NM_174936.4(PCSK9):c.709C>T (p.Arg237Trp) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (4 submissions)
Last evaluated:: Sep 1, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV001284675.29

Allele description [Variation Report for NM_174936.4(PCSK9):c.709C>T (p.Arg237Trp)]

NM_174936.4(PCSK9):c.709C>T (p.Arg237Trp)

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.709C>T (p.Arg237Trp)

HGVS:

NC_000001.11:g.55052701C>T
NG_009061.1:g.18155C>T
NM_001407240.1:c.832C>T
NM_001407241.1:c.709C>T
NM_001407242.1:c.712C>T
NM_001407243.1:c.652C>T
NM_001407244.1:c.709C>T
NM_001407245.1:c.517C>T
NM_001407246.1:c.334C>T
NM_001407247.1:c.709C>T
NM_174936.4:c.709C>TMANE SELECT
NP_001394169.1:p.Arg278Trp
NP_001394170.1:p.Arg237Trp
NP_001394171.1:p.Arg238Trp
NP_001394172.1:p.Arg218Trp
NP_001394173.1:p.Arg237Trp
NP_001394174.1:p.Arg173Trp
NP_001394175.1:p.Arg112Trp
NP_001394176.1:p.Arg237Trp
NP_777596.2:p.Arg237Trp
NP_777596.2:p.Arg237Trp
LRG_275t1:c.709C>T
LRG_275:g.18155C>T
LRG_275p1:p.Arg237Trp
NC_000001.10:g.55518374C>T
NM_174936.3:c.709C>T
NP_777596.2:p.R237W
NR_110451.2:n.368C>T
NR_110451.3:n.1042C>T
NR_176318.1:n.683C>T
NR_176319.1:n.999C>T
NR_176320.1:n.1122C>T
NR_176321.1:n.999C>T
NR_176322.1:n.999C>T
NR_176323.1:n.999C>T
NR_176324.1:n.1261C>T
Q8NBP7:p.Arg237Trp

Protein change:

R112W

Links:

UniProtKB: Q8NBP7#VAR_025452; dbSNP: rs148195424

NCBI 1000 Genomes Browser:

rs148195424

Molecular consequence:

NM_001407240.1:c.832C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001407241.1:c.709C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001407242.1:c.712C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001407243.1:c.652C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001407244.1:c.709C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001407245.1:c.517C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001407246.1:c.334C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001407247.1:c.709C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_174936.4:c.709C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001470596	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Likely benign (Dec 28, 2022)	unknown	clinical testing	PubMed (13) [See all records that cite these PMIDs] 27765764, 16465619, 16571601, 24507775, 16424354, 29259136, 18262190, 17765244, 20623344, 33303402, 33231818, 15358785, 26467025
SCV001715291	Mayo Clinic Laboratories, Mayo Clinic	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jun 9, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001874182	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (May 26, 2022)	germline	clinical testing	Citation Link,
SCV004042432	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Likely benign (Sep 1, 2023)	germline	clinical testing	Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Polygenic Versus Monogenic Causes of Hypercholesterolemia Ascertained Clinically.

Wang J, Dron JS, Ban MR, Robinson JF, McIntyre AD, Alazzam M, Zhao PJ, Dilliott AA, Cao H, Huff MW, Rhainds D, Low-Kam C, Dubé MP, Lettre G, Tardif JC, Hegele RA.

Arterioscler Thromb Vasc Biol. 2016 Dec;36(12):2439-2445. Epub 2016 Oct 20.

PubMed [citation]

PMID:: 27765764

A spectrum of PCSK9 alleles contributes to plasma levels of low-density lipoprotein cholesterol.

Kotowski IK, Pertsemlidis A, Luke A, Cooper RS, Vega GL, Cohen JC, Hobbs HH.

Am J Hum Genet. 2006 Mar;78(3):410-22. Epub 2006 Jan 20.

PubMed [citation]

PMID:: 16465619
PMCID:: PMC1380285

See all PubMed Citations (14)

Details of each submission

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV001470596.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (13)

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

From Mayo Clinic Laboratories, Mayo Clinic, SCV001715291.1

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

#	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		1	not provided	not provided	not provided

From GeneDx, SCV001874182.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Also identified in patients with hypercholesterolemia in published literature (de Paiva Silvino et al., 2020; Gill et al., 2021; Meshkov et al., 2021); at least one patient also harbored a pathogenic variant in the LDLR gene (Wang et al., 2016); Published functional studies demonstrate loss-of-function with a modest effect, resulting in a 16% increased level of cell surface LDL-receptors and a 35% increase in the internalization of LDL when compared to wild-type PCSK9 (Cameron et al., 2006); This variant is associated with the following publications: (PMID: 18300938, 25046268, 16424354, 16465619, 17765244, 21943799, 28157721, 17435765, 16912035, 15358785, 24507775, 27535533, 16571601, 26582918, 27765764, 33418990, 33231818, 33303402)

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

From CeGaT Center for Human Genetics Tuebingen, SCV004042432.11

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	not provided

Description

PCSK9: BS1

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

Last Updated: Nov 24, 2024

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