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NM_000527.5(LDLR):c.941-2A>G AND Familial hypercholesterolemia

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Aug 8, 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:
RCV001034626.8

Allele description [Variation Report for NM_000527.5(LDLR):c.941-2A>G]

NM_000527.5(LDLR):c.941-2A>G

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.941-2A>G
HGVS:
  • NC_000019.10:g.11110650A>G
  • NG_009060.1:g.26270A>G
  • NM_000527.5:c.941-2A>GMANE SELECT
  • NM_001195798.2:c.941-2A>G
  • NM_001195799.2:c.818-2A>G
  • NM_001195800.2:c.437-2A>G
  • NM_001195803.2:c.560-2A>G
  • LRG_274t1:c.941-2A>G
  • LRG_274:g.26270A>G
  • NC_000019.9:g.11221326A>G
  • NM_000527.4:c.941-2A>G
  • c.941-2A>G
Links:
LDLR-LOVD, British Heart Foundation: LDLR_000879; dbSNP: rs112366278
NCBI 1000 Genomes Browser:
rs112366278
Molecular consequence:
  • NM_000527.5:c.941-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001195798.2:c.941-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001195799.2:c.818-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001195800.2:c.437-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001195803.2:c.560-2A>G - 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
SCV000544681Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Aug 8, 2023) 		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

Intronic mutations outside of Alu-repeat-rich domains of the LDL receptor gene are a cause of familial hypercholesterolemia.

Amsellem S, Briffaut D, Carrié A, Rabès JP, Girardet JP, Fredenrich A, Moulin P, Krempf M, Reznik Y, Vialettes B, de Gennes JL, Brukert E, Benlian P.

Hum Genet. 2002 Dec;111(6):501-10. Epub 2002 Sep 13.

PubMed [citation]
PMID:
12436241

Genetic testing of Korean familial hypercholesterolemia using whole-exome sequencing.

Han SM, Hwang B, Park TG, Kim DI, Rhee MY, Lee BK, Ahn YK, Cho BR, Woo J, Hur SH, Jeong JO, Park S, Jang Y, Lee MG, Bang D, Lee JH, Lee SH.

PLoS One. 2015;10(5):e0126706. doi: 10.1371/journal.pone.0126706.

PubMed [citation]
PMID:
25962062
PMCID:
PMC4427254
See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000544681.7

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

Description

Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 251554). This variant is also known as IVS6-2A>G. Disruption of this splice site has been observed in individuals with familial hypercholesterolemia (PMID: 12436241, 25962062). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 6 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