NM_000527.5(LDLR):c.190+4A>T AND Familial hypercholesterolemia

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Jan 19, 2024
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:: RCV000771311.14

Allele description [Variation Report for NM_000527.5(LDLR):c.190+4A>T]

NM_000527.5(LDLR):c.190+4A>T

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.190+4A>T

Other names:

IVS2 ds A-T +4

HGVS:

NC_000019.10:g.11100349A>T
NG_009060.1:g.15969A>T
NM_000527.5:c.190+4A>TMANE SELECT
NM_001195798.2:c.190+4A>T
NM_001195799.2:c.190+4A>T
NM_001195800.2:c.190+4A>T
NM_001195803.2:c.190+4A>T
LRG_274t1:c.190+4A>T
LRG_274:g.15969A>T
NC_000019.9:g.11211025A>T
NM_000527.4:c.190+4A>T
c.190+4A>T

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000028; dbSNP: rs769446356

NCBI 1000 Genomes Browser:

rs769446356

Molecular consequence:

NM_000527.5:c.190+4A>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001195798.2:c.190+4A>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001195799.2:c.190+4A>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001195800.2:c.190+4A>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001195803.2:c.190+4A>T - intron variant - [Sequence Ontology: SO:0001627]

Condition(s)

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

Recent activity

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LOC112904125 [Agrilus planipennis]
LOC112904125 [Agrilus planipennis]
Gene ID:112904125

Gene
CDS1 [Pan paniscus]
CDS1 [Pan paniscus]
Gene ID:100993468

Gene
CDIPT [Pan paniscus]
CDIPT [Pan paniscus]
Gene ID:100974496

Gene
Nigericin
Nigericin
A polyether antibiotic which affects ion transport and ATPase activity in mitochondria. It is produced by Streptomyces hygroscopicus. (From Merck Index, 11th ed)...<br/>Year introduced: 1991(1975)

MeSH
MIR595 microRNA 595 [Homo sapiens]
MIR595 microRNA 595 [Homo sapiens]
Gene ID:693180

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000752427	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 19, 2024)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 15199436, 16205024, 16250003, 21418584, 27765764, 19208450, 17576681, 9536098, 28492532
SCV000903567	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 22, 2022)	germline	clinical testing	PubMed (12) [See all records that cite these PMIDs] 16205024, 16250003, 16792510, 19208450, 21418584, 22883975, 23680767, 24075752, 25682442, 27765764, 31345425, 25741868
SCV001361873	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Feb 6, 2019)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 15199436, 16205024, 19208450, 16250003, 20236128, 21418584 Citation Link,
SCV001435003	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 30, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001445925	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 9, 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
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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

Statistical features of human exons and their flanking regions.

Zhang MQ.

Hum Mol Genet. 1998 May;7(5):919-32.

PubMed [citation]

PMID:: 9536098

See all PubMed Citations (17)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000752427.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

This sequence change falls in intron 2 of the LDLR gene. It does not directly change the encoded amino acid sequence of the LDLR protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs769446356, gnomAD 0.02%). This variant has been observed in individuals with familial hypercholesterolemia (PMID: 15199436, 16205024, 16250003, 21418584, 27765764). ClinVar contains an entry for this variant (Variation ID: 225097). Studies have shown that this variant alters LDLR gene expression (PMID: 19208450). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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.

#	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 Color Diagnostics, LLC DBA Color Health, SCV000903567.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (12)

Description

This variant causes an A>T nucleotide substitution at the +4 position of intron 2 of the LDLR gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. A functional RNA study has demonstrated that this variant causes aberrant splicing and degradation of the mutant transcript (PMID: 19208450). Lymphocytes from a heterozygous carrier showed that the levels of cell-surface LDLR protein and internalized LDL were decreased by ~40% and ~55%, respectively, compared to normal cells (PMID: 19208450). This variant has been reported in at least fifteen individuals diagnosed with familial hypercholesterolemia (PMID: 16205024, 16250003, 16792510, 21418584, 22883975, 23680767, 24075752, 25682442, 27765764, 31345425). This variant has been identified in 5/281964 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of LDLR function is a known mechanism of disease. Based on available evidence, this variant 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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001361873.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

Variant summary: The variant, LDLR c.190+4A>T alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 5 splicing donor site. Two predict the variant weakens a 5' donor site. A functional study, Holla_2009, detected aberrant splicing and found the variant to cause a decrease in LDLR at the cell surface (~40% of normal) and internalization (~55% of normal). The variant allele was found at a frequency of 1.8e-05 in 276542 control chromosomes (gnomAD). c.190+4A>T has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (Al-Khateeb_2011, Fouchier_2005, Taylor_2010, Leren_2004, Punzalan_2005). These data indicate that the variant is very likely to be associated with disease. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant three times as likely pathogenic/pathogenic and once as uncertain significance. Based on the evidence outlined above, the variant was 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, SCV001435003.1

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

Description

The c.190+4A>T variant in the LDLR gene in intron 2 is predicted to disrupts splicing resulting in an abnormal mRNA transcript. This variant has been reported in multiple unrelated individuals with familial hypercholesterolemia (PMID: 15199436, 16205024, 21418584, 27765764). Functional studies have shown reduced internalization and cell surface LDLR protein when this variant is present (PMID: 19208450). The c.190+4A>T variant in the LDLR gene is classified as likely 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 Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego, SCV001445925.1

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

Description

This variant has been previously reported as a heterozygous change in patients with familial hypercholesterolemia (PMID: 15199436, 16205024, 16250003, 21418584, 27765764). Functional studies conducted in EBV-transformed lymphocytes demonstrated that this variant leads to reduced LDLR transcript levels, reduced LDLR protein present at the cell surface, and reduced levels of internalized LDL (PMID: 19208450). This variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.002% (5/276382) and thus is presumed to be rare. Multiple splice prediction tools suggest this variant is likely to interfere with normal splicing. Based on the available evidence, the c.190+4A>T variant is classified as Pathogenic.

#	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		not provided	not provided	not provided	not provided

Last Updated: Nov 3, 2024

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