NM_000527.5(LDLR):c.1061-8T>C AND Hypercholesterolemia, familial, 1

Germline classification:: Benign (13 submissions)
Last evaluated:: Mar 25, 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:: RCV000030123.31

Allele description [Variation Report for NM_000527.5(LDLR):c.1061-8T>C]

NM_000527.5(LDLR):c.1061-8T>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.1061-8T>C

Other names:

IVS7 as T-C -8; .

HGVS:

NC_000019.10:g.11111506T>C
NG_009060.1:g.27126T>C
NM_000527.5:c.1061-8T>CMANE SELECT
NM_001195798.2:c.1061-8T>C
NM_001195799.2:c.938-8T>C
NM_001195800.2:c.557-8T>C
NM_001195803.2:c.680-8T>C
LRG_274t1:c.1061-8T>C
LRG_274:g.27126T>C
NC_000019.9:g.11222182T>C
NM_000527.4:c.1061-8T>C
NM_001195803.1:c.680-8T>C
c.1061-8T>C

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000154;

Molecular consequence:

NM_000527.5:c.1061-8T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001195798.2:c.1061-8T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001195799.2:c.938-8T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001195800.2:c.557-8T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001195803.2:c.680-8T>C - 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

Recent activity

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recombination activating protein 1, partial [Blennius multifilis]
recombination activating protein 1, partial [Blennius multifilis]
gi|2553036187|gb|WKW49151.1|

Protein
LOC17884861 [Capsella rubella]
LOC17884861 [Capsella rubella]
Gene ID:17884861

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000052778	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	uncertain (Aug 18, 2011)	germline	curation, clinical testing	PubMed (11) [See all records that cite these PMIDs] 8697568, 17765246, 18325082, 15035285, 10735632, 15241806, 15576851, 15998910, 17335829, 18239150, 19007590 Citation Link,
SCV000257699	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	criteria provided, single submitter (DGD Variant Analysis Guidelines)	Likely benign (Jun 17, 2015)	unknown	clinical testing	DGD_Variant_Analysis_Guidelines.docx, Citation Link,
SCV000295183	LDLR-LOVD, British Heart Foundation	criteria provided, single submitter (ACGS Guidelines, 2013)	Benign (Mar 25, 2016)	germline	literature only	PubMed (8) [See all records that cite these PMIDs] 10735632, 10790219, 15576851, 15998910, 9727746, 8697568, 19411563, 20145306 Citation Link,
SCV000322930	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	criteria provided, single submitter (ACMG Guidelines, 2015)	Benign (Mar 1, 2016)	germline	research	PubMed (3) [See all records that cite these PMIDs] 25741868, 19411563, 19208450
SCV000323106	Cardiovascular Biomarker Research Laboratory, Mayo Clinic - RIGHT	criteria provided, single submitter (Mayo Cardiovascular Biomarkers Research Laboratory LDLR variant interpretation criteria, 2015)	Likely benign (Aug 31, 2016)	germline	research	PubMed (1) [See all records that cite this PMID] Kullo Lab Assertion Criteria_01072016.pdf, Citation Link,
SCV000484782	Robarts Research Institute, Western University	criteria provided, single submitter (Wang et al. (Arterioscler Thromb Vasc Biol. 2016))	Benign (Aug 22, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000588550	Laboratory of Genetics and Molecular Cardiology, University of São Paulo - HipercolBrasil	criteria provided, single submitter (ACMG Guidelines, 2015)	Benign (Mar 1, 2016)	germline	research	PubMed (3) [See all records that cite these PMIDs] 25741868, 19411563, 19208450
SCV000606310	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	no assertion criteria provided	Benign	germline	research
SCV000607555	Fundacion Hipercolesterolemia Familiar - SAFEHEART	criteria provided, single submitter (ACMG Guidelines, 2015)	Benign (Mar 1, 2016)	germline	research	PubMed (3) [See all records that cite these PMIDs] 25741868, 19411563, 19208450
SCV000733818	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus	no assertion criteria provided	Benign	germline	clinical testing
SCV001190847	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	no assertion criteria provided	Benign (Feb 5, 2020)	germline	clinical testing
SCV001286365	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Benign (Feb 12, 2018)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 19411563, 17426749, 8697568 Citation Link,
SCV002506403	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	reviewed by expert panel (ClinGen FH ACMG Specifications v1-2)	Benign (Mar 25, 2022)	germline	curation	Citation Link

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	1	not provided	not provided	not provided	not provided	clinical testing, research, curation
not provided	germline	yes	64	not provided	not provided	63	not provided	clinical testing, research, literature only, curation
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
White	germline	no	not provided	not provided	not provided	1013	not provided	research

Citations

PubMed

Familial hypercholesterolaemia in Portugal.

Bourbon M, Alves AC, Medeiros AM, Silva S, Soutar AK; Investigators of Portuguese FH Study..

Atherosclerosis. 2008 Feb;196(2):633-42. Epub 2007 Aug 31.

PubMed [citation]

PMID:: 17765246

Update and analysis of the University College London low density lipoprotein receptor familial hypercholesterolemia database.

Leigh SE, Foster AH, Whittall RA, Hubbart CS, Humphries SE.

Ann Hum Genet. 2008 Jul;72(Pt 4):485-98. doi: 10.1111/j.1469-1809.2008.00436.x. Epub 2008 Mar 5.

PubMed [citation]

PMID:: 18325082

See all PubMed Citations (20)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000052778.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	curation	PubMed (11)
2	not provided	1	not provided	not provided	curation	PubMed (11)
3	not provided	2	not provided	not provided	curation	PubMed (11)
4	not provided	3	not provided	not provided	curation	PubMed (11)
5	not provided	35	not provided	not provided	curation	PubMed (11)
6	not provided	8	not provided	not provided	curation	PubMed (11)
7	not provided	1	not provided	not provided	curation	PubMed (11)
8	not provided	4	not provided	not provided	curation	PubMed (11)
9	not provided	not provided	not provided	not provided	clinical testing	PubMed (11)

Description

"Author mentions this variant found in pt along with two other variants 335del10 and T705I (or GE's T726I with correction factor applied), All three variants found in same allele: 335del10 is predicted to cause truncated protein and pathogenicity of two other variants yet to be determined (T726I is VUS in CRLG db); Controls not tested.": PubMed [ID: 15035285]
"Mentions to have found in Dutch study population of FH pts but number of pts carrying this variant not specified (assumed at least 1), Controls not tested.": PubMed [ID: 10735632]
"The variant found in Spanish pt along with T705I (T726I), both in same allele (not same as pt reported in Jensen_1996 paper above); T726I is a VUS; Controls not tested.": PubMed [ID: 15241806]
"Found in 3 pts; Controls not Tested.": PubMed [ID: 15576851]
"Variant found in high frequency, 35 out of 3600 pts, and described to be in tight LD with T705I; these pts had higner mean cholesterol levels; Controls not tested": PubMed [ID: 15998910]
"Variant found in index pt and 7 affected relatives in het state; affected grandmother did not carry variant (discordant); authors state that variant does NOT cosegregate with disease in this family, Controls not tested": PubMed [ID: 17335829]
"Found in a pt with homozygous FH (14mmol/L----indication for testing is anything more than 7.5mmol/L); compound het with Cys88Tyr; controls not tested.": PubMed [ID: 18239150]
"Variant found in 4 pts, three pts with T705I (T726I) along with this variant, one pt with E31X and T705I (T726I) along with this variant, Controls not tested.": PubMed [ID: 19007590]

Description

Converted during submission to Uncertain significance.

#	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	2	not provided	not provided		2	not provided	not provided	not provided
4	germline	yes	3	not provided	not provided		3	not provided	not provided	not provided
5	germline	yes	35	not provided	not provided		35	not provided	not provided	not provided
6	germline	yes	8	not provided	not provided		8	not provided	not provided	not provided
7	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided
8	germline	yes	4	not provided	not provided		4	not provided	not provided	not provided
9	germline	unknown	not provided	Blood	assert pathogenicity		not provided	not provided	not provided	See 9

Co-occurrences

#	Zygosity	Alleles	Number of Observations
9	SingleHeterozygote	LDLR:c.1959T>C, LDLR:c.1773C>T, LDLR:c.1060+10G>C, LDLR:c.2232A>G, LDLR:c.1413A>G, LDLR:c.2177C>T	1

From Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia, SCV000257699.2

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

From LDLR-LOVD, British Heart Foundation, SCV000295183.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	literature only	PubMed (8)
2	not provided	1	not provided	not provided	literature only	PubMed (8)
3	not provided	1	not provided	not provided	literature only	PubMed (8)
4	not provided	1	not provided	not provided	literature only	PubMed (8)
5	not provided	1	not provided	not provided	literature only	PubMed (8)
6	not provided	1	not provided	not provided	literature only	PubMed (8)
7	not provided	1	not provided	not provided	literature only	PubMed (8)
8	not provided	1	not provided	not provided	literature only	PubMed (8)

#	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
8	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, SCV000322930.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (3)
2	not provided	not provided	not provided	not provided	research	PubMed (3)

Description

%MAF (ExAC):0.642

"Heterozygous patients' lymphocytes, RNA assays / Heterozygous patients' Epstein Barr virus transformed lymphocytes, RNA assays"

PubMed [ID: 19411563]

Description

2/75 Portuguese normolipidemic individuals

#	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
2	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Cardiovascular Biomarker Research Laboratory, Mayo Clinic - RIGHT, SCV000323106.1

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

Description

MAF =<0.3%

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	1013	not provided	assert pathogenicity		not provided	not provided	not provided	not provided

From Robarts Research Institute, Western University, SCV000484782.1

#	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 Laboratory of Genetics and Molecular Cardiology, University of São Paulo - HipercolBrasil, SCV000588550.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (3)
2	not provided	not provided	not provided	not provided	research	PubMed (3)

Description

%MAF(ExAC):0.642

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

PubMed [ID: 19411563]

#	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 Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum, SCV000606310.1

#	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, SCV000607555.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (3)
2	not provided	not provided	not provided	not provided	research	PubMed (3)

Description

%MAF(ExAC):0.642

"Htz patients' lymphocytes, RNA assays / Htz patients' Epstein Barr virus transformed lymphocytes, RNA assays"

PubMed [ID: 19411563]

#	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, SCV000733818.1

#	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 Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City, SCV001190847.1

#	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 Illumina Laboratory Services, Illumina, SCV001286365.1

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

Description

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.

#	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 ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel, SCV002506403.1

#	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.1061-8T>C variant is classified as Benign for Familial Hypercholesterolemia by applying evidence codes (BA1, BS3_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: BA1: PopMax FAF = 0.008564 in African/African American population in gnomAD (gnomAD v2.2.1). BS3_Supporting: Heterozygous patient cells were used for RNA assays (Level 3 experiment) shown normal LDLR transcripts reported from 2 research labs: Bourbon et al, Unidade de Investigacao Cardiovascular, Instituto Nacional de Saude Dr. Ricardo Jorge, Lisboa, Portugal, (PMID 19411563); Holla et al, Medical Genetics Laboratory, Department of Medical Genetics, Rikshospitalet University Hospital, Oslo, Norway, (PMID 19208450). Functional studies is consistent with no damaging effect.

#	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: Nov 3, 2024

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