NM_174936.4(PCSK9):c.2048dup (p.His683fs) AND Familial hypercholesterolemia

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Nov 20, 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:: RCV003582168.1

Allele description [Variation Report for NM_174936.4(PCSK9):c.2048dup (p.His683fs)]

NM_174936.4(PCSK9):c.2048dup (p.His683fs)

Gene:

PCSK9:proprotein convertase subtilisin/kexin type 9 [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

1p32.3

Genomic location:

Preferred name:

NM_174936.4(PCSK9):c.2048dup (p.His683fs)

HGVS:

NC_000001.11:g.55063553dup
NG_009061.1:g.29007dup
NM_001407240.1:c.2171dup
NM_001407241.1:c.2090dup
NM_001407242.1:c.2051dup
NM_001407243.1:c.1991dup
NM_001407244.1:c.1874dup
NM_001407245.1:c.1856dup
NM_001407246.1:c.1673dup
NM_001407247.1:c.1547dup
NM_174936.4:c.2048dupMANE SELECT
NP_001394169.1:p.His724fs
NP_001394170.1:p.His697fs
NP_001394171.1:p.His684fs
NP_001394172.1:p.His664fs
NP_001394173.1:p.His625fs
NP_001394174.1:p.His619fs
NP_001394175.1:p.His558fs
NP_001394176.1:p.His516fs
NP_777596.2:p.His683Glnfs
NP_777596.2:p.His683fs
LRG_275t1:c.2048dup
LRG_275:g.29007dup
LRG_275p1:p.His683Glnfs
NC_000001.10:g.55529226dup
NM_174936.3:c.2048dup
NR_110451.3:n.2329dup
NR_176318.1:n.2132dup
NR_176319.1:n.2607dup
NR_176320.1:n.2571dup
NR_176321.1:n.2286dup
NR_176322.1:n.2241dup
NR_176323.1:n.2160dup
NR_176324.1:n.2548dup

Protein change:

H516fs

Molecular consequence:

NM_001407240.1:c.2171dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001407241.1:c.2090dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001407242.1:c.2051dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001407243.1:c.1991dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001407244.1:c.1874dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001407245.1:c.1856dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001407246.1:c.1673dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001407247.1:c.1547dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_174936.4:c.2048dup - frameshift variant - [Sequence Ontology: SO:0001589]
NR_110451.3:n.2329dup - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_176318.1:n.2132dup - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_176319.1:n.2607dup - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_176320.1:n.2571dup - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_176321.1:n.2286dup - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_176322.1:n.2241dup - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_176323.1:n.2160dup - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_176324.1:n.2548dup - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Familial hypercholesterolemia
Identifiers:: MONDO: MONDO:0005439; MedGen: C0020445; OMIM: PS143890

Recent activity

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Homo sapiens transmembrane protein 63C, mRNA (cDNA clone MGC:168227 IMAGE:902060...
Homo sapiens transmembrane protein 63C, mRNA (cDNA clone MGC:168227 IMAGE:9020604), complete cds
gi|187953290|gb|BC136614.1|

Nucleotide
protein NETWORKED 1D-like [Cucurbita maxima]
protein NETWORKED 1D-like [Cucurbita maxima]
gi|1281015671|ref|XP_022991964.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004358834	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Nov 20, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 29036232, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004358834

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Nov 20, 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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Rare and common variants of APOB and PCSK9 in Korean patients with extremely low low-density lipoprotein-cholesterol levels.

Lee CJ, Lee Y, Park S, Kang SM, Jang Y, Lee JH, Lee SH.

PLoS One. 2017;12(10):e0186446. doi: 10.1371/journal.pone.0186446.

PubMed [citation]

PMID:: 29036232
PMCID:: PMC5643101

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 Color Diagnostics, LLC DBA Color Health, SCV004358834.1

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

Description

This variant inserts 1 nucleotide in exon 12 of the PCSK9 gene, creating a frameshift in the last exon and addition of 27 new amino acids before introducing a stop codon. This results in a protein product that is 17 amino acids longer than the normal protein product. This variant has been reported in one individual characterized as having extremely low circulating LDL-C levels (PMID: 29036232). 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	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 1, 2024

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