NM_000527.4(LDLR):c.1586+5G>C AND Familial hypercholesterolemia

Clinical significance:Likely pathogenic (Last evaluated: Apr 6, 2016)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000586202.3

Allele description [Variation Report for NM_000527.4(LDLR):c.1586+5G>C]

NM_000527.4(LDLR):c.1586+5G>C

Gene:
LDLR:low density lipoprotein receptor [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
19p13.2
Genomic location:
Preferred name:
NM_000527.4(LDLR):c.1586+5G>C
HGVS:
  • NC_000019.10:g.11113767G>C
  • NG_009060.1:g.29387G>C
  • NM_000527.4:c.1586+5G>C
  • NM_001195798.2:c.1586+5G>C
  • NM_001195799.2:c.1463+5G>C
  • NM_001195800.2:c.1082+5G>C
  • NM_001195803.2:c.1205+5G>C
  • LRG_274t1:c.1586+5G>C
  • LRG_274:g.29387G>C
  • NC_000019.9:g.11224443G>C
  • NM_000527.4(LDLR):c.1586+5G>C
Links:
dbSNP: rs781362878
NCBI 1000 Genomes Browser:
rs781362878
Molecular consequence:
  • NM_000527.4:c.1586+5G>C - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001195798.2:c.1586+5G>C - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001195799.2:c.1463+5G>C - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001195800.2:c.1082+5G>C - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001195803.2:c.1205+5G>C - intron variant - [Sequence Ontology: SO:0001627]

Condition(s)

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

Recent activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...

Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000697203Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Likely pathogenic
(Apr 6, 2016)
germlineclinical testing

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

LabCorp Variant Classification Summary - May 2015.docx,

Citation Link,

SCV001422708Broad Institute Rare Disease Group, Broad Instituteno assertion criteria providedUncertain significance
(Jan 22, 2020)
germlinecuration

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

Citation Link,

SCV001460279Natera, Inc.no assertion criteria providedLikely pathogenic
(Sep 16, 2020)
germlineclinical testing

Summary from all submissions

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

Citations

PubMed

The use of next-generation sequencing in clinical diagnosis of familial hypercholesterolemia.

Vandrovcova J, Thomas ER, Atanur SS, Norsworthy PJ, Neuwirth C, Tan Y, Kasperaviciute D, Biggs J, Game L, Mueller M, Soutar AK, Aitman TJ.

Genet Med. 2013 Dec;15(12):948-57. doi: 10.1038/gim.2013.55. Epub 2013 May 16.

PubMed [citation]
PMID:
23680767

LDLR and ApoB are major genetic causes of autosomal dominant hypercholesterolemia in a Taiwanese population.

Yang KC, Su YN, Shew JY, Yang KY, Tseng WK, Wu CC, Lee YT.

J Formos Med Assoc. 2007 Oct;106(10):799-807.

PubMed [citation]
PMID:
17964958

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000697203.1

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

Description

Variant summary: c.1586+5G>C affects a conserved nucleotide, resulting in an intronic change. Mutation taster predicts this variant to be disease-causing. 5/5 programs in Alamut predict a loss (or weakening effect) of the canonical splicing donor site and ESE finder predicts changes of binding motifs for RNA splicing enhancers. This variant was not found in 117702 control chromosomes. This variant has been reported in multiple FH pts with evidence of segregation (Yang_JFormosMedAssoc_2008a). Taken together, this variant was classified as Likely Pathogenic until more information becomes available.

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

From Broad Institute Rare Disease Group, Broad Institute, SCV001422708.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcuration PubMed (1)

Description

The c.1586+5G>C variant in LDLR has been reported in at least 2 Taiwanese individuals with familial hypercholesterolemia (PMID: 17964958), and has been identified in 0.02% (4/18384) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs781362878). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported in ClinVar as likely pathogenic and pathogenic (Variation ID#: 440652). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. This variant is located in the 5' splice region. Computational tools do suggest an impact to splicing. However, this information is not predictive enough to determine/rule out pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PP3, PS4 (Richards 2015).

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

From Natera, Inc., SCV001460279.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Aug 27, 2021

Support Center