NM_000527.5(LDLR):c.314-2A>G AND Familial hypercholesterolemia

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jul 28, 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:: RCV003581465.2

Allele description [Variation Report for NM_000527.5(LDLR):c.314-2A>G]

NM_000527.5(LDLR):c.314-2A>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.314-2A>G

HGVS:

NC_000019.10:g.11105218A>G
NG_009060.1:g.20838A>G
NG_140410.1:g.435A>G
NM_000527.5:c.314-2A>GMANE SELECT
NM_001195798.2:c.314-2A>G
NM_001195799.2:c.191-2A>G
NM_001195800.2:c.314-2174A>G
NM_001195803.2:c.314-1347A>G
LRG_274:g.20838A>G
NC_000019.9:g.11215894A>G

Molecular consequence:

NM_001195800.2:c.314-2174A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001195803.2:c.314-1347A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.314-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001195798.2:c.314-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001195799.2:c.191-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]

Condition(s)

Name:: Familial hypercholesterolemia
Identifiers:: MONDO: MONDO:0005439; MedGen: C0020445; OMIM: PS143890

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004298310	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jul 28, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 16199547, 20809525, 28645073, 27824480, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004298310

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jul 28, 2023)

germline

clinical testing

PubMed (5)
[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

Splicing in action: assessing disease causing sequence changes.

Baralle D, Baralle M.

J Med Genet. 2005 Oct;42(10):737-48. Review.

PubMed [citation]

PMID:: 16199547
PMCID:: PMC1735933

Molecular spectrum of autosomal dominant hypercholesterolemia in France.

Marduel M, Carrié A, Sassolas A, Devillers M, Carreau V, Di Filippo M, Erlich D, Abifadel M, Marques-Pinheiro A, Munnich A, Junien C; French ADH Research Network., Boileau C, Varret M, Rabès JP.

Hum Mutat. 2010 Nov;31(11):E1811-24. doi: 10.1002/humu.21348.

PubMed [citation]

PMID:: 20809525
PMCID:: PMC3152176

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004298310.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change affects an acceptor splice site in intron 3 of the LDLR gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525, 28645073). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with familial hypercholesterolemia (PMID: 27824480). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as 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: Sep 29, 2024

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