NM_174936.4(PCSK9):c.1274A>G (p.Asn425Ser) AND Hypercholesterolemia, familial, 1

Germline classification:: Benign (3 submissions)
Last evaluated:: May 28, 2019
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:: RCV000336569.10

Allele description [Variation Report for NM_174936.4(PCSK9):c.1274A>G (p.Asn425Ser)]

NM_174936.4(PCSK9):c.1274A>G (p.Asn425Ser)

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.1274A>G (p.Asn425Ser)

HGVS:

NC_000001.11:g.55058129A>G
NG_009061.1:g.23583A>G
NM_001407240.1:c.1397A>G
NM_001407241.1:c.1274A>G
NM_001407242.1:c.1277A>G
NM_001407243.1:c.1217A>G
NM_001407245.1:c.1082A>G
NM_001407246.1:c.899A>G
NM_174936.4:c.1274A>GMANE SELECT
NP_001394169.1:p.Asn466Ser
NP_001394170.1:p.Asn425Ser
NP_001394171.1:p.Asn426Ser
NP_001394172.1:p.Asn406Ser
NP_001394174.1:p.Asn361Ser
NP_001394175.1:p.Asn300Ser
NP_777596.2:p.Asn425Ser
NP_777596.2:p.Asn425Ser
LRG_275t1:c.1274A>G
LRG_275:g.23583A>G
LRG_275p1:p.Asn425Ser
NC_000001.10:g.55523802A>G
NM_174936.3:c.1274A>G
NR_110451.2:n.933A>G
NR_110451.3:n.1607A>G
NR_176318.1:n.1248A>G
NR_176319.1:n.1833A>G
NR_176320.1:n.1687A>G
NR_176321.1:n.1564A>G
NR_176322.1:n.1467A>G
NR_176323.1:n.1564A>G
NR_176324.1:n.1826A>G
Q8NBP7:p.Asn425Ser

Protein change:

N300S

Links:

UniProtKB: Q8NBP7#VAR_021337; dbSNP: rs28362261

Molecular consequence:

NM_001407240.1:c.1397A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407241.1:c.1274A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407242.1:c.1277A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407243.1:c.1217A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407245.1:c.1082A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407246.1:c.899A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_174936.4:c.1274A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hypercholesterolemia, familial, 1
Synonyms:: LDL RECEPTOR DISORDER; Hyperlipoproteinemia Type IIa; HYPER-LOW-DENSITY-LIPOPROTEINEMIA; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0007750; MedGen: C0745103; Orphanet: 391665; OMIM: 143890

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001135295	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Benign (May 28, 2019)	unknown	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001135295

Mendelics

criteria provided, single submitter

(Mendelics Assertion Criteria 2017)

Benign
(May 28, 2019)

unknown

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	not applicable	not applicable	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	research, curation
not provided	unknown	unknown	not provided	not provided	not provided	not provided	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

Degradation of LDLR protein mediated by 'gain of function' PCSK9 mutants in normal and ARH cells.

Fasano T, Sun XM, Patel DD, Soutar AK.

Atherosclerosis. 2009 Mar;203(1):166-71. doi: 10.1016/j.atherosclerosis.2008.10.027. Epub 2008 Nov 6.

PubMed [citation]

PMID:: 19081568

Details of each submission

From Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge, SCV000599431.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (2)
2	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

%MAF(ExAC):0.1544

"Assay Description:PCSK9 from transfected cells (HEK), normolipidemic EBV-transformed lymphocytes, imunoblotting and FACS assays"

PubMed [ID: 19081568]

#	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
2	not applicable	not applicable	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum, SCV000606702.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	not provided

#	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

From Mendelics, SCV001135295.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Flagged submissions

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000599431	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	flagged submission Reason: Older and outlier claim with insufficient supporting evidence Notes: None (ACMG Guidelines, 2015)	Uncertain significance (Mar 1, 2016)	germline, not applicable	curation, literature only	PubMed (2) [See all records that cite these PMIDs] 25741868, 19081568
SCV000606702	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	flagged submission Reason: Older and outlier claim with insufficient supporting evidence Notes: None	Pathogenic	germline	research

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000599431

Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge

flagged submission

Reason: Older and outlier claim with insufficient supporting evidence

Notes: None

(ACMG Guidelines, 2015)

Uncertain significance
(Mar 1, 2016)

germline, not applicable

curation, literature only

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

SCV000606702

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

flagged submission

Reason: Older and outlier claim with insufficient supporting evidence

Notes: None

Pathogenic

germline

research

Last Updated: Jun 20, 2026

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