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NM_000527.5(LDLR):c.694+1G>C AND Familial hypercholesterolemia

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Apr 16, 2018
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
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:
RCV002233349.5

Allele description

NM_000527.5(LDLR):c.694+1G>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.694+1G>C
HGVS:
  • NC_000019.10:g.11105601G>C
  • NG_009060.1:g.21221G>C
  • NM_000527.5:c.694+1G>CMANE SELECT
  • NM_001195798.2:c.694+1G>C
  • NM_001195799.2:c.571+1G>C
  • NM_001195800.2:c.314-1791G>C
  • NM_001195803.2:c.314-964G>C
  • LRG_274t1:c.694+1G>C
  • LRG_274:g.21221G>C
  • NC_000019.9:g.11216277G>C
  • NM_000527.4:c.694+1G>C
  • p.(?)
Links:
dbSNP: rs879254646
NCBI 1000 Genomes Browser:
rs879254646
Molecular consequence:
  • NM_001195800.2:c.314-1791G>C - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001195803.2:c.314-964G>C - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000527.5:c.694+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001195798.2:c.694+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001195799.2:c.571+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]

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
SCV000829708Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Apr 16, 2018) 		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

Molecular genetic analysis of 1053 Danish individuals with clinical signs of familial hypercholesterolemia.

Brusgaard K, Jordan P, Hansen H, Hansen AB, Hørder M.

Clin Genet. 2006 Mar;69(3):277-83.

PubMed [citation]
PMID:
16542394

Splicing in action: assessing disease causing sequence changes.

Baralle D, Baralle M.

J Med Genet. 2005 Oct;42(10):737-48. Review.

PubMed [citation]
PMID:
16199547
PMCID:
PMC1735933
See all PubMed Citations (4)

Details of each submission

From Invitae, SCV000829708.4

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

Description

This sequence change affects a donor splice site in intron 4 of the LDLR gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with LDLR-related disease. 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. Other substitutions at this nucleotide (c.694+1G>A, c.694+1G>T) have been reported in individuals affected with hypercholesterolemia (PMID: 16542394, 20809525). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525). For these reasons, this variant has been classified as Pathogenic.

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

Last Updated: Sep 1, 2024