NM_000527.5(LDLR):c.1586+5G>A AND Cardiovascular phenotype

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jan 15, 2018
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:: RCV002401938.2

Allele description [Variation Report for NM_000527.5(LDLR):c.1586+5G>A]

NM_000527.5(LDLR):c.1586+5G>A

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.1586+5G>A

HGVS:

NC_000019.10:g.11113767G>A
NG_009060.1:g.29387G>A
NM_000527.5:c.1586+5G>AMANE SELECT
NM_001195798.2:c.1586+5G>A
NM_001195799.2:c.1463+5G>A
NM_001195800.2:c.1082+5G>A
NM_001195803.2:c.1205+5G>A
LRG_274t1:c.1586+5G>A
LRG_274:g.29387G>A
NC_000019.9:g.11224443G>A
NM_000527.4:c.1586+5G>A
c.1586+5G>A

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001463; dbSNP: rs781362878

NCBI 1000 Genomes Browser:

rs781362878

Molecular consequence:

NM_000527.5:c.1586+5G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001195798.2:c.1586+5G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001195799.2:c.1463+5G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001195800.2:c.1082+5G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001195803.2:c.1205+5G>A - 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
SCV002705210	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Jan 15, 2018)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 10668928, 16250003, 17539906, 19208450, 19446849, 25463123 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002705210

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Jan 15, 2018)

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

Normolipidemia and hypercholesterolemia in persons heterozygous for the same 1592 + 5G --> A splice site mutation in the low-density lipoprotein receptor gene.

Jensen HK, Jensen LG, Holst HU, Andreasen PH, Hansen PS, Larsen ML, Kølvraa S, Bolund L, Gregersen N, Faergeman O.

Clin Genet. 1999 Nov;56(5):378-88.

PubMed [citation]

PMID:: 10668928

Update of the molecular basis of familial hypercholesterolemia in The Netherlands.

Fouchier SW, Kastelein JJ, Defesche JC.

Hum Mutat. 2005 Dec;26(6):550-6.

PubMed [citation]

PMID:: 16250003

See all PubMed Citations (6)

Details of each submission

From Ambry Genetics, SCV002705210.2

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

Description

The c.1586+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 10 in the LDLR gene. This alteration has been detected in individuals with confirmed familial hypercholesterolemia (FH) and in FH cohorts (Fouchier SW et al. Hum. Mutat., 2005 Dec;26:550-6; Taylor A et al. Clin. Genet., 2007 Jun;71:561-8; Guardamagna O et al. J. Pediatr., 2009 Aug;155:199-204.e2; Mollaki V et al. Atherosclerosis, 2014 Dec;237:798-804). Segregation with hypercholesterolemia has been observed with this alteration (reported as c.1592+5G>A); of note, in at least one family some heterozygotes had normal or near normal cholesterol levels at the time of testing (Jensen HK et al. Clin. Genet., 1999 Nov;56:378-88). RNA splicing studies have revealed exon-skipping and use of a cryptic donor site in mutant transcripts, while functional studies demonstrated some reduction in LDLR activity and conflicting membrane-trafficking results (Jensen HK et al. Clin. Genet., 1999 Nov;56:378-88; Holla ØL et al. Mol. Genet. Metab., 2009 Apr;96:245-52). This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site; however, direct evidence is unavailable. Based on the majority of available evidence to date, this variant is likely to be 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: May 7, 2024

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