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NM_000527.5(LDLR):c.1358+1G>A AND Familial hypercholesterolemia

Germline classification:
Pathogenic (1 submission)
Last evaluated:
May 19, 2023
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:
RCV003581623.2

Allele description [Variation Report for NM_000527.5(LDLR):c.1358+1G>A]

NM_000527.5(LDLR):c.1358+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.1358+1G>A
Other names:
IVS9 ds G-A +1
HGVS:
  • NC_000019.10:g.11113450G>A
  • NG_009060.1:g.29070G>A
  • NM_000527.5:c.1358+1G>AMANE SELECT
  • NM_001195798.2:c.1358+1G>A
  • NM_001195799.2:c.1235+1G>A
  • NM_001195800.2:c.854+1G>A
  • NM_001195803.2:c.977+1G>A
  • LRG_274t1:c.1358+1G>A
  • LRG_274:g.29070G>A
  • NC_000019.9:g.11224126G>A
  • NM_000527.4:c.1358+1G>A
  • c.1358+1G>A
Links:
LDLR-LOVD, British Heart Foundation: LDLR_000341; dbSNP: rs775924858
NCBI 1000 Genomes Browser:
rs775924858
Molecular consequence:
  • NM_000527.5:c.1358+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001195798.2:c.1358+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001195799.2:c.1235+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001195800.2:c.854+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001195803.2:c.977+1G>A - 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
SCV004298356Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(May 19, 2023) 		germlineclinical testing

PubMed (7)
[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

Identification of a splice-site mutation in the low density lipoprotein receptor gene by denaturing gradient gel electrophoresis.

Top B, van der Zee A, Havekes LM, van 't Hooft FM, Frants RR.

Hum Genet. 1993 Jun;91(5):480-4.

PubMed [citation]
PMID:
8314561

Familial hypercholesterolemia in St-Petersburg: the known and novel mutations found in the low density lipoprotein receptor gene in Russia.

Zakharova FM, Damgaard D, Mandelshtam MY, Golubkov VI, Nissen PH, Nilsen GG, Stenderup A, Lipovetsky BM, Konstantinov VO, Denisenko AD, Vasilyev VB, Faergeman O.

BMC Med Genet. 2005 Feb 8;6:6.

PubMed [citation]
PMID:
15701167
PMCID:
PMC551615
See all PubMed Citations (7)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004298356.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (7)

Description

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 251802). This variant is also known as IVS9+1G>A. Disruption of this splice site has been observed in individuals with familial hypercholesterolemia (PMID: 8314561, 15701167, 18096825). This variant is present in population databases (rs775924858, gnomAD 0.0009%). This sequence change affects a donor splice site in intron 9 of the LDLR gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525, 28645073).

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

Last Updated: Sep 29, 2024