NM_174936.4(PCSK9):c.1781C>A (p.Ala594Asp) AND Hypercholesterolemia, autosomal dominant, 3

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Oct 6, 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:: RCV004016792.2

Allele description [Variation Report for NM_174936.4(PCSK9):c.1781C>A (p.Ala594Asp)]

NM_174936.4(PCSK9):c.1781C>A (p.Ala594Asp)

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.1781C>A (p.Ala594Asp)

HGVS:

NC_000001.11:g.55061474C>A
NG_009061.1:g.26928C>A
NM_001407240.1:c.1904C>A
NM_001407241.1:c.1823C>A
NM_001407242.1:c.1784C>A
NM_001407243.1:c.1724C>A
NM_001407244.1:c.1607C>A
NM_001407245.1:c.1589C>A
NM_001407246.1:c.1406C>A
NM_001407247.1:c.1280C>A
NM_174936.4:c.1781C>AMANE SELECT
NP_001394169.1:p.Ala635Asp
NP_001394170.1:p.Ala608Asp
NP_001394171.1:p.Ala595Asp
NP_001394172.1:p.Ala575Asp
NP_001394173.1:p.Ala536Asp
NP_001394174.1:p.Ala530Asp
NP_001394175.1:p.Ala469Asp
NP_001394176.1:p.Ala427Asp
NP_777596.2:p.Ala594Asp
NP_777596.2:p.Ala594Asp
LRG_275t1:c.1781C>A
LRG_275:g.26928C>A
LRG_275p1:p.Ala594Asp
NC_000001.10:g.55527147C>A
NM_174936.3:c.1781C>A
NR_110451.3:n.2062C>A
NR_176318.1:n.1865C>A
NR_176319.1:n.2340C>A
NR_176320.1:n.2304C>A
NR_176321.1:n.2019C>A
NR_176322.1:n.1974C>A
NR_176323.1:n.1893C>A
NR_176324.1:n.2281C>A

Protein change:

A427D

Molecular consequence:

NM_001407240.1:c.1904C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407241.1:c.1823C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407242.1:c.1784C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407243.1:c.1724C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407244.1:c.1607C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407245.1:c.1589C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407246.1:c.1406C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407247.1:c.1280C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_174936.4:c.1781C>A - missense variant - [Sequence Ontology: SO:0001583]
NR_110451.3:n.2062C>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_176318.1:n.1865C>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_176319.1:n.2340C>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_176320.1:n.2304C>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_176321.1:n.2019C>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_176322.1:n.1974C>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_176323.1:n.1893C>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_176324.1:n.2281C>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

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
SCV004834904	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Oct 6, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 33147992, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004834904

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Oct 6, 2023)

germline

clinical testing

PubMed (2)
[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	1	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

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

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From All of Us Research Program, National Institutes of Health, SCV004834904.1

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

Description

This missense variant replaces alanine with aspartic acid at codon 594 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in multiple individuals in one kindred, including two affected with familial hypercholesterolemia and four unaffected (PMID: 33147992). It has also been reported in both heterozygosity and homozygosity in multiple individuals from an ostensibly healthy population (van Zyl 2013, dissertation, North-West University). This variant has been identified in 3/264928 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		1	not provided	not provided	not provided

Last Updated: May 7, 2024

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