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NM_000527.5(LDLR):c.2547+1G>A AND Familial hypercholesterolemia

Germline classification:
Pathogenic (2 submissions)
Last evaluated:
Feb 5, 2022
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
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:
RCV001043694.7

Allele description [Variation Report for NM_000527.5(LDLR):c.2547+1G>A]

NM_000527.5(LDLR):c.2547+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.2547+1G>A
HGVS:
  • NC_000019.10:g.11129671G>A
  • NG_009060.1:g.45291G>A
  • NM_000527.5:c.2547+1G>AMANE SELECT
  • NM_001195798.2:c.2547+1G>A
  • NM_001195799.2:c.2424+1G>A
  • NM_001195800.2:c.2043+1G>A
  • NM_001195803.2:c.2013+1G>A
  • LRG_274t1:c.2547+1G>A
  • LRG_274:g.45291G>A
  • NC_000019.9:g.11240347G>A
  • NM_000527.4:c.2547+1G>A
  • c.2547+1G>A
Links:
LDLR-LOVD, British Heart Foundation: LDLR_000308; dbSNP: rs879255224
NCBI 1000 Genomes Browser:
rs879255224
Molecular consequence:
  • NM_000527.5:c.2547+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001195798.2:c.2547+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001195799.2:c.2424+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001195800.2:c.2043+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001195803.2:c.2013+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]

Condition(s)

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

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001207452Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Feb 5, 2022) 		germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV001434859Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine
criteria provided, single submitter

(ACMG Guidelines, 2015)		Pathogenic
(Feb 1, 2019) 		germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

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

Citations

PubMed

Familial hypercholesterolaemia in Portugal.

Bourbon M, Alves AC, Medeiros AM, Silva S, Soutar AK; Investigators of Portuguese FH Study..

Atherosclerosis. 2008 Feb;196(2):633-42. Epub 2007 Aug 31.

PubMed [citation]
PMID:
17765246

Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.

Buratti E, Chivers M, Královicová J, Romano M, Baralle M, Krainer AR, Vorechovsky I.

Nucleic Acids Res. 2007;35(13):4250-63. Epub 2007 Jun 18.

PubMed [citation]
PMID:
17576681
PMCID:
PMC1934990
See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001207452.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

This sequence change affects a donor splice site in intron 17 of the LDLR gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely disrupts the C-terminus of the protein. 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: 17765246; Invitae). ClinVar contains an entry for this variant (Variation ID: 252352). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that disruption of this splice site results in skipping of exon 17 and introduces a new termination codon (PMID: 20828696). However the mRNA is not expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.

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

From Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine, SCV001434859.1

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

Description

The c.2547+1G>A variant in the LDLR gene disrupts the canonical splice donor site in intron 17 and is predicted to result in abnormal splicing of LDLR mRNA. This variant is absent from general population databases and has been reported in two unrelated individuals with hypercholesterolemia (PMID 17765246). In addition, skipping of exon 17 and a premature codon at aa805 were observed using mRNA extracted from the blood sample of an individual carrying this variant (PMID 20828696). Thus, this c.2547+1G>A variant in the LDLR gene is classified as pathogenic.

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

Last Updated: Sep 29, 2024