM_001407242.1:c.1550G>T
NM_001407243.1:c.1490G>T
NM_001407244.1:c.1373G>T
NM_001407245.1:c.1355G>T
NM_001407246.1:c.1172G>T
NM_174936.4:c.1547G>TMANE SELECT
NP_001394169.1:p.Gly557Val
NP_001394170.1:p.Gly530Val
NP_001394171.1:p.Gly517Val
NP_001394172.1:p.Gly497Val
NP_001394173.1:p.Gly458Val
NP_001394174.1:p.Gly452Val
NP_001394175.1:p.Gly391Val
NP_777596.2:p.Gly516Val
NP_777596.2:p.Gly516Val
LRG_275t1:c.1547G>T
LRG_275:g.24983G>T
LRG_275p1:p.Gly516Val
NC_000001.10:g.55525202G>T
NM_174936.3:c.1547G>T
NR_110451.2:n.1154G>T
NR_110451.3:n.1828G>T
NR_176318.1:n.1521G>T
NR_176319.1:n.2106G>T
NR_176320.1:n.1960G>T
NR_176321.1:n.1785G>T
NR_176322.1:n.1740G>T
NR_176324.1:n.2047G>T

Protein change:

G391V

Links:

Molecular consequence:

NM_001407240.1:c.1670G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001407241.1:c.1589G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001407242.1:c.1550G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001407243.1:c.1490G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001407244.1:c.1373G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001407245.1:c.1355G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001407246.1:c.1172G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_174936.4:c.1547G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003934239	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (May 8, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 26802169, 33147992, 35910211, 36187800 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003934239

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(May 8, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Global molecular analysis and APOE mutations in a cohort of autosomal dominant hypercholesterolemia patients in France.

Wintjens R, Bozon D, Belabbas K, MBou F, Girardet JP, Tounian P, Jolly M, Boccara F, Cohen A, Karsenty A, Dubern B, Carel JC, Azar-Kolakez A, Feillet F, Labarthe F, Gorsky AM, Horovitz A, Tamarindi C, Kieffer P, Lienhardt A, Lascols O, Di Filippo M, et al.

J Lipid Res. 2016 Mar;57(3):482-91. doi: 10.1194/jlr.P055699. Epub 2016 Jan 22.

PubMed [citation]

PMID:: 26802169
PMCID:: PMC4766997

Novel PCSK9 (Proprotein Convertase Subtilisin Kexin Type 9) Variants in Patients With Familial Hypercholesterolemia From Cape Town.

Huijgen R, Blom DJ, Hartgers ML, Chemello K, Benito-Vicente A, Uribe KB, Behardien Z, Blackhurst DM, Brice BC, Defesche JC, de Jong AG, Jooste RJ, Solomon GAE, Wolmarans KH, Hovingh GK, Martin C, Lambert G, Marais AD.

Arterioscler Thromb Vasc Biol. 2021 Feb;41(2):934-943. doi: 10.1161/ATVBAHA.120.314482. Epub 2020 Nov 5. Erratum in: Arterioscler Thromb Vasc Biol. 2021 Jan;41(1):e77. doi: 10.1161/ATV.0000000000000137.

PubMed [citation]

PMID:: 33147992

See all PubMed Citations (4)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV003934239.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

Variant summary: PCSK9 c.1547G>T (p.Gly516Val) results in a non-conservative amino acid change located in the Proprotein convertase subtilisin/kexin type 9, C-terminal domain 1 (IPR041254) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 31398 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1547G>T has been reported in the literature in individuals affected with Familial Hypercholesterolemia as well as in carriers (Wintjens_2016, Huijgen_2020, Diboun_2022). These reports do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. At least two functional studies report this variant showed higher affinities for the LDLR than WT PCSK9 in transfected cells and in vitro studies confirm that PCSK9-G516V qualifies as a genuine GOF mutation (Huijgen_2020, Sarkar_2022). The following publications have been ascertained in the context of this evaluation (PMID: 35910211, 33147992, 36187800, 26802169). Four ClinVar submitters (evaluation after 2014) cite this variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 1, 2024

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