NM_174936.4(PCSK9):c.1837C>A (p.His613Asn) AND Hypercholesterolemia, autosomal dominant, 3

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jul 5, 2022
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:: RCV001046308.7

Allele description [Variation Report for NM_174936.4(PCSK9):c.1837C>A (p.His613Asn)]

NM_174936.4(PCSK9):c.1837C>A (p.His613Asn)

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.1837C>A (p.His613Asn)

HGVS:

NC_000001.11:g.55061530C>A
NG_009061.1:g.26984C>A
NM_001407240.1:c.1960C>A
NM_001407241.1:c.1879C>A
NM_001407242.1:c.1840C>A
NM_001407243.1:c.1780C>A
NM_001407244.1:c.1663C>A
NM_001407245.1:c.1645C>A
NM_001407246.1:c.1462C>A
NM_001407247.1:c.1336C>A
NM_174936.4:c.1837C>AMANE SELECT
NP_001394169.1:p.His654Asn
NP_001394170.1:p.His627Asn
NP_001394171.1:p.His614Asn
NP_001394172.1:p.His594Asn
NP_001394173.1:p.His555Asn
NP_001394174.1:p.His549Asn
NP_001394175.1:p.His488Asn
NP_001394176.1:p.His446Asn
NP_777596.2:p.His613Asn
NP_777596.2:p.His613Asn
LRG_275t1:c.1837C>A
LRG_275:g.26984C>A
LRG_275p1:p.His613Asn
NC_000001.10:g.55527203C>A
NM_174936.3:c.1837C>A
NR_110451.2:n.1444C>A
NR_110451.3:n.2118C>A
NR_176318.1:n.1921C>A
NR_176319.1:n.2396C>A
NR_176320.1:n.2360C>A
NR_176321.1:n.2075C>A
NR_176322.1:n.2030C>A
NR_176323.1:n.1949C>A
NR_176324.1:n.2337C>A

Protein change:

H446N

Links:

dbSNP: rs1644758908

NCBI 1000 Genomes Browser:

rs1644758908

Molecular consequence:

NM_001407240.1:c.1960C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407241.1:c.1879C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407242.1:c.1840C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407243.1:c.1780C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407244.1:c.1663C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407245.1:c.1645C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407246.1:c.1462C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407247.1:c.1336C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_174936.4:c.1837C>A - missense variant - [Sequence Ontology: SO:0001583]

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
SCV001210205	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jul 5, 2022)	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

SCV001210205

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jul 5, 2022)

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	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. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001210205.5

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

Description

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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PCSK9 protein function. ClinVar contains an entry for this variant (Variation ID: 843634). This variant has not been reported in the literature in individuals affected with PCSK9-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces histidine, which is basic and polar, with asparagine, which is neutral and polar, at codon 613 of the PCSK9 protein (p.His613Asn).

#	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: Sep 29, 2024

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