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NM_000527.5(LDLR):c.1359-3C>T AND Familial hypercholesterolemia

Germline classification:
Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:
Oct 22, 2022
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:
RCV001182460.5

Allele description [Variation Report for NM_000527.5(LDLR):c.1359-3C>T]

NM_000527.5(LDLR):c.1359-3C>T

Genes:
LDLR:low density lipoprotein receptor [Gene - OMIM - HGNC]
MIR6886:microRNA 6886 [Gene - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
19p13.2
Genomic location:
Preferred name:
NM_000527.5(LDLR):c.1359-3C>T
HGVS:
  • NC_000019.10:g.11113532C>T
  • NG_009060.1:g.29152C>T
  • NM_000527.5:c.1359-3C>TMANE SELECT
  • NM_001195798.2:c.1359-3C>T
  • NM_001195799.2:c.1236-3C>T
  • NM_001195800.2:c.855-3C>T
  • NM_001195803.2:c.978-3C>T
  • LRG_274t1:c.1359-3C>T
  • LRG_274:g.29152C>T
  • NC_000019.9:g.11224208C>T
  • NM_000527.4:c.1359-3C>T
  • NR_106946.1:n.59C>T
  • c.1359-3C>T
Links:
LDLR-LOVD, British Heart Foundation: LDLR_000191; dbSNP: rs775657243
NCBI 1000 Genomes Browser:
rs775657243
Molecular consequence:
  • NM_000527.5:c.1359-3C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001195798.2:c.1359-3C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001195799.2:c.1236-3C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001195800.2:c.855-3C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001195803.2:c.978-3C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NR_106946.1:n.59C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

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
SCV001347906Color Diagnostics, LLC DBA Color Health
criteria provided, single submitter

(ACMG Guidelines, 2015)		Likely benign
(Jul 6, 2017) 		germlineclinical testing

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

SCV003302458Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Uncertain significance
(Oct 22, 2022) 		germlineclinical testing

PubMed (4)
[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

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

Frequency of low-density lipoprotein receptor gene mutations in patients with a clinical diagnosis of familial combined hyperlipidemia in a clinical setting.

Civeira F, Jarauta E, Cenarro A, García-Otín AL, Tejedor D, Zambón D, Mallen M, Ros E, Pocoví M.

J Am Coll Cardiol. 2008 Nov 4;52(19):1546-53. doi: 10.1016/j.jacc.2008.06.050.

PubMed [citation]
PMID:
19007590
See all PubMed Citations (5)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV001347906.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003302458.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

This sequence change falls in intron 9 of the LDLR gene. It does not directly change the encoded amino acid sequence of the LDLR protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs775657243, gnomAD 0.01%). This variant has been observed in individuals with familial hypercholesterolemia (PMID: 19007590; Invitae). ClinVar contains an entry for this variant (Variation ID: 251810). Variants that disrupt 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 is not likely to affect RNA splicing. 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

Last Updated: Sep 29, 2024