NM_000527.5(LDLR):c.1586+5G>C AND Familial hypercholesterolemia 1

Clinical significance:Conflicting interpretations of pathogenicity, Likely pathogenic(1);Uncertain significance(1) (Last evaluated: Mar 10, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000508837.4

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

NM_000527.5(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_000527.5(LDLR):c.1586+5G>C
HGVS:
  • NC_000019.10:g.11113767G>C
  • NC_000019.10:g.11113767G>C
  • NG_009060.1:g.29387G>C
  • NM_000527.4:c.1586+5G>C
  • NM_000527.5:c.1586+5G>CMANE SELECT
  • 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_000527.5: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 1 (FHCL1)
Synonyms:
LDL RECEPTOR DISORDER; Hyperlipoproteinemia Type IIa; HYPER-LOW-DENSITY-LIPOPROTEINEMIA; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0007750; MedGen: C0745103; Orphanet: 391665; OMIM: 143890

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000606462Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrumno assertion criteria providedPathogenicgermlineresearch

SCV000627020Invitaecriteria provided, single submitter
Likely pathogenic
(May 30, 2017)
germlineclinical testing

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

SCV001432659Brunham Lab, Centre for Heart and Lung Innovation,University of British Columbiacriteria provided, single submitter
Uncertain significance
(Mar 10, 2019)
germlineresearch

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyes4not providednot provided4not providedresearch
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing, research

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):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753
See all PubMed Citations (3)

Details of each submission

From Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum, SCV000606462.1

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

From Invitae, SCV000627020.1

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

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, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with hypercholesterolemia (PMID: 17964958, Invitae). This sequence change has been reported in an individual in the Universal Mutation Database (PMID: 12124988). Nucleotide substitutions within the consensus splice site are relatively common causes 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 currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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

From Brunham Lab, Centre for Heart and Lung Innovation,University of British Columbia, SCV001432659.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedresearch PubMed (2)
2not provided1not providednot providedresearch PubMed (2)
3not provided1not providednot providedresearch PubMed (2)
4not provided1not providednot providedresearch PubMed (2)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyes1not providednot provided1not providednot providednot provided
2germlineyes1not providednot provided1not providednot providednot provided
3germlineyes1not providednot provided1not providednot providednot provided
4germlineyes1not providednot provided1not providednot providednot provided

Last Updated: Oct 25, 2021

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