NM_174936.4(PCSK9):c.1555G>A (p.Gly519Ser) AND Hypercholesterolemia, autosomal dominant, 3

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Aug 15, 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:: RCV004008877.2

Allele description [Variation Report for NM_174936.4(PCSK9):c.1555G>A (p.Gly519Ser)]

NM_174936.4(PCSK9):c.1555G>A (p.Gly519Ser)

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.1555G>A (p.Gly519Ser)

HGVS:

NC_000001.11:g.55059537G>A
NG_009061.1:g.24991G>A
NM_001407240.1:c.1678G>A
NM_001407241.1:c.1597G>A
NM_001407242.1:c.1558G>A
NM_001407243.1:c.1498G>A
NM_001407244.1:c.1381G>A
NM_001407245.1:c.1363G>A
NM_001407246.1:c.1180G>A
NM_174936.4:c.1555G>AMANE SELECT
NP_001394169.1:p.Gly560Ser
NP_001394170.1:p.Gly533Ser
NP_001394171.1:p.Gly520Ser
NP_001394172.1:p.Gly500Ser
NP_001394173.1:p.Gly461Ser
NP_001394174.1:p.Gly455Ser
NP_001394175.1:p.Gly394Ser
NP_777596.2:p.Gly519Ser
NP_777596.2:p.Gly519Ser
LRG_275t1:c.1555G>A
LRG_275:g.24991G>A
LRG_275p1:p.Gly519Ser
NC_000001.10:g.55525210G>A
NM_174936.3:c.1555G>A
NR_110451.2:n.1162G>A
NR_110451.3:n.1836G>A
NR_176318.1:n.1529G>A
NR_176319.1:n.2114G>A
NR_176320.1:n.1968G>A
NR_176321.1:n.1793G>A
NR_176322.1:n.1748G>A
NR_176324.1:n.2055G>A

Protein change:

G394S

Links:

dbSNP: rs2100330525

NCBI 1000 Genomes Browser:

rs2100330525

Molecular consequence:

NM_001407240.1:c.1678G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407241.1:c.1597G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407242.1:c.1558G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407243.1:c.1498G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407244.1:c.1381G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407245.1:c.1363G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407246.1:c.1180G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_174936.4:c.1555G>A - 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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ptpn5 protein tyrosine phosphatase non-receptor type 5 [Danio rerio]
ptpn5 protein tyrosine phosphatase non-receptor type 5 [Danio rerio]
Gene ID:559524

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004845820	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Aug 15, 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

SCV004845820

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Aug 15, 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, SCV004845820.1

#	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 glycine with serine at codon 519 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 familial hypercholesterolemia in the literature. This variant has not been identified 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: Sep 1, 2024

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