NM_000527.5(LDLR):c.2547+1G>A AND Familial hypercholesterolemia

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Feb 5, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV001043694.6

Allele description [Variation Report for NM_000527.5(LDLR):c.2547+1G>A]

NM_000527.5(LDLR):c.2547+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.2547+1G>A

HGVS:

NC_000019.10:g.11129671G>A
NG_009060.1:g.45291G>A
NM_000527.5:c.2547+1G>AMANE SELECT
NM_001195798.2:c.2547+1G>A
NM_001195799.2:c.2424+1G>A
NM_001195800.2:c.2043+1G>A
NM_001195803.2:c.2013+1G>A
LRG_274t1:c.2547+1G>A
LRG_274:g.45291G>A
NC_000019.9:g.11240347G>A
NM_000527.4:c.2547+1G>A
c.2547+1G>A

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000308; dbSNP: rs879255224

NCBI 1000 Genomes Browser:

rs879255224

Molecular consequence:

NM_000527.5:c.2547+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001195798.2:c.2547+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001195799.2:c.2424+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001195800.2:c.2043+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001195803.2:c.2013+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]

Condition(s)

Name:: Familial hypercholesterolemia (FH)
Identifiers:: MONDO: MONDO:0005439; MedGen: C0020445; OMIM: PS143890

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001207452	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Feb 5, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 17765246, 17576681, 9536098, 20828696, 28492532
SCV001434859	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 1, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001207452

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Feb 5, 2022)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV001434859

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Feb 1, 2019)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Familial hypercholesterolaemia in Portugal.

Bourbon M, Alves AC, Medeiros AM, Silva S, Soutar AK; Investigators of Portuguese FH Study..

Atherosclerosis. 2008 Feb;196(2):633-42. Epub 2007 Aug 31.

PubMed [citation]

PMID:: 17765246

Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.

Buratti E, Chivers M, Královicová J, Romano M, Baralle M, Krainer AR, Vorechovsky I.

Nucleic Acids Res. 2007;35(13):4250-63. Epub 2007 Jun 18.

PubMed [citation]

PMID:: 17576681
PMCID:: PMC1934990

See all PubMed Citations (6)

Details of each submission

From Invitae, SCV001207452.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change affects a donor splice site in intron 17 of the LDLR gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely disrupts the C-terminus of the protein. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with familial hypercholesterolemia (PMID: 17765246; Invitae). ClinVar contains an entry for this variant (Variation ID: 252352). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that disruption of this splice site results in skipping of exon 17 and introduces a new termination codon (PMID: 20828696). However the mRNA is not expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine, SCV001434859.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

The c.2547+1G>A variant in the LDLR gene disrupts the canonical splice donor site in intron 17 and is predicted to result in abnormal splicing of LDLR mRNA. This variant is absent from general population databases and has been reported in two unrelated individuals with hypercholesterolemia (PMID 17765246). In addition, skipping of exon 17 and a premature codon at aa805 were observed using mRNA extracted from the blood sample of an individual carrying this variant (PMID 20828696). Thus, this c.2547+1G>A variant in the LDLR gene is classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Feb 14, 2024

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