NM_000527.5(LDLR):c.940+2T>C AND Hypercholesterolemia, familial, 1

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Mar 25, 2016
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:: RCV000211690.8

Allele description [Variation Report for NM_000527.5(LDLR):c.940+2T>C]

NM_000527.5(LDLR):c.940+2T>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.940+2T>C

HGVS:

NC_000019.10:g.11107516T>C
NG_009060.1:g.23136T>C
NM_000527.5:c.940+2T>CMANE SELECT
NM_001195798.2:c.940+2T>C
NM_001195799.2:c.817+2T>C
NM_001195800.2:c.436+2T>C
NM_001195803.2:c.559+2T>C
LRG_274t1:c.940+2T>C
LRG_274:g.23136T>C
NC_000019.9:g.11218192T>C
NM_000527.4:c.940+2T>C
c.940+2T>C

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001878; dbSNP: rs875989912

NCBI 1000 Genomes Browser:

rs875989912

Molecular consequence:

NM_000527.5:c.940+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001195798.2:c.940+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001195799.2:c.817+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001195800.2:c.436+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001195803.2:c.559+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]

Observations:

Condition(s)

Name:: Hypercholesterolemia, familial, 1
Synonyms:: LDL RECEPTOR DISORDER; Hyperlipoproteinemia Type IIa; HYPER-LOW-DENSITY-LIPOPROTEINEMIA; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0007750; MedGen: C0745103; Orphanet: 391665; OMIM: 143890

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000268592	Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	no assertion criteria provided	Pathogenic (Dec 11, 2015)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000295079	LDLR-LOVD, British Heart Foundation	criteria provided, single submitter (ACGS Guidelines, 2013)	Likely pathogenic (Mar 25, 2016)	germline	literature only	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000599352	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 1, 2016)	germline, not applicable	curation, literature only	PubMed (2) [See all records that cite these PMIDs] 25741868, 19208450
SCV005088709	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	biparental	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	not applicable	not applicable	not provided	not provided	not provided	not provided	not provided	literature only
not provided	biparental	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	curation
not provided	germline	yes	2	not provided	not provided	1	not provided	clinical testing, literature only

Citations

PubMed

Application of molecular genetics for diagnosing familial hypercholesterolemia in Norway: results from a family-based screening program.

Leren TP, Manshaus T, Skovholt U, Skodje T, Nossen IE, Teie C, Sørensen S, Bakken KS.

Semin Vasc Med. 2004 Feb;4(1):75-85. Review.

PubMed [citation]

PMID:: 15199436

Effects of intronic mutations in the LDLR gene on pre-mRNA splicing: Comparison of wet-lab and bioinformatics analyses.

Holla ØL, Nakken S, Mattingsdal M, Ranheim T, Berge KE, Defesche JC, Leren TP.

Mol Genet Metab. 2009 Apr;96(4):245-52. doi: 10.1016/j.ymgme.2008.12.014. Epub 2009 Feb 10.

PubMed [citation]

PMID:: 19208450

See all PubMed Citations (3)

Details of each submission

From Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital, SCV000268592.1

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

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

From LDLR-LOVD, British Heart Foundation, SCV000295079.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	literature only	PubMed (1)

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

From Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge, SCV000599352.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (2)
2	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

"Assay Description:Htz patients' Epstein Barr virus transformed lymphocytes, RNA assays"

PubMed [ID: 19208450]

#	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
2	not applicable	not applicable	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India, SCV005088709.1

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

Description

In-silico tools (Human Splicing Finder and Splice AI) are consistent in predicting to alter the acceptor splice site which may lead to aberrant splicing leading to either the formation of a truncated protein or the transcript to undergo nonsense-mediated mRNA decay. This variant present at a consensus splice site is reported to cause intron inclusion without evidence of degradation of the mutant transcripts (Holla ØL et al., 2009). This variant is reported in the ClinVar database with pathogenic/likely pathogenic interpretation in three independent submissions (ClinVar ID: 226340). The clinical features observed in the proband and her similarly affected sibling are in concordance with hypercholesterolemia, familial, 1.

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

Last Updated: Aug 4, 2024

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