NM_000527.5(LDLR):c.2389+4A>G AND Cardiovascular phenotype

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Apr 9, 2021
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:: RCV002450747.2

Allele description [Variation Report for NM_000527.5(LDLR):c.2389+4A>G]

NM_000527.5(LDLR):c.2389+4A>G

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.2389+4A>G

HGVS:

NC_000019.10:g.11128089A>G
NG_009060.1:g.43709A>G
NM_000527.5:c.2389+4A>GMANE SELECT
NM_001195798.2:c.2389+4A>G
NM_001195799.2:c.2266+4A>G
NM_001195800.2:c.1885+4A>G
NM_001195803.2:c.1855+4A>G
LRG_274t1:c.2389+4A>G
LRG_274:g.43709A>G
NC_000019.9:g.11238765A>G
NM_000527.4:c.2389+4A>G
c.2389+4A>G

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001640; dbSNP: rs758493597

Molecular consequence:

NM_000527.5:c.2389+4A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001195798.2:c.2389+4A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001195799.2:c.2266+4A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001195800.2:c.1885+4A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001195803.2:c.1855+4A>G - intron variant - [Sequence Ontology: SO:0001627]

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
SCV002737313	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Apr 9, 2021)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 15241806, 19318025, 28475941, 30312929, 34456049, 36769678 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002737313

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Apr 9, 2021)

germline

clinical testing

PubMed (6)
[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

Molecular characterization of familial hypercholesterolemia in Spain: identification of 39 novel and 77 recurrent mutations in LDLR.

Mozas P, Castillo S, Tejedor D, Reyes G, Alonso R, Franco M, Saenz P, Fuentes F, Almagro F, Mata P, Pocoví M.

Hum Mutat. 2004 Aug;24(2):187.

PubMed [citation]

PMID:: 15241806

Genetic diagnosis of familial hypercholesterolemia using a DNA-array based platform.

Alonso R, Defesche JC, Tejedor D, Castillo S, Stef M, Mata N, Gomez-Enterria P, Martinez-Faedo C, Forga L, Mata P.

Clin Biochem. 2009 Jun;42(9):899-903. doi: 10.1016/j.clinbiochem.2009.01.017. Epub 2009 Feb 6.

PubMed [citation]

PMID:: 19318025

See all PubMed Citations (6)

Details of each submission

From Ambry Genetics, SCV002737313.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

The c.2389+4A>G pathogenic mutation results from an A to G substitution 4 nucleotides after coding exon 16 in the LDLR gene. This variant has been identified in several cohorts of individuals with familial hypercholesterolemia in Spain; however, clinical information is limited (Alonso R et al. Clin. Biochem., 2009 Jun;42:899-903; Mozas P et al. Hum. Mutat., 2004 Aug;24:187; Bourbon M et al. Atherosclerosis, 2017 07;262:8-13; Ibarretxe D et al. Atherosclerosis, 2018 11;278:210-216). This variant co-segregated with disease in one family tested in our laboratory, and RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). The resulting transcript is in-frame and is not expected to trigger nonsense-mediated mRNA decay; however, the impacted region is critical for protein function (Ambry internal data). Other pathogenic alterations impacting the same donor site (c.2389G>T and c.2389+1G>T) have been shown to have a similar impact on splicing (Bourbon M et al. J. Med. Genet., 2009 May;46:352-7; Holla ØL et al. Mol. Genet. Metab., 2009 Apr;96:245-52). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

#	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 27, 2025

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