NM_174936.4(PCSK9):c.520C>T (p.Pro174Ser) AND Familial hypercholesterolemia

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Feb 27, 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:: RCV000771583.5

Allele description [Variation Report for NM_174936.4(PCSK9):c.520C>T (p.Pro174Ser)]

NM_174936.4(PCSK9):c.520C>T (p.Pro174Ser)

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.520C>T (p.Pro174Ser)

HGVS:

NC_000001.11:g.55046643C>T
NG_009061.1:g.12097C>T
NM_174936.4:c.520C>TMANE SELECT
NP_777596.2:p.Pro174Ser
NP_777596.2:p.Pro174Ser
LRG_275t1:c.520C>T
LRG_275:g.12097C>T
LRG_275p1:p.Pro174Ser
NC_000001.10:g.55512316C>T
NM_174936.3:c.520C>T

Protein change:

P174S

Links:

dbSNP: rs533273863

NCBI 1000 Genomes Browser:

rs533273863

Molecular consequence:

NM_174936.4:c.520C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Familial hypercholesterolemia (FH)
Identifiers:: MONDO: MONDO:0005439; MedGen: C0020445; OMIM: PS143890

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000904167	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Feb 27, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 22417841, 23997648, 31386798, 33418990, 34341098, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000904167

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Feb 27, 2023)

germline

clinical testing

PubMed (6)
[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	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Effect of mutations in LDLR and PCSK9 genes on phenotypic variability in Tunisian familial hypercholesterolemia patients.

Slimani A, Jelassi A, Jguirim I, Najah M, Rebhi L, Omezzine A, Maatouk F, Hamda KB, Kacem M, Rabès JP, Abifadel M, Boileau C, Rouis M, Slimane MN, Varret M.

Atherosclerosis. 2012 May;222(1):158-66. doi: 10.1016/j.atherosclerosis.2012.02.018. Epub 2012 Feb 19.

PubMed [citation]

PMID:: 22417841

Autosomal dominant hypercholesterolemia: needs for early diagnosis and cascade screening in the tunisian population.

Jelassi A, Najah M, Slimani A, Jguirim I, Slimane MN, Varret M.

Curr Genomics. 2013 Mar;14(1):25-32. doi: 10.2174/138920213804999200.

PubMed [citation]

PMID:: 23997648
PMCID:: PMC3580777

See all PubMed Citations (6)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV000904167.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This missense variant replaces proline with serine at codon 174 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). A functional study has shown the mutant protein to exhibit loss of function phenotype both extracellularly and intracellularly, which is likely due to a weaker binding to the LDLR protein (PMID: 31386798). This variant has been observed in individuals with lower than expected cholesterol (PMID: 22417841, 23997648), as well as in an individual affected with hypercholesterolemia (PMID: 33418990). This variant has also been observed in healthy individuals over age 70 without coronary heart disease, where the mean LDL level of carriers (127.6 mg/dl) was slightly higher than that of non-carriers (119.9 mg/dl) (PMID: 34341098). This variant has been identified in 20/282112 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.

#	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: May 7, 2024

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