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NM_174936.3(PCSK9):c.1120G>T (p.Asp374Tyr)

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Interpretation:
Pathogenic/Likely pathogenic​

Review status:
criteria provided, multiple submitters, no conflicts
Submissions:
6 (Most recent: Mar 9, 2020)
Last evaluated:
Jan 2, 2018
Accession:
VCV000002875.3
Variation ID:
2875
Description:
single nucleotide variant
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NM_174936.3(PCSK9):c.1120G>T (p.Asp374Tyr)

Allele ID
17914
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
1p32.3
Genomic location
1: 55057454 (GRCh38) GRCh38 UCSC
1: 55523127 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
LRG_275:g.22908G>T
Q8NBP7:p.Asp374Tyr
NM_174936.3(PCSK9):c.1120G>T
... more HGVS
Protein change
-
Other names
D374Y
Canonical SPDI
NC_000001.11:55057453:G:T
Functional consequence
-
Global minor allele frequency (GMAF)
-

Allele frequency
-
Links
ClinGen: CA023106
UniProtKB: Q8NBP7#VAR_058532
OMIM: 607786.0003
dbSNP: rs137852912
Varsome
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Pathogenic/Likely pathogenic 3 criteria provided, multiple submitters, no conflicts Jan 2, 2018 RCV000505195.3
Pathogenic 3 no assertion criteria provided Jan 22, 2020 RCV000003009.5
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Gene OMIM ClinGen Gene Dosage Sensitivity Curation Variation viewer Related variants
HI score Help TS score Help Within gene All
PCSK9 Dosage sensitivity unlikely No evidence available GRCh38
GRCh37
777 791

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
Pathogenic
(Jan 02, 2018)
criteria provided, single submitter
Method: clinical testing
Familial hypercholesterolemia 1
(Autosomal dominant inheritance)
Allele origin: germline
Robarts Research Institute,Western University
Accession: SCV000782972.1
Submitted: (Apr 09, 2018)
Evidence details
Likely pathogenic
(Mar 01, 2016)
criteria provided, single submitter
Method: curation, literature only
Familial hypercholesterolemia
(Autosomal dominant inheritance)
Allele origin: germline, not applicable
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge
Accession: SCV000599430.1
Submitted: (Apr 17, 2017)
Evidence details
Pathogenic
(-)
no assertion criteria provided
Method: research
Familial hypercholesterolemia
Allele origin: germline
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum
Accession: SCV000606699.1
Submitted: (Apr 25, 2017)
Evidence details
Pathogenic
(Feb 12, 2008)
no assertion criteria provided
Method: literature only
HYPERCHOLESTEROLEMIA, FAMILIAL, 3
Allele origin: germline
OMIM
Accession: SCV000023167.3
Submitted: (Dec 30, 2010)
Evidence details
Publications
PubMed (5)
Pathogenic
(Dec 08, 2016)
no assertion criteria provided
Method: literature only
Familial hypercholesterolemia 3
Allele origin: germline
GeneReviews
Accession: SCV000490156.1
Submitted: (Dec 08, 2016)
Evidence details
Other databases
https://www.ncbi.nlm.nih.gov/boo…
Pathogenic
(Jan 22, 2020)
no assertion criteria provided
Method: curation
Familial hypercholesterolemia 3
(Autosomal dominant inheritance)
Allele origin: germline
Broad Institute Rare Disease Group, Broad Institute
Accession: SCV001422592.1
Submitted: (Mar 09, 2020)
Evidence details
Publications
PubMed (4)
Other databases
https://erepo.clinicalgenome.org…
Comment:
The p.Asp374Tyr variant in PCSK9 has been reported in at least 10 families with hypercholesterolemia, segregated with disease in 20 affected relatives from 5 families, … (more)

Functional evidence

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There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Citations for this variant

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Title Author Journal Year Link
Familial Hypercholesterolemia Youngblom E - 2016 PMID: 24404629
Degradation of LDLR protein mediated by 'gain of function' PCSK9 mutants in normal and ARH cells. Fasano T Atherosclerosis 2009 PMID: 19081568
Molecular basis for LDL receptor recognition by PCSK9. Kwon HJ Proceedings of the National Academy of Sciences of the United States of America 2008 PMID: 18250299
Low-density lipoprotein receptor activity in Epstein-Barr virus-transformed lymphocytes from heterozygotes for the D374Y mutation in the PCSK9 gene. Holla ØL Scandinavian journal of clinical and laboratory investigation 2006 PMID: 16777760
Effect of mutations in the PCSK9 gene on the cell surface LDL receptors. Cameron J Human molecular genetics 2006 PMID: 16571601
Severe hypercholesterolemia in four British families with the D374Y mutation in the PCSK9 gene: long-term follow-up and treatment response. Naoumova RP Arteriosclerosis, thrombosis, and vascular biology 2005 PMID: 16224054
Evidence for effect of mutant PCSK9 on apolipoprotein B secretion as the cause of unusually severe dominant hypercholesterolaemia. Sun XM Human molecular genetics 2005 PMID: 15772090
NARC-1/PCSK9 and its natural mutants: zymogen cleavage and effects on the low density lipoprotein (LDL) receptor and LDL cholesterol. Benjannet S The Journal of biological chemistry 2004 PMID: 15358785
Mutations in the PCSK9 gene in Norwegian subjects with autosomal dominant hypercholesterolemia. Leren TP Clinical genetics 2004 PMID: 15099351
A mutation in PCSK9 causing autosomal-dominant hypercholesterolemia in a Utah pedigree. Timms KM Human genetics 2004 PMID: 14727179
Genetic localization to chromosome 1p32 of the third locus for familial hypercholesterolemia in a Utah kindred. Hunt SC Arteriosclerosis, thrombosis, and vascular biology 2000 PMID: 10764678
Evidence for a third genetic locus causing familial hypercholesterolemia. A non-LDLR, non-APOB kindred. Haddad L Journal of lipid research 1999 PMID: 10357843
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/91a85a05-1acc-49d4-94d6-f64b591cfa6b - - - -
https://www.ncbi.nlm.nih.gov/books/NBK174884/ - - - -

Text-mined citations for rs137852912...

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These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 18, 2021