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NM_000527.5(LDLR):c.1586+5G>A AND Familial hypercholesterolemia

Germline classification:
Pathogenic (3 submissions)
Last evaluated:
Jul 17, 2024
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:
RCV001044315.8

Allele description [Variation Report for NM_000527.5(LDLR):c.1586+5G>A]

NM_000527.5(LDLR):c.1586+5G>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.1586+5G>A
HGVS:
  • NC_000019.10:g.11113767G>A
  • NG_009060.1:g.29387G>A
  • NM_000527.5:c.1586+5G>AMANE SELECT
  • NM_001195798.2:c.1586+5G>A
  • NM_001195799.2:c.1463+5G>A
  • NM_001195800.2:c.1082+5G>A
  • NM_001195803.2:c.1205+5G>A
  • LRG_274t1:c.1586+5G>A
  • LRG_274:g.29387G>A
  • NC_000019.9:g.11224443G>A
  • NM_000527.4:c.1586+5G>A
  • c.1586+5G>A
Links:
LDLR-LOVD, British Heart Foundation: LDLR_001463; dbSNP: rs781362878
NCBI 1000 Genomes Browser:
rs781362878
Molecular consequence:
  • NM_000527.5:c.1586+5G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001195798.2:c.1586+5G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001195799.2:c.1463+5G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001195800.2:c.1082+5G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001195803.2:c.1205+5G>A - 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

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000697204Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)		Pathogenic
(Jul 17, 2024) 		germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV001208106Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Oct 28, 2023) 		germlineclinical testing

PubMed (10)
[See all records that cite these PMIDs]

SCV004358535Color Diagnostics, LLC DBA Color Health
criteria provided, single submitter

(ACMG Guidelines, 2015)		Pathogenic
(Oct 16, 2023) 		germlineclinical testing

PubMed (13)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

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

Statistical features of human exons and their flanking regions.

Zhang MQ.

Hum Mol Genet. 1998 May;7(5):919-32.

PubMed [citation]
PMID:
9536098
See all PubMed Citations (18)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000697204.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

Variant summary: LDLR c.1586+5G>A, also reported as "1592+5G>A", 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 abolishes a 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing in patient cells, resulting in an in-frame deletion of exon 10 (contains pathogenic missense) and an in-frame insertion of 22 amino acids (example, Jensen_1999). The variant allele was found at a frequency of 2.1e-05 in 1604438 control chromosomes in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in LDLR causing Familial Hypercholesterolemia (2.1e-05 vs 0.0013). c.1586+5G>A has been reported in the heterozygous state in the literature in multiple individuals affected with Familial Hypercholesterolemia (example, Jensen_1999). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of wild type receptor surface expression in vitro (example, Jensen_1999). The following publications have been ascertained in the context of this evaluation (PMID: 10668928, 19208450). ClinVar contains an entry for this variant (Variation ID: 251909). Based on the evidence outlined above, the variant was classified as pathogenic.

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001208106.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (10)

Description

This sequence change falls in intron 10 of the LDLR gene. It does not directly change the encoded amino acid sequence of the LDLR protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs781362878, gnomAD 0.02%). This variant has been observed in individuals with hypercholesterolemia (PMID: 7635461, 10668928, 17539906, 19208450, 19446849, 25463123). This variant is also known as c.1592+5G>A. ClinVar contains an entry for this variant (Variation ID: 251909). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of 10, but is expected to preserve the integrity of the reading-frame (PMID: 10668928, 19208450). This variant disrupts the c.1586+5 nucleotide in the LDLR gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 17964958; Invitae). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

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

From Color Diagnostics, LLC DBA Color Health, SCV004358535.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (13)

Description

This variant causes a G to A nucleotide substitution at the +5 position of intron 10 of the LDLR gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Molecular studies of the impact of this variant on RNA splicing demonstrated two aberrant mRNAs due to either in-frame skipping of exon 10 or the activation of a cryptic splice site in intron 10 inserting 66 intronic base pairs (PMID: 10668928). Additionally, this variant was shown to cause aberrant LDL receptor trafficking in transfected COS7 cells (PMID: 10668928). This variant has been reported in over 10 individuals affected with familial hypercholesterolemia (PMID: 7635461, 10668928, 16250003, 17539906, 19446849, 25463123, 31947532, 32660911, 32977124, 33418990, 34037665, 36960729). It has been shown that this variant segregates with disease in multiple affected individuals in one family (PMID: 10668928). This variant has been identified in 8/250846 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of LDLR function is a known mechanism of disease (clinicalgenome.org). A different variant occurring at the same position, c.1586+5G>C, is known to be pathogenic (ClinVar variation ID: 440652), indicating that c.G nucleotide at this position is important for normal RNA splicing. Based on the available evidence, this variant is classified as Pathogenic.

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

Last Updated: Oct 26, 2024