NM_174936.4(PCSK9):c.520C>T (p.Pro174Ser) AND Hypercholesterolemia, autosomal dominant, 3

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Feb 5, 2024
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:: RCV000644534.6

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]

Observations:

Condition(s)

Name:: Hypercholesterolemia, autosomal dominant, 3 (FHCL3)
Synonyms:: Familial hypercholesterolemia 3; Familial Hypercholesterolemia, Autosomal Dominant, 3
Identifiers:: MONDO: MONDO:0011369; MedGen: C1863551; OMIM: 603776

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000766234	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (May 6, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 31386798, 28492532
SCV002787928	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Aug 27, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004842348	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Feb 5, 2024)	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

SCV000766234

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(May 6, 2022)

germline

clinical testing

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

SCV002787928

Fulgent Genetics, Fulgent Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Aug 27, 2021)

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV004842348

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Feb 5, 2024)

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	17	not provided	not provided	108544	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

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

See all PubMed Citations (7)

Details of each submission

From Invitae, SCV000766234.3

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

Description

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 174 of the PCSK9 protein (p.Pro174Ser). This variant is present in population databases (rs533273863, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with PCSK9-related conditions. ClinVar contains an entry for this variant (Variation ID: 496561). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change affects PCSK9 function (PMID: 31386798). 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.

#	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 Fulgent Genetics, Fulgent Genetics, SCV002787928.1

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

From All of Us Research Program, National Institutes of Health, SCV004842348.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	17	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	108544	not provided	not provided		17	not provided	not provided	not provided

Last Updated: May 7, 2024

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