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NM_000527.5(LDLR):c.2389+4A>G AND Familial hypercholesterolemia

Germline classification:
Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:
Nov 15, 2023
Review status:
criteria provided, conflicting classifications
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:
RCV000812185.6

Allele description [Variation Report for NM_000527.5(LDLR):c.2389+4A>G]

NM_000527.5(LDLR):c.2389+4A>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.2389+4A>G
HGVS:
  • NC_000019.10:g.11128089A>G
  • NG_009060.1:g.43709A>G
  • NM_000527.5:c.2389+4A>GMANE SELECT
  • NM_001195798.2:c.2389+4A>G
  • NM_001195799.2:c.2266+4A>G
  • NM_001195800.2:c.1885+4A>G
  • NM_001195803.2:c.1855+4A>G
  • LRG_274t1:c.2389+4A>G
  • LRG_274:g.43709A>G
  • NC_000019.9:g.11238765A>G
  • NM_000527.4:c.2389+4A>G
  • c.2389+4A>G
Links:
LDLR-LOVD, British Heart Foundation: LDLR_001640; dbSNP: rs758493597
NCBI 1000 Genomes Browser:
rs758493597
Molecular consequence:
  • NM_000527.5:c.2389+4A>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001195798.2:c.2389+4A>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001195799.2:c.2266+4A>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001195800.2:c.1885+4A>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001195803.2:c.1855+4A>G - intron variant - [Sequence Ontology: SO:0001627]

Condition(s)

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

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Assertion and evidence details

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Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000952490Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Uncertain significance
(Oct 4, 2018) 		germlineclinical testing

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

SCV004222664Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)		Likely pathogenic
(Nov 15, 2023) 		germlineclinical testing

PubMed (6)
[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

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Molecular characterization of familial hypercholesterolemia in Spain: identification of 39 novel and 77 recurrent mutations in LDLR.

Mozas P, Castillo S, Tejedor D, Reyes G, Alonso R, Franco M, Saenz P, Fuentes F, Almagro F, Mata P, Pocoví M.

Hum Mutat. 2004 Aug;24(2):187.

PubMed [citation]
PMID:
15241806
See all PubMed Citations (7)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000952490.1

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

Description

This sequence change falls in intron 16 of the LDLR gene. It does not directly change the encoded amino acid sequence of the LDLR protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs758493597, ExAC 0.002%). This variant has been observed in several individuals affected with familial hypercholesterolemia (PMID: 15241806). ClinVar contains an entry for this variant (Variation ID: 252304). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004222664.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

Variant summary: LDLR c.2389+4A>G alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Four predict the variant weakens a 5' donor site. Four predict the variant creates a 3' acceptor site. Additionally, mRNA from carriers of this variant showed an additional band which PCR confirmed was lacking exon 16 (Aparicio_2023). The variant allele was found at a frequency of 4e-06 in 251356 control chromosomes. c.2389+4A>G has been reported in the literature in individuals affected with Familial Hypercholesterolemia in Spanish cohorts and registries, however these reports are lacking full clinical details of the individuals carrying the variant (Mozas_2004, Merino_2007, Alonso_2008, Martin-Campos_2018, Marco-Benedi_2022). However, a recent report showed that carriers of this variant have a high prevalence of familial history of premature ASCVD and hypercholesterolemia as well as significantly worse LDLc levels than the rest of the genetically confirmed FH cohort. In this cohort, a female carrier presented tendon xanthoma and a male carrier presented both corneal arcus and tendon xanthomas (Aparicio_2023). This last report provides strong evidence for causality. Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments. Four labs, including the ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel, classified the variant as VUS while one classified as likley benign and one classified as pathogenic. It is important to note, however, that all clinvar submitters have last updated their evidence prior to the recent report from Aparicio. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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

Last Updated: Sep 29, 2024