NM_174936.4(PCSK9):c.2017A>G (p.Thr673Ala) AND Hypercholesterolemia, autosomal dominant, 3

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Apr 10, 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:: RCV004011871.2

Allele description [Variation Report for NM_174936.4(PCSK9):c.2017A>G (p.Thr673Ala)]

NM_174936.4(PCSK9):c.2017A>G (p.Thr673Ala)

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.2017A>G (p.Thr673Ala)

HGVS:

NC_000001.11:g.55063522A>G
NG_009061.1:g.28976A>G
NM_001407240.1:c.2140A>G
NM_001407241.1:c.2059A>G
NM_001407242.1:c.2020A>G
NM_001407243.1:c.1960A>G
NM_001407244.1:c.1843A>G
NM_001407245.1:c.1825A>G
NM_001407246.1:c.1642A>G
NM_001407247.1:c.1516A>G
NM_174936.4:c.2017A>GMANE SELECT
NP_001394169.1:p.Thr714Ala
NP_001394170.1:p.Thr687Ala
NP_001394171.1:p.Thr674Ala
NP_001394172.1:p.Thr654Ala
NP_001394173.1:p.Thr615Ala
NP_001394174.1:p.Thr609Ala
NP_001394175.1:p.Thr548Ala
NP_001394176.1:p.Thr506Ala
NP_777596.2:p.Thr673Ala
NP_777596.2:p.Thr673Ala
LRG_275t1:c.2017A>G
LRG_275:g.28976A>G
LRG_275p1:p.Thr673Ala
NC_000001.10:g.55529195A>G
NM_174936.3:c.2017A>G
NR_110451.3:n.2298A>G
NR_176318.1:n.2101A>G
NR_176319.1:n.2576A>G
NR_176320.1:n.2540A>G
NR_176321.1:n.2255A>G
NR_176322.1:n.2210A>G
NR_176323.1:n.2129A>G
NR_176324.1:n.2517A>G

Protein change:

T506A

Molecular consequence:

NM_001407240.1:c.2140A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407241.1:c.2059A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407242.1:c.2020A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407243.1:c.1960A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407244.1:c.1843A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407245.1:c.1825A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407246.1:c.1642A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407247.1:c.1516A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_174936.4:c.2017A>G - missense variant - [Sequence Ontology: SO:0001583]
NR_110451.3:n.2298A>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_176318.1:n.2101A>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_176319.1:n.2576A>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_176320.1:n.2540A>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_176321.1:n.2255A>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_176322.1:n.2210A>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_176323.1:n.2129A>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_176324.1:n.2517A>G - 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

Recent activity

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Golgin subfamily A member 6-like protein 4, putative [Theobroma cacao]
Golgin subfamily A member 6-like protein 4, putative [Theobroma cacao]
gi|590676320|ref|XP_007039702.1||gn _WGS:ALXC|Thecc1EG015873p1

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004830622	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Apr 10, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004830622

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Apr 10, 2023)

germline

clinical testing

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

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

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, SCV004830622.1

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

Description

This missense variant replaces threonine with alanine at codon 673 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 not been reported in individuals affected with PCSK9-related disorders in the literature. This variant has been identified in 1/249384 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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