NM_000527.5(LDLR):c.1284C>G (p.Asn428Lys) AND Cardiovascular phenotype

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Mar 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:: RCV004020963.1

Allele description [Variation Report for NM_000527.5(LDLR):c.1284C>G (p.Asn428Lys)]

NM_000527.5(LDLR):c.1284C>G (p.Asn428Lys)

Gene:

LDLR:low density lipoprotein receptor [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

19p13.2

Genomic location:

Preferred name:

NM_000527.5(LDLR):c.1284C>G (p.Asn428Lys)

Other names:

NM_000527.5(LDLR):c.1284C>G; p.Asn428Lys

HGVS:

NC_000019.10:g.11113375C>G
NG_009060.1:g.28995C>G
NM_000527.5:c.1284C>GMANE SELECT
NM_001195798.2:c.1284C>G
NM_001195799.2:c.1161C>G
NM_001195800.2:c.780C>G
NM_001195803.2:c.903C>G
NP_000518.1:p.Asn428Lys
NP_000518.1:p.Asn428Lys
NP_001182727.1:p.Asn428Lys
NP_001182728.1:p.Asn387Lys
NP_001182729.1:p.Asn260Lys
NP_001182732.1:p.Asn301Lys
LRG_274t1:c.1284C>G
LRG_274:g.28995C>G
LRG_274p1:p.Asn428Lys
NC_000019.9:g.11224051C>G
NM_000527.4:c.1284C>G
c.1284C>G

Protein change:

N260K

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000540; dbSNP: rs368708058

NCBI 1000 Genomes Browser:

rs368708058

Molecular consequence:

NM_000527.5:c.1284C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1284C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1161C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.780C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.903C>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Cardiovascular phenotype
Identifiers:: MedGen: CN230736

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003907261	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Mar 20, 2023)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 11005141, 11238294, 11668640, 11810272, 11845603, 11857755, 20736250, 21382890, 34363016, 35047021, 36499307 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003907261

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Mar 20, 2023)

germline

clinical testing

PubMed (11)
[See all records that cite these PMIDs]

Citation Link

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

Low-density lipoprotein receptor gene mutations in a Southeast Asian population with familial hypercholesterolemia.

Khoo KL, van Acker P, Defesche JC, Tan H, van de Kerkhof L, Heijnen-van Eijk SJ, Kastelein JJ, Deslypere JP.

Clin Genet. 2000 Aug;58(2):98-105.

PubMed [citation]

PMID:: 11005141

Compound heterozygous familial hypercholesterolemia and familial defective apolipoprotein B-100 produce exaggerated hypercholesterolemia.

Tai ES, Koay ES, Chan E, Seng TJ, Loh LM, Sethi SK, Tan CE.

Clin Chem. 2001 Mar;47(3):438-43.

PubMed [citation]

PMID:: 11238294

See all PubMed Citations (11)

Details of each submission

From Ambry Genetics, SCV003907261.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (11)

Description

The c.1284C>G (p.N428K) alteration is located in exon 9 (coding exon 9) of the LDLR gene. This alteration results from a C to G substitution at nucleotide position 1284, causing the asparagine (N) at amino acid position 428 to be replaced by a lysine (K). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant (also referred to as p.N407K) has been detected in several unrelated individuals with familial hypercholesterolemia (FH) (Khoo, 2000; Fouchier, 2001; van der Graaf, 2011; García-García, 2001; Bunn, 2002; Rimbert, 2021; Razman, 2022). This variant has also been detected in additional FH and dyslipidemia cohorts (Vergotine, 2001; Murdock, 2021). In one study, this variant co-occurred with an APOB variant in a proband reported to have more severe hypercholesterolemia than relatives with only one variant (Tai, 2001; Taylor, 2010). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.

#	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: Nov 3, 2024

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