NM_000527.5(LDLR):c.314-2A>C AND Cardiovascular phenotype

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Feb 16, 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:: RCV002321913.2

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

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

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>C

Other names:

IVS3 as A-C -2

HGVS:

NC_000019.10:g.11105218A>C
NG_009060.1:g.20838A>C
NG_140410.1:g.435A>C
NM_000527.5:c.314-2A>CMANE SELECT
NM_001195798.2:c.314-2A>C
NM_001195799.2:c.191-2A>C
NM_001195800.2:c.314-2174A>C
NM_001195803.2:c.314-1347A>C
LRG_274t1:c.314-2A>C
LRG_274:g.20838A>C
NC_000019.9:g.11215894A>C
NM_000527.4:c.314-2A>C
c.314-2A>C

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000982; dbSNP: rs879254470

NCBI 1000 Genomes Browser:

rs879254470

Molecular consequence:

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

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
SCV002608980	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Feb 16, 2022)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 11668627, 27765764, 31447099, 32041611, 33303402, 34037665 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002608980

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Feb 16, 2022)

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

Low density lipoprotein receptor (LDLR) gene mutations in Canadian subjects with familial hypercholesterolemia, but not of French descent.

Wang J, Huff E, Janecka L, Hegele RA.

Hum Mutat. 2001 Oct;18(4):359.

PubMed [citation]

PMID:: 11668627

Polygenic Versus Monogenic Causes of Hypercholesterolemia Ascertained Clinically.

Wang J, Dron JS, Ban MR, Robinson JF, McIntyre AD, Alazzam M, Zhao PJ, Dilliott AA, Cao H, Huff MW, Rhainds D, Low-Kam C, Dubé MP, Lettre G, Tardif JC, Hegele RA.

Arterioscler Thromb Vasc Biol. 2016 Dec;36(12):2439-2445. Epub 2016 Oct 20.

PubMed [citation]

PMID:: 27765764

See all PubMed Citations (6)

Details of each submission

From Ambry Genetics, SCV002608980.2

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

Description

The c.314-2A>C intronic pathogenic mutation results from an A to C substitution two nucleotides upstream from coding exon 4 in the LDLR gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and may result in the creation or strengthening of a novel splice acceptor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown; however, the impacted region is critical for protein function (Ambry internal data). This alteration has been described in familial hypercholesterolemia (FH) cohorts (Wang J et al. Hum Mutat. 2001;18:359; Wang J et al. Arterioscler Thromb Vasc Biol, 2016 12;36:2439-2445; Sturm AC et al. JAMA Cardiol, 2021 08;6:902-909). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Another alteration impacting the same acceptor site (c.314-1G>A) has also been detected in individuals with FH (Huijgen et al 2010; Hum Mut 31(6):752-60; Lombardi P et al. Hum Mutat, 1998;Suppl 1:S172-4; Luirink IK et al. Atherosclerosis, 2019 06;285:87-92). 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 29, 2024

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