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NM_000527.5(LDLR):c.2140+1G>A AND Cardiovascular phenotype

Germline classification:
Pathogenic (1 submission)
Last evaluated:
May 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:
RCV002426486.2

Allele description [Variation Report for NM_000527.5(LDLR):c.2140+1G>A]

NM_000527.5(LDLR):c.2140+1G>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.2140+1G>A
Other names:
IVS14 ds G-A +1
HGVS:
  • NC_000019.10:g.11120523G>A
  • NG_009060.1:g.36143G>A
  • NM_000527.5:c.2140+1G>AMANE SELECT
  • NM_001195798.2:c.2140+1G>A
  • NM_001195799.2:c.2017+1G>A
  • NM_001195800.2:c.1636+1G>A
  • NM_001195803.2:c.1606+290G>A
  • LRG_274t1:c.2140+1G>A
  • LRG_274:g.36143G>A
  • NC_000019.9:g.11231199G>A
  • NM_000527.4:c.2140+1G>A
  • c.2140+1G>A
Nucleotide change:
IVS14, G-A, +1
Links:
LDLR-LOVD, British Heart Foundation: LDLR_000282; OMIM: 606945.0063; dbSNP: rs145787161
NCBI 1000 Genomes Browser:
rs145787161
Molecular consequence:
  • NM_001195803.2:c.1606+290G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000527.5:c.2140+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001195798.2:c.2140+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001195799.2:c.2017+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001195800.2:c.1636+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]

Condition(s)

Name:
Cardiovascular phenotype
Identifiers:
MedGen: CN230736

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002729253Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Pathogenic
(May 26, 2022) 		germlineclinical testing

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

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Intronic mutations at splice junctions in the low-density lipoprotein receptor gene.

Peeters AV, Thiart R, de Villiers JN, Jensen HK, Van Gaal LF, Kotze MJ.

Mol Cell Probes. 1999 Aug;13(4):257-60.

PubMed [citation]
PMID:
10441197

A molecular genetic service for diagnosing individuals with familial hypercholesterolaemia (FH) in the United Kingdom.

Heath KE, Humphries SE, Middleton-Price H, Boxer M.

Eur J Hum Genet. 2001 Apr;9(4):244-52.

PubMed [citation]
PMID:
11313767
See all PubMed Citations (7)

Details of each submission

From Ambry Genetics, SCV002729253.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (7)

Description

The c.2140+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 14 of the LDLR gene. This canonical splice site alteration has been reported in individuals with familial hypercholesterolemia (FH) and shown to segregate with the disease in a multi-generational family (Takada D et al. J. Hum. Genet., 2002;47:656-64; Mozas P et al. Hum. Mutat., 2004 Aug;24:187; Medeiros AM et al. Atherosclerosis, 2010 Oct;212:553-8). Moreover, this alteration has been shown to cause aberrant splicing that results in loss of the protein (Takada D et al. J. Hum. Genet., 2002;47:656-64). Additional alterations impacting the same donor site (c.2140+1G>T and c.2140+1G>C) have also been described in FH cases (Peeters AV et al. Mol Cell Probes, 1999 Aug;13:257-60; Heath KE et al. Eur J Hum Genet, 2001 Apr;9:244-52). 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 13, 2024