NM_174936.4(PCSK9):c.835C>A (p.Pro279Thr) AND not provided

Germline classification:: Benign (2 submissions)
Last evaluated:: Jul 3, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000588730.5

Allele description [Variation Report for NM_174936.4(PCSK9):c.835C>A (p.Pro279Thr)]

NM_174936.4(PCSK9):c.835C>A (p.Pro279Thr)

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.835C>A (p.Pro279Thr)

HGVS:

NC_000001.11:g.55056028C>A
NG_009061.1:g.21482C>A
NM_001407240.1:c.958C>A
NM_001407241.1:c.835C>A
NM_001407242.1:c.838C>A
NM_001407243.1:c.778C>A
NM_001407244.1:c.835C>A
NM_001407245.1:c.643C>A
NM_001407246.1:c.460C>A
NM_001407247.1:c.835C>A
NM_174936.4:c.835C>AMANE SELECT
NP_001394169.1:p.Pro320Thr
NP_001394170.1:p.Pro279Thr
NP_001394171.1:p.Pro280Thr
NP_001394172.1:p.Pro260Thr
NP_001394173.1:p.Pro279Thr
NP_001394174.1:p.Pro215Thr
NP_001394175.1:p.Pro154Thr
NP_001394176.1:p.Pro279Thr
NP_777596.2:p.Pro279Thr
NP_777596.2:p.Pro279Thr
LRG_275t1:c.835C>A
LRG_275:g.21482C>A
LRG_275p1:p.Pro279Thr
NC_000001.10:g.55521701C>A
NM_174936.3:c.835C>A
NR_110451.2:n.494C>A
NR_110451.3:n.1168C>A
NR_176318.1:n.809C>A
NR_176319.1:n.1125C>A
NR_176320.1:n.1248C>A
NR_176321.1:n.1125C>A
NR_176322.1:n.1125C>A
NR_176323.1:n.1125C>A
NR_176324.1:n.1387C>A

Protein change:

P154T

Links:

dbSNP: rs72646509

NCBI 1000 Genomes Browser:

rs72646509

Molecular consequence:

NM_001407240.1:c.958C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407241.1:c.835C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407242.1:c.838C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407243.1:c.778C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407244.1:c.835C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407245.1:c.643C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407246.1:c.460C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407247.1:c.835C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_174936.4:c.835C>A - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000700004	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Benign (May 22, 2017)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25412415, 24507775 LabCorp Variant Classification Summary - May 2015.docx, Citation Link,
SCV004222386	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Benign (Jul 3, 2023)	unknown	clinical testing	PubMed (3) [See all records that cite these PMIDs] 25412415, 24507775, 26467025

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000700004

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Benign
(May 22, 2017)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

LabCorp Variant Classification Summary - May 2015.docx,

Citation Link,

SCV004222386

Quest Diagnostics Nichols Institute San Juan Capistrano

criteria provided, single submitter

(Quest Diagnostics criteria)

Benign
(Jul 3, 2023)

unknown

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

Both rare and common variants in PCSK9 influence plasma low-density lipoprotein cholesterol level in American Indians.

Tsai CW, North KE, Tin A, Haack K, Franceschini N, Saroja Voruganti V, Laston S, Zhang Y, Best LG, MacCluer JW, Beaty TH, Navas-Acien A, Kao WH, Howard BV.

J Clin Endocrinol Metab. 2015 Feb;100(2):E345-9. doi: 10.1210/jc.2014-3340. Epub 2014 Nov 20.

PubMed [citation]

PMID:: 25412415
PMCID:: PMC4318886

Whole-exome sequencing identifies rare and low-frequency coding variants associated with LDL cholesterol.

Lange LA, Hu Y, Zhang H, Xue C, Schmidt EM, Tang ZZ, Bizon C, Lange EM, Smith JD, Turner EH, Jun G, Kang HM, Peloso G, Auer P, Li KP, Flannick J, Zhang J, Fuchsberger C, Gaulton K, Lindgren C, Locke A, Manning A, et al.

Am J Hum Genet. 2014 Feb 6;94(2):233-45. doi: 10.1016/j.ajhg.2014.01.010.

PubMed [citation]

PMID:: 24507775
PMCID:: PMC3928660

See all PubMed Citations (3)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000700004.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

Variant summary: The PCSK9 c.835C>A (p.Pro279Thr) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 41/94810 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.004103 (31/7556). This frequency is about 205 times the estimated maximal expected allele frequency of a pathogenic PCSK9 variant (0.00002), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. The variant has been reported in the literature as a SNP and has been observed at equal frequencies both in patients with low LDL-C and high LDL-C. Therefore, its role in the pathophysiology of Familial Hypercholesterolemia and early onset CAD is suspect. One clinical diagnostic laboratory classified this variant as uncertain significance. Taken together, due to the relatively high frequency of the variant in the control population, this variant has been classified as benign.

#	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

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV004222386.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

#	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

Last Updated: Sep 29, 2024

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