NM_000527.5(LDLR):c.1586+5G>A AND Hypercholesterolemia, familial, 1

Germline classification:: Conflicting interpretations of pathogenicity (12 submissions)
Last evaluated:: Jun 22, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV000237174.18

Allele description [Variation Report for NM_000527.5(LDLR):c.1586+5G>A]

NM_000527.5(LDLR):c.1586+5G>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.1586+5G>A

HGVS:

NC_000019.10:g.11113767G>A
NG_009060.1:g.29387G>A
NM_000527.5:c.1586+5G>AMANE SELECT
NM_001195798.2:c.1586+5G>A
NM_001195799.2:c.1463+5G>A
NM_001195800.2:c.1082+5G>A
NM_001195803.2:c.1205+5G>A
LRG_274t1:c.1586+5G>A
LRG_274:g.29387G>A
NC_000019.9:g.11224443G>A
NM_000527.4:c.1586+5G>A
c.1586+5G>A

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001463; dbSNP: rs781362878

NCBI 1000 Genomes Browser:

rs781362878

Molecular consequence:

NM_000527.5:c.1586+5G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001195798.2:c.1586+5G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001195799.2:c.1463+5G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001195800.2:c.1082+5G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001195803.2:c.1205+5G>A - intron variant - [Sequence Ontology: SO:0001627]

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
SCV000295512	LDLR-LOVD, British Heart Foundation	criteria provided, single submitter (ACGS Guidelines, 2013)	Likely pathogenic (Mar 25, 2016)	germline	literature only	PubMed (6) [See all records that cite these PMIDs] 10668928, 16250003, 17539906, 19446849, 7635461, 25463123 Citation Link,
SCV000583852	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 30, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000606461	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	no assertion criteria provided	Pathogenic	germline	research
SCV002581306	MGZ Medical Genetics Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Feb 17, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002762690	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSLVariantClassificationCriteria RUGD 01 April 2020)	Likely pathogenic (Apr 29, 2022)	unknown	clinical testing	PubMed (11) [See all records that cite these PMIDs] 10668928, 16250003, 17964958, 27578104, 28964736, 32660911, 32977124, 33418990, 33740630, 34037665, 7635461 Citation Link,
SCV004810144	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Apr 4, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004812558	Molecular Genetics, Royal Melbourne Hospital See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 30, 2023)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 7635461, 10668928, 19208450, 19446849, 25463123, 31345425, 33418990, 25741868
SCV004822567	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (Aug 28, 2023)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 7635461, 10668928, 16250003, 17539906, 19446849, 25463123, 31947532, 32660911, 32977124, 25741868
SCV005068206	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jun 22, 2024)	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	yes	13	1	not provided	2607	not provided	clinical testing, literature only, research
not provided	germline	unknown	3	not provided	not provided	108544	not provided	clinical testing, research
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

LDLR and ApoB are major genetic causes of autosomal dominant hypercholesterolemia in a Taiwanese population.

Yang KC, Su YN, Shew JY, Yang KY, Tseng WK, Wu CC, Lee YT.

J Formos Med Assoc. 2007 Oct;106(10):799-807.

PubMed [citation]

PMID:: 17964958

Genetic causes of monogenic familial hypercholesterolemia in the Greek population: Lessons, mistakes, and the way forward.

Mollaki V, Drogari E.

J Clin Lipidol. 2016 Jul-Aug;10(4):748-756. doi: 10.1016/j.jacl.2016.02.020. Epub 2016 Mar 23. Review.

PubMed [citation]

PMID:: 27578104

See all PubMed Citations (18)

Details of each submission

From LDLR-LOVD, British Heart Foundation, SCV000295512.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	literature only	PubMed (6)
2	not provided	1	not provided	not provided	literature only	PubMed (6)
3	not provided	1	not provided	not provided	literature only	PubMed (6)
4	not provided	1	not provided	not provided	literature only	PubMed (6)
5	not provided	1	not provided	not provided	literature only	PubMed (6)
6	not provided	1	not provided	not provided	literature only	PubMed (6)

#	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
2	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided
3	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided
4	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided
5	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided
6	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

From Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix, SCV000503370.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (1)

Description

subjects mutated among 2600 FH index cases screened = 2

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	2600	not provided	not provided		2	not provided	not provided	not provided

From U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille, SCV000583852.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (1)

Description

Dutch Lipid Clinic Scoring : Definite FH

#	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		2	not provided	1	not provided

From Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum, SCV000606461.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	not provided

#	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 Fundacion Hipercolesterolemia Familiar - SAFEHEART, SCV000607609.1

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

Description

%MAF(ExAC):0.003401

"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	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia, SCV001432658.1

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

#	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 MGZ Medical Genetics Center, SCV002581306.1

#	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 Illumina Laboratory Services, Illumina, SCV002762690.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (11)

Description

The LDLR c.1586+5G>A variant, also known as c.1592+5G>A, occurs in a splice region and results in the substitution of a guanine at nucleotide position c.1586+5 with an adenine. Across a selection of the available literature, the c.1586+5G>A variant has been identified in at least seven individuals with clinically diagnosed familial hypercholesterolemia and was shown to segregate with the disorder (Ekstrom et al. 1995; Jensen et al. 1999; Fouchier et al. 2005; Mollaki et al. 2016; Bertolini et al. 2020; Meshkov et al. 2020; Lamiquiz-Moneo et al. 2021; Leren et al. 2021; Sturm et al. 2021). Another variant at the same nucleotide position, has been reported as c.1592+5G>C in a heterozygous state in three individuals with familial hypercholesterolemia (Yang et al. 2007; Defesche et al. 2017). This variant is reported in the Genome Aggregation Database in six alleles at a frequency of 0.000196 in the South Asian population (version 2.1.1). Analysis of mRNA from patient cells with sequence analysis found that the c.1586+5G>A variant results in alternate RNA splicing mechanisms that cause the activation of a cryptic splice site within intron 10 or skipping of exon 10 and causes defects in receptor transport in vitro (Jensen et al. 1999). Based on the available evidence, the c.1586+5G>A variant is classified as likely pathogenic for familial hypercholesterolemia.

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

From Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, SCV004810144.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Molecular Genetics, Royal Melbourne Hospital, SCV004812558.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This sequence change in LDLR is an intronic variant located in intron 10 (also described as c.1592+5G>A). The highest population minor allele frequency in gnomAD v2.1 is 0.02% (6/30,588 alleles) in the South Asian population, which is lower than the credible allele frequency for this LDLR. This variant has been reported in at least 10 probands/families meeting a clinical diagnosis of familial hypercholesterolaemia and segregates with disease in multiple families (PMID: 7635461, 10668928, 19208450, 19446849, 25463123, 31345425, 33418990; ClinVar: SCV000503370.1, SCV000583852.1). The results from multiple in silico splicing predictors (SpliceAI, MaxEntScan, NNSplice) indicate that this variant may impact splicing by disrupting the donor splice site of intron 10 of LDLR. This prediction is confirmed by RT-PCR of EBV-transformed lymphocytes. The assay demonstrated that the variant impacts splicing by causing in-frame exon 10 skipping and 66 bp insertion of intron 10 through cryptic donor site activation (PMID: 10668928, 19208450). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as PATHOGENIC. Following criteria are met: PS4, PP1_Strong, PS3_Supporting, PM2_Supporting, PP3.

#	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

From All of Us Research Program, National Institutes of Health, SCV004822567.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	not provided	not provided	clinical testing	PubMed (10)

Description

This variant causes a G to A nucleotide substitution at the +5 position of intron 10 of the LDLR gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Molecular studies of the impact of this variant on RNA splicing demonstrated two aberrant mRNAs due to either in-frame skipping of exon 10 or the activation of a cryptic splice site in intron 10 inserting 66 intronic base pairs (PMID: 10668928). Additionally, this variant was shown to cause aberrant LDL receptor trafficking in transfected COS7 cells (PMID: 10668928). This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 7635461, 10668928, 16250003, 17539906, 19446849, 25463123, 32660911). This variant has also been observed in compound heterozygous state in individuals affected with homozygous familial hypercholesterolemia (PMID: 31947532, 32977124), indicating that this variant contributes to disease. It has been shown that this variant segregates with disease in multiple affected individuals in one family (PMID: 10668928). This variant has been identified in 8/250846 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of LDLR function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		3	not provided	not provided	not provided

From Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics, SCV005068206.1

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

Description

A heterozygous 5’ splice site proximal variant in intron 10 of the LDLR gene that affects the position 5 nucleotides downstream of exon 10 was detected. The observed variant c.1586+5G>A has not been reported in the 1000 genomes, gnomAD (v3.1) and gnomAD (v2.1) databases and has a minor allele frequency of 0.0004% in the topmed database. The reference base is conserved across species. In summary, the variant meets our criteria to be classified as a variant of uncertain significance.

#	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

Flagged submissions

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000503370	Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	flagged submission Reason: Older and outlier claim with insufficient supporting evidence Notes: None (ACMG Guidelines, 2015)	Uncertain significance (Dec 16, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000607609	Fundacion Hipercolesterolemia Familiar - SAFEHEART	flagged submission Reason: Older and outlier claim with insufficient supporting evidence Notes: None (ACMG Guidelines, 2015)	Uncertain significance (Mar 1, 2016)	germline	research	PubMed (2) [See all records that cite these PMIDs] 25741868, 19208450
SCV001432658	Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	flagged submission Reason: Older and outlier claim with insufficient supporting evidence Notes: None (ACMG Guidelines, 2015)	Uncertain significance (Jun 5, 2019)	germline	research	PubMed (2) [See all records that cite these PMIDs] 25741868, 31345425

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000503370

Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix

flagged submission

Reason: Older and outlier claim with insufficient supporting evidence

Notes: None