NM_000527.4(LDLR):c.694+2T>C AND Hypercholesterolemia, familial, 1

Germline classification:: Pathogenic/Likely pathogenic (7 submissions)
Last evaluated:: Sep 4, 2020
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:: RCV000003936.19

Allele description [Variation Report for NM_000527.4(LDLR):c.694+2T>C]

NM_000527.4(LDLR):c.694+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_000527.4(LDLR):c.694+2T>C

HGVS:

NC_000019.10:g.11105602T>C
NG_009060.1:g.21222T>C
NM_000527.5:c.694+2T>CMANE SELECT
NM_001195798.2:c.694+2T>C
NM_001195799.2:c.571+2T>C
NM_001195800.2:c.314-1790T>C
NM_001195803.2:c.314-963T>C
LRG_274t1:c.694+2T>C
LRG_274:g.21222T>C
NC_000019.9:g.11216278T>C
NM_000527.4:c.694+2T>C
c.694+2T>C

Nucleotide change:

IVS4, T-C, +2

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000500; OMIM: 606945.0056; dbSNP: rs200238879

NCBI 1000 Genomes Browser:

rs200238879

Molecular consequence:

NM_001195800.2:c.314-1790T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001195803.2:c.314-963T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.694+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001195798.2:c.694+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001195799.2:c.571+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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LOC117100488 [Anneissia japonica]
LOC117100488 [Anneissia japonica]
Gene ID:117100488

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000024101	OMIM	no assertion criteria provided	Pathogenic (Jan 1, 1997)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000294919	LDLR-LOVD, British Heart Foundation	criteria provided, single submitter (ACGS Guidelines, 2013)	Pathogenic (Mar 25, 2016)	germline	literature only	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000503226	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)	Likely pathogenic (Dec 16, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000583730	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]
SCV000607495	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, 9222758
SCV004022252	deCODE genetics, Amgen	no assertion criteria provided	Pathogenic (Jul 21, 2023)	germline	research
SCV004848470	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 4, 2020)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 27135400, 26327206, 9222758, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	yes	5	2	not provided	2601	not provided	clinical testing, literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, research
Icelandic	germline	yes	80	not provided	not provided	not provided	not provided	research

Citations

PubMed

Variants with large effects on blood lipids and the role of cholesterol and triglycerides in coronary disease.

Helgadottir A, Gretarsdottir S, Thorleifsson G, Hjartarson E, Sigurdsson A, Magnusdottir A, Jonasdottir A, Kristjansson H, Sulem P, Oddsson A, Sveinbjornsson G, Steinthorsdottir V, Rafnar T, Masson G, Jonsdottir I, Olafsson I, Eyjolfsson GI, Sigurdardottir O, Daneshpour MS, Khalili D, Azizi F, Swinkels DW, et al.

Nat Genet. 2016 Jun;48(6):634-9. doi: 10.1038/ng.3561. Epub 2016 May 2.

PubMed [citation]

PMID:: 27135400
PMCID:: PMC9136713

A Splice Region Variant in LDLR Lowers Non-high Density Lipoprotein Cholesterol and Protects against Coronary Artery Disease.

Gretarsdottir S, Helgason H, Helgadottir A, Sigurdsson A, Thorleifsson G, Magnusdottir A, Oddsson A, Steinthorsdottir V, Rafnar T, de Graaf J, Daneshpour MS, Hedayati M, Azizi F, Grarup N, Jørgensen T, Vestergaard H, Hansen T, Eyjolfsson G, Sigurdardottir O, Olafsson I, Kiemeney LA, Pedersen O, et al.

PLoS Genet. 2015 Sep;11(9):e1005379. doi: 10.1371/journal.pgen.1005379.

PubMed [citation]

PMID:: 26327206
PMCID:: PMC4556698

See all PubMed Citations (4)

Details of each submission

From OMIM, SCV000024101.2

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

Description

Gudnason et al. (1997) stated that haplotype analysis in 18 apparently unrelated families with FH (FHCL1; 143890) in Iceland has identified at least 5 different chromosomes cosegregating with hypercholesterolemia. The most common haplotype was identified in 11 of the 18 families, indicating a founder mutation. By using SSCP analysis and direct sequencing of amplified DNA, Gudnason et al. (1997) identified a T-to-C transition in the second nucleotide in the 5-prime part of intron 4 of the LDLR gene. This mutation was present in 10 of the 18 families. In half of the cases, these families could be traced to a common ancestor by going back no further than the 18th century. The mutation was predicted to affect correct splicing of exon 4, and analysis at the cellular level demonstrated an abnormal mRNA containing intron 4 sequence in lymphoblastoid cells from a patient carrying the mutation. Translation of the mRNA would lead to a premature stop codon and a truncated nonfunctional protein of 285 amino acids.

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

From LDLR-LOVD, British Heart Foundation, SCV000294919.2

#	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 Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix, SCV000503226.1

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

Description

subject mutated among 2600 FH index cases screened = 1 , family member = 1

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

From U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille, SCV000583730.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	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		3	not provided	2	not provided

From Fundacion Hipercolesterolemia Familiar - SAFEHEART, SCV000607495.1

#	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

"Epstein Barr virus transformed lymphocytes, RNA assays"

PubMed [ID: 9222758]

#	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 deCODE genetics, Amgen, SCV004022252.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Icelandic	80	not provided	not provided	research	not provided

Description

The variant NM_000527.5:c.694+2T>C (chr19:11105602) in LDLR was detected in 41 heterozygotes out of 58K WGS Icelanders (MAF= 0,035%). Following imputation in a set of 166K Icelanders (80 imputed heterozygotes) we observed an association with LDL cholesterol using measurements from 128289 individuals (Effect (SD)= 2.19, P= 1.02e-52), Non-HDL cholesterol using measurements from 136901 individuals (Effect (SD)= 1.99, P= 1.81e-44), pure hypercholesterolaemia using 1515 cases and 283197 controls (OR= 25.81, P= 8.16e-12) and myocardial infarction using 25692 cases and 320832 controls (OR= 4.78, P= 4.69e-06). This variant has been reported in ClinVar previously as pathogenic/likely pathogenic. Based on ACMG criteria (PVS1, PS4, PP5) this variant classifies 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		80	not provided	not provided	not provided

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004848470.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

The c.694+2T>C variant in LDLR has been previously reported as a founder mutation causative for familial hypercholesterolemia in the Icelandic population, as it was identified via haplotype analysis in several affected probands who shared a common ancestor and was reported to segregate with disease (Gudnason 1997 PMID: 9222758). This variant has also been shown to have a statstically significant association to increased non-HDL cholesterol levels and increased risk for coronary artery disease (Helgadottir 2016 PMID: 27135400, Gretarsdottir 2015 PMID: 26327206). It has been reported in ClinVar (Variation ID 3738) but was absent from large population studies. This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. Furthermore, RT-PCR performed on blood cells from a patient heterozygous for this variant revealed abnormal mRNA containing intron 4 sequence (Gudnason 1997 PMID: 9222758). Loss of function of the LDLR gene is an established disease mechanism in autosomal dominant familial hypercholesterolemia. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant familial hypercholesterolemia. ACMG/AMP criteria applied: PP1_Strong, PM2, PVS1_Moderate, PS4_Moderate, PS3_Supporting.

#	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: Sep 29, 2024

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