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NM_000527.5(LDLR):c.1988-1G>A AND Familial hypercholesterolemia

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Dec 5, 2022
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:
RCV003581673.2

Allele description [Variation Report for NM_000527.5(LDLR):c.1988-1G>A]

NM_000527.5(LDLR):c.1988-1G>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.1988-1G>A
HGVS:
  • NC_000019.10:g.11120369G>A
  • NG_009060.1:g.35989G>A
  • NM_000527.5:c.1988-1G>AMANE SELECT
  • NM_001195798.2:c.1988-1G>A
  • NM_001195799.2:c.1865-1G>A
  • NM_001195800.2:c.1484-1G>A
  • NM_001195803.2:c.1606+136G>A
  • LRG_274t1:c.1988-1G>A
  • LRG_274:g.35989G>A
  • NC_000019.9:g.11231045G>A
  • NM_000527.4:c.1988-1G>A
Links:
dbSNP: rs1555807335
NCBI 1000 Genomes Browser:
rs1555807335
Molecular consequence:
  • NM_001195803.2:c.1606+136G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000527.5:c.1988-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001195798.2:c.1988-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001195799.2:c.1865-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001195800.2:c.1484-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]

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
SCV004297872Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Dec 5, 2022) 		germlineclinical testing

PubMed (6)
[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

Clinical course of homozygous familial hypercholesterolemia during childhood: report on 4 unrelated patients with homozygous or compound heterozygous mutations in the LDLR gene.

Kubalska J, Chmara M, Limon J, Wierzbicka A, Prokurat S, Szaplyko J, Kowalik A, Mierzewska H, Defesche JC, Pronicka E.

J Appl Genet. 2008;49(1):109-13. doi: 10.1007/BF03195256.

PubMed [citation]
PMID:
18263977

Spectrum of mutations and phenotypic expression in patients with autosomal dominant hypercholesterolemia identified in Italy.

Bertolini S, Pisciotta L, Rabacchi C, Cefalù AB, Noto D, Fasano T, Signori A, Fresa R, Averna M, Calandra S.

Atherosclerosis. 2013 Apr;227(2):342-8. doi: 10.1016/j.atherosclerosis.2013.01.007. Epub 2013 Jan 19.

PubMed [citation]
PMID:
23375686
See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004297872.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the LDLR protein in which other variant(s) (p.Cys667Tyr) have been determined to be pathogenic (PMID: 18263977, 23375686, 27765764). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Studies have shown that disruption of this splice site results in skipping of exon 14, but is expected to preserve the integrity of the reading-frame (PMID: 19208450). ClinVar contains an entry for this variant (Variation ID: 438329). Disruption of this splice site has been observed in individual(s) with autosomal dominant familial hypercholesterolemia (PMID: 16792510). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 13 of the LDLR gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product.

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

Last Updated: Sep 29, 2024