NM_000527.5(LDLR):c.1586+5G>A AND Homozygous familial hypercholesterolemia

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Aug 26, 2022
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:: RCV004017559.1

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:: Homozygous familial hypercholesterolemia
Synonyms:: Familial hypercholesterolemia - homozygous
Identifiers:: MONDO: MONDO:0018328; MedGen: C0342881

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PF3D7_1232900 [Plasmodium falciparum 3D7]
PF3D7_1232900 [Plasmodium falciparum 3D7]
Gene ID:811369

Gene
Gene Links for GEO Profiles (Select 85798739) (1)
Gene
Profile neighbors for GEO Profiles (Select 85798199) (199)
GEO Profiles
PF3D7_1108400 [Plasmodium falciparum 3D7]
PF3D7_1108400 [Plasmodium falciparum 3D7]
Gene ID:810647

Gene
Gene Links for GEO Profiles (Select 85798328) (1)
Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004848107	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (Aug 26, 2022)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 25463123, 17539906, 16250003, 7635461, 19446849, 10668928, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004848107

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely Pathogenic
(Aug 26, 2022)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

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

Familial Hypercholesterolemia in Greek children and their families: genotype-to-phenotype correlations and a reconsideration of LDLR mutation spectrum.

Mollaki V, Progias P, Drogari E.

Atherosclerosis. 2014 Dec;237(2):798-804. doi: 10.1016/j.atherosclerosis.2014.09.031. Epub 2014 Oct 30.

PubMed [citation]

PMID:: 25463123

Multiplex ARMS analysis to detect 13 common mutations in familial hypercholesterolaemia.

Taylor A, Tabrah S, Wang D, Sozen M, Duxbury N, Whittall R, Humphries SE, Norbury G.

Clin Genet. 2007 Jun;71(6):561-8.

PubMed [citation]

PMID:: 17539906

See all PubMed Citations (7)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004848107.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

The c.1586+5G>A variant in LDLR has been reported in 7 individuals with familial hypercholesterolemia (FH) and segregated with disease in at least 7 affected relatives from 2 families (Ekstrom 1995, Jensen 1999, Fouchier 2005, Taylor 2007, Guardamagna 2009, Mollaki 2014). Additionally, this variant has been identified in 6/30752 South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/) and is present in ClinVar (Variation ID: 251909). Please note that for diseases with clinical variability, reduced penetrance, or recessive inheritance, pathogenic variants may be present at a low frequency in the general population. In vitro functional studies provide some evidence that the c.1586+5G>A variant may impact protein function (Jensen 1999. This variant is located in the 5' splice region. Computational tools do suggest an impact to splicing. In summary, although additional studies are required to fully establish its clinical significance, the c.1586+5G>A variant is likely pathogenic for FH in an autosomal dominant manner based on cased observations, segregation studies, functional and computational evidence. The ACMG/AMP Criteria applied: PP1_Strong, PS4_Moderate, PP3, PS3_Supporting.

#	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: Oct 26, 2024

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