NM_000527.5(LDLR):c.1359-1G>A AND Hypercholesterolemia, familial, 1

Germline classification:: Pathogenic (15 submissions)
Last evaluated:: Aug 28, 2022
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV000172962.34

Allele description [Variation Report for NM_000527.5(LDLR):c.1359-1G>A]

NM_000527.5(LDLR):c.1359-1G>A

Genes:

LDLR:low density lipoprotein receptor [Gene - OMIM - HGNC]
MIR6886:microRNA 6886 [Gene - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

19p13.2

Genomic location:

Preferred name:

NM_000527.5(LDLR):c.1359-1G>A

Other names:

IVS9 as G-A -1

HGVS:

NC_000019.10:g.11113534G>A
NG_009060.1:g.29154G>A
NM_000527.5:c.1359-1G>AMANE SELECT
NM_001195798.2:c.1359-1G>A
NM_001195799.2:c.1236-1G>A
NM_001195800.2:c.855-1G>A
NM_001195803.2:c.978-1G>A
LRG_274t1:c.1359-1G>A
LRG_274:g.29154G>A
NC_000019.9:g.11224210G>A
NM_000527.4:c.1359-1G>A
NR_106946.1:n.61G>A
c.1359-1G>A

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001405; dbSNP: rs139617694

NCBI 1000 Genomes Browser:

rs139617694

Molecular consequence:

NR_106946.1:n.61G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NM_000527.5:c.1359-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001195798.2:c.1359-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001195799.2:c.1236-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001195800.2:c.855-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001195803.2:c.978-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]

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

Recent activity

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Rhodobacter sphaeroides strain RSF3 16S ribosomal RNA gene, partial sequence
Rhodobacter sphaeroides strain RSF3 16S ribosomal RNA gene, partial sequence
gi|557836197|gb|KF606893.1|

Nucleotide
Cereibacter sphaeroides strain PNSBFraternidad_1 16S ribosomal RNA gene, partial...
Cereibacter sphaeroides strain PNSBFraternidad_1 16S ribosomal RNA gene, partial sequence
gi|1018684906|gb|KU992651.1|

Nucleotide
Garymunida squamosa voucher NMV<AUS>:J57243 cytochrome oxidase subunit I (COI) g...
Garymunida squamosa voucher NMV<AUS>:J57243 cytochrome oxidase subunit I (COI) gene, partial cds; mitochondrial
gi|1865527867|gb|MK848030.1|

Nucleotide
cytochrome c oxidase subunit I, partial (mitochondrion) [Celastrina lavendularis...
cytochrome c oxidase subunit I, partial (mitochondrion) [Celastrina lavendularis limbata]
gi|2644499093|gb|WRI52353.1|

Protein
4930488B01Rik RIKEN cDNA 4930488B01 gene [Mus musculus]
4930488B01Rik RIKEN cDNA 4930488B01 gene [Mus musculus]
Gene ID:75036

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000212138	Institute for Integrative and Experimental Genomics, University of Luebeck	criteria provided, single submitter (Submitter's publication)	Likely pathogenic	germline	research	PubMed (1) [See all records that cite this PMID]
SCV000268613	Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	no assertion criteria provided	Pathogenic (Mar 17, 2014)	germline	clinical testing
SCV000295393	LDLR-LOVD, British Heart Foundation	criteria provided, single submitter (ACGS Guidelines, 2013)	Likely pathogenic (Mar 25, 2016)	germline	literature only	PubMed (7) [See all records that cite these PMIDs] 11668640, 11857755, 12436241, 7616128, 9254862, 15199436, 25154303 Citation Link,
SCV000484787	Robarts Research Institute, Western University	criteria provided, single submitter (Wang et al. (Arterioscler Thromb Vasc Biol. 2016))	Likely pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000503342	Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 16, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000583825	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 30, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000606409	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	no assertion criteria provided	Pathogenic	germline	research
SCV000607593	Fundacion Hipercolesterolemia Familiar - SAFEHEART	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 1, 2016)	germline	research	PubMed (2) [See all records that cite these PMIDs] 25741868, 19208450
SCV000733821	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV002568030	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	reviewed by expert panel (ClinGen FH ACMG Specifications v1-2)	Pathogenic (Aug 28, 2022)	germline	curation	Citation Link,
SCV002798849	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 7, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003825400	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 10, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004046792	Institute of Human Genetics, University Hospital of Duesseldorf	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	not provided	PubMed (1) [See all records that cite this PMID]
SCV004171581	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	no assertion criteria provided	Pathogenic (Nov 24, 2023)	germline	clinical testing
SCV004829745	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 18, 2023)	germline	clinical testing	PubMed (14) [See all records that cite these PMIDs] 7616128, 9254862, 10090473, 10735632, 11668640, 11857755, 12436241, 15241806, 21382890, 21475731, 25154303, 33955087, 34037665, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	40	1	not provided	2607	not provided	clinical testing, research, literature only, not provided
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	3	not provided	not provided	108544	not provided	clinical testing, research, curation

Citations

PubMed

Systematic analysis of variants related to familial hypercholesterolemia in families with premature myocardial infarction.

Brænne I, Kleinecke M, Reiz B, Graf E, Strom T, Wieland T, Fischer M, Kessler T, Hengstenberg C, Meitinger T, Erdmann J, Schunkert H.

Eur J Hum Genet. 2016 Feb;24(2):191-7. doi: 10.1038/ejhg.2015.100. Epub 2015 Jun 3.

PubMed [citation]

PMID:: 26036859
PMCID:: PMC4717192

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

See all PubMed Citations (18)

Details of each submission

From Institute for Integrative and Experimental Genomics, University of Luebeck, SCV000212138.1

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

From Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital, SCV000268613.1

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

#	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, SCV000295393.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	literature only	PubMed (7)
2	not provided	1	not provided	not provided	literature only	PubMed (7)
3	not provided	1	not provided	not provided	literature only	PubMed (7)
4	not provided	1	not provided	not provided	literature only	PubMed (7)
5	not provided	1	not provided	not provided	literature only	PubMed (7)
6	not provided	1	not provided	not provided	literature only	PubMed (7)
7	not provided	1	not provided	not provided	literature only	PubMed (7)

#	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
7	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

From Robarts Research Institute, Western University, SCV000484787.1

#	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 Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix, SCV000503342.1

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

Description

subjects mutated among 2600 FH index cases screened = 11 , family members = 2 with co-segregation / previously described in association with FH

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	2600	not provided	not provided		11	not provided	not provided	not provided

From U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille, SCV000583825.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	20	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		20	not provided	13	not provided

From Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum, SCV000606409.1

#	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, SCV000607593.1

#	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

"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 Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus, SCV000733821.1

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

#	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 ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel, SCV002568030.1

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

Description

The NM_000527.5(LDLR):c.1359-1G>A variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PVS1, PP1_Strong, PS4, PM2, PP4 and PS3_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PVS1 - variant is in canonical - 1 splice site and causes a frameshift in exon 10 (p.Thr454Leufs*51, from Holla et al., 2009 (PMID 19208450)), so PVS1 is met. PP1_strong - variant segregates with FH phenotype in 9 informative meiosis from at least 5 families: - 5 informative meiosis from 4 families from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière): 5 relatives with the variant have LDL-C >75th percentile. - 4 informative meiosis from at least 1 family from Mayo lab (Mayo Clinic Atherosclerosis and Lipid Genomics Laboratory), Ambry lab (Ambry Genetics) and Arca lab (Research Lab of Molecular Genetics of Lipid Metabolism - Prof. M.Arca), but are confirmed to be the same: 2 relatives with the variant had LDL >75th percentile and 2 relatives negative for variant had LDL <50th percentile. --- so PP1_Strong is met. PS4 - variant meets PM2 and was identified in: - 25 unrelated index cases (22 cases with DLCN >=6, 3 with possible Simon Broome FH from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière), France; - 2 unrelated index cases (MFH101: DLCN of 8, MFH116: meets MEDPED definite) reported by Mayo lab (Mayo Clinic Atherosclerosis and Lipid Genomics Laboratory), Ambry lab (Ambry Genetics) and Arca lab (Research Lab of Molecular Genetics of Lipid Metabolism - Prof. M.Arca), but are confirmed to be the same; - 1 index case with Dutch lipid clinic network >=6 from Robarts Research Institute, Canada; - 1 index case with DLCN >= 6 from Color Health, Inc., USA. --- 29 cases (no additional bibliographic search was done because number of index cases is already over 10), so PS4 is met. PM2 - PopMax MAF = 0.00002940 (0.003%) in European non-Finnish genomes (gnomAD v3.1.2). It is below 0.02%, so PM2 is met. PP4 - variant meets PM2 and was identified in at least 29 unrelated index cases (see PS4 for details), so PP4 is met. PS3_supporting - Level 2/3 FS: Holla et al., 2009 (PMID 19208450): Htz patients' Epstein Barr virus transformed lymphocytes, RNA assays - results: skipping of the first 7 nts from exon 10 in 23% of mRNAs (p.Thr454Leufs*51) --- aberrant transcript is confirmed by sequencing and is quantified, but it is not above 25% of total transcript, so PS3_Supporting is met.

#	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 Fulgent Genetics, Fulgent Genetics, SCV002798849.1

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV003825400.2

#	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 Institute of Human Genetics, University Hospital of Duesseldorf, SCV004046792.1

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

From Zotz-Klimas Genetics Lab, MVZ Zotz Klimas, SCV004171581.1

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

#	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, SCV004829745.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	not provided	not provided	clinical testing	PubMed (14)

Description

This variant causes a G to A nucleotide substitution at the -1 position of intron 9 of the LDLR gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. A quantitative RNA study has shown that this variant causes a deletion of the first seven nucleotides of exon 10 due to a cryptic splice acceptor activation, and is expected to cause a frameshift and premature truncation (PMID: 10090473). This variant has been reported in hundreds of individuals affected with familial hypercholesterolemia (PMID: 7616128, 9254862, 10090473, 10735632, 11668640, 11857755, 12436241, 15241806, 21382890, 21475731, 25154303, 33955087, 34037665). It has been shown that this variant segregates with disease in multiple affected individuals in two families (PMID: 9254862, 25154303). This variant has not been identified 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 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

Last Updated: Oct 26, 2024

Relating variation to medicine