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NM_174936.4(PCSK9):c.1773C>G (p.His591Gln) AND Familial hypercholesterolemia

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Sep 14, 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:
RCV000771326.6

Allele description [Variation Report for NM_174936.4(PCSK9):c.1773C>G (p.His591Gln)]

NM_174936.4(PCSK9):c.1773C>G (p.His591Gln)

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.1773C>G (p.His591Gln)
HGVS:
  • NC_000001.11:g.55061466C>G
  • NG_009061.1:g.26920C>G
  • NM_001407240.1:c.1896C>G
  • NM_001407241.1:c.1815C>G
  • NM_001407242.1:c.1776C>G
  • NM_001407243.1:c.1716C>G
  • NM_001407244.1:c.1599C>G
  • NM_001407245.1:c.1581C>G
  • NM_001407246.1:c.1398C>G
  • NM_001407247.1:c.1272C>G
  • NM_174936.4:c.1773C>GMANE SELECT
  • NP_001394169.1:p.His632Gln
  • NP_001394170.1:p.His605Gln
  • NP_001394171.1:p.His592Gln
  • NP_001394172.1:p.His572Gln
  • NP_001394173.1:p.His533Gln
  • NP_001394174.1:p.His527Gln
  • NP_001394175.1:p.His466Gln
  • NP_001394176.1:p.His424Gln
  • NP_777596.2:p.His591Gln
  • NP_777596.2:p.His591Gln
  • LRG_275t1:c.1773C>G
  • LRG_275:g.26920C>G
  • LRG_275p1:p.His591Gln
  • NC_000001.10:g.55527139C>G
  • NM_174936.3:c.1773C>G
  • NR_110451.2:n.1380C>G
  • NR_110451.3:n.2054C>G
  • NR_176318.1:n.1857C>G
  • NR_176319.1:n.2332C>G
  • NR_176320.1:n.2296C>G
  • NR_176321.1:n.2011C>G
  • NR_176322.1:n.1966C>G
  • NR_176323.1:n.1885C>G
  • NR_176324.1:n.2273C>G
Protein change:
H424Q
Links:
dbSNP: rs529912877
NCBI 1000 Genomes Browser:
rs529912877
Molecular consequence:
  • NM_001407240.1:c.1896C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001407241.1:c.1815C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001407242.1:c.1776C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001407243.1:c.1716C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001407244.1:c.1599C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001407245.1:c.1581C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001407246.1:c.1398C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001407247.1:c.1272C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_174936.4:c.1773C>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000903593Color Diagnostics, LLC DBA Color Health
criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain significance
(Sep 14, 2023) 		germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Stepwise processing analyses of the single-turnover PCSK9 protease reveal its substrate sequence specificity and link clinical genotype to lipid phenotype.

Chorba JS, Galvan AM, Shokat KM.

J Biol Chem. 2018 Feb 9;293(6):1875-1886. doi: 10.1074/jbc.RA117.000754. Epub 2017 Dec 19. Erratum in: J Biol Chem. 2018 May 4;293(18):6692. doi: 10.1074/jbc.AAC118.003335.

PubMed [citation]
PMID:
29259136
PMCID:
PMC5808750

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, SCV000903593.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

This missense variant replaces histidine with glutamine at codon 591 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). A functional study has shown that the variant causes increased PCSK9 proteolysis (PMID: 29259136). This variant has not been reported in individuals affected with PCSK9-related disorders in the literature. This variant has been identified in 33/234832 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024