NM_000527.5(LDLR):c.2312-3C>A AND Cardiovascular phenotype

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Sep 3, 2024
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:: RCV002426992.3

Allele description [Variation Report for NM_000527.5(LDLR):c.2312-3C>A]

NM_000527.5(LDLR):c.2312-3C>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.2312-3C>A

HGVS:

NC_000019.10:g.11128005C>A
NG_009060.1:g.43625C>A
NM_000527.5:c.2312-3C>AMANE SELECT
NM_001195798.2:c.2312-3C>A
NM_001195799.2:c.2189-3C>A
NM_001195800.2:c.1808-3C>A
NM_001195803.2:c.1778-3C>A
LRG_274t1:c.2312-3C>A
LRG_274:g.43625C>A
NC_000019.9:g.11238681C>A
NM_000527.4:c.2312-3C>A
c.2312-3C>A
p.(Ala771_Ile796del)

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000948;

Molecular consequence:

NM_000527.5:c.2312-3C>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001195798.2:c.2312-3C>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001195799.2:c.2189-3C>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001195800.2:c.1808-3C>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001195803.2:c.1778-3C>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
SCV002731831	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Sep 3, 2024)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 11317362, 11668640, 12417285, 16115486, 16627557, 18718593, 20045108, 28353356, 28965616, 31491741 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002731831

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Sep 3, 2024)

germline

clinical testing

PubMed (10)
[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

LDL receptor cDNA sequence analysis in familial hypercholesterolemia patients: 5 novel mutations with high prevalence in families originating from southern Italy.

Liguori R, Bianco AM, Argiriou A, Pauciullo P, Giannino A, Rubba P, De Simone V.

Hum Mutat. 2001 May;17(5):433.

PubMed [citation]

PMID:: 11317362

Molecular genetics of familial hypercholesterolemia in Spain: Ten novel LDLR mutations and population analysis.

García-García AB, Real JT, Puig O, Cebolla E, Marín-García P, Martínez Ferrandis JI, García-Sogo M, Civera M, Ascaso JF, Carmena R, Armengod ME, Chaves FJ.

Hum Mutat. 2001 Nov;18(5):458-9.

PubMed [citation]

PMID:: 11668640

See all PubMed Citations (10)

Details of each submission

From Ambry Genetics, SCV002731831.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

The c.2312-3C>A intronic variant results from a C to A substitution 3 nucleotides upstream from coding exon 16 in the LDLR gene. This alteration has been detected in numerous individuals with familial hypercholesterolemia (FH) from a variety of ethnic backgrounds, and segregation with disease has been reported in multiple families (Liguori R et al. Hum. Mutat., 2001 May;17:433; García-García AB et al. Hum. Mutat., 2001 Nov;18:458-9; Pisciotta L et al. Atherosclerosis, 2005 Sep;182:153-9; Miyake Y et al. Atherosclerosis, 2009 Mar;203:153-60; Rubba P et al. Eur J Prev Cardiol, 2017 Jul;24:1051-1059). In silico splice site analysis predicts that this alteration may weaken the native splice acceptor site. Functional studies have demonstrated skipping of exon 16, with the in-frame deletion of 26 amino acids, and reduced LDLR activity to approximately 50% of wild-type (Romano M et al. Atherosclerosis, 2010 Jun;210:493-6). This nucleotide position is highly conserved in available vertebrate species. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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: Feb 25, 2025

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