NM_000527.5(LDLR):c.1706-10G>A AND Hypercholesterolemia, familial, 1

Germline classification:: Likely benign (16 submissions)
Last evaluated:: Mar 16, 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:: RCV000211645.34

Allele description [Variation Report for NM_000527.5(LDLR):c.1706-10G>A]

NM_000527.5(LDLR):c.1706-10G>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.1706-10G>A

Other names:

HGVS:

NC_000019.10:g.11116849G>A
NG_009060.1:g.32469G>A
NM_000527.5:c.1706-10G>AMANE SELECT
NM_001195798.2:c.1706-10G>A
NM_001195799.2:c.1583-10G>A
NM_001195800.2:c.1202-10G>A
NM_001195803.2:c.1325-10G>A
LRG_274t1:c.1706-10G>A
LRG_274:g.32469G>A
NC_000019.9:g.11227525G>A
NM_000527.4:c.1706-10G>A
c.1706-10G>A

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000229;

Molecular consequence:

NM_000527.5:c.1706-10G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001195798.2:c.1706-10G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001195799.2:c.1583-10G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001195800.2:c.1202-10G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001195803.2:c.1325-10G>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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Ralstonia pickettii strain DSM6297 flagellin (fliC) gene, partial cds
Ralstonia pickettii strain DSM6297 flagellin (fliC) gene, partial cds
gi|28974936|gb|AY192717.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000268631	Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	no assertion criteria provided	Benign (Apr 2, 2015)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000295599	LDLR-LOVD, British Heart Foundation	criteria provided, single submitter (ACGS Guidelines, 2013)	Likely benign (Mar 25, 2016)	germline	literature only	PubMed (7) [See all records that cite these PMIDs] 10206683, 11810272, 15200491, 15556094, 19446849, 16542394, 20145306 Citation Link,
SCV000322971	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign (Mar 1, 2016)	germline	research	PubMed (3) [See all records that cite these PMIDs] 25741868, 26020417, 19208450
SCV000323103	Cardiovascular Biomarker Research Laboratory, Mayo Clinic - RIGHT	criteria provided, single submitter (Mayo Cardiovascular Biomarkers Research Laboratory LDLR variant interpretation criteria, 2015)	Uncertain significance (Aug 31, 2016)	germline	research	PubMed (1) [See all records that cite this PMID] Kullo Lab Assertion Criteria_01072016.pdf, Citation Link,
SCV000503394	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)	Benign (Dec 16, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000583867	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign (Mar 30, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000588603	Laboratory of Genetics and Molecular Cardiology, University of São Paulo - HipercolBrasil	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign (Mar 1, 2016)	germline	research	PubMed (3) [See all records that cite these PMIDs] 25741868, 25741862, 19208450
SCV000606493	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	no assertion criteria provided	Benign	germline	research
SCV000607628	Fundacion Hipercolesterolemia Familiar - SAFEHEART	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign (Mar 1, 2016)	germline	research	PubMed (3) [See all records that cite these PMIDs] 25741868, 26020417, 19208450
SCV000733826	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus	no assertion criteria provided	Likely benign	germline	clinical testing
SCV000748152	Iberoamerican FH Network	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign (Mar 1, 2016)	germline	research	PubMed (3) [See all records that cite these PMIDs] 25741868, 25741862, 19208450
SCV000782923	Robarts Research Institute, Western University	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign (Jan 2, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001281863	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Uncertain significance (Aug 28, 2018)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 15241806, 19208450, 10206683 Citation Link,
SCV002506376	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	reviewed by expert panel (ClinGen FH ACMG Specifications v1-2)	Likely benign (Mar 16, 2022)	germline	curation	Citation Link,
SCV002804653	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign (Apr 28, 2022)	unknown	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, research, curation
not provided	germline	yes	10	1	not provided	2607	not provided	clinical testing, research, literature only
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

The molecular basis of familial hypercholesterolemia in The Netherlands.

Fouchier SW, Defesche JC, Umans-Eckenhausen MW, Kastelein JP.

Hum Genet. 2001 Dec;109(6):602-15. Epub 2001 Nov 9.

PubMed [citation]

PMID:: 11810272

FH clinical phenotype in Greek patients with LDL-R defective vs. negative mutations.

Dedoussis GV, Skoumas J, Pitsavos C, Choumerianou DM, Genschel J, Schmidt H, Stefanadis C.

Eur J Clin Invest. 2004 Jun;34(6):402-9.

PubMed [citation]

PMID:: 15200491

See all PubMed Citations (13)

Details of each submission

From Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital, SCV000268631.1

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

From LDLR-LOVD, British Heart Foundation, SCV000295599.2

#	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 Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia, SCV000296925.3

#	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 Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge, SCV000322971.1

#	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):0.2529

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

PubMed [ID: 26020417]

Description

1/125 non-FH 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, SCV000323103.1

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

Description

MAF =<0.3%, LDL-C >=160 mg/dL

#	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 Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix, SCV000503394.1

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

Description

subjects mutated among 2600 FH index cases screened = 15

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

From U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille, SCV000583867.1

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

Description

Dutch Lipid Clinic Scoring : Possible 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		1	not provided	1	not provided

From Laboratory of Genetics and Molecular Cardiology, University of São Paulo - HipercolBrasil, SCV000588603.1

#	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):0.2529

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

PubMed [ID: 25741862]

#	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, SCV000606493.1

#	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, SCV000607628.1

#	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):0.2529

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

PubMed [ID: 26020417]

#	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, SCV000733826.1

#	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 Iberoamerican FH Network, SCV000748152.1

#	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):0.2529

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

PubMed [ID: 25741862]

#	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 Robarts Research Institute, Western University, SCV000782923.1

#	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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Illumina Laboratory Services, Illumina, SCV001281863.1

#	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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

#	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, SCV002506376.1

#	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.1706-10G>A variant is classified as Likely benign for Familial Hypercholesterolemia by applying evidence codes BS1, BS3_supporting and PP1_moderate 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: BS1 - FAF = 0.002911 (0.2911%) in Latino/Admixed American exomes (gnomAD v2.1.1), so BS1 is Met. BS3_supporting - 2 Level 3 assays: PMID: 25741862: Heterozygous patients' lymphocytes, RNA assays - result - Normal LDLR transcripts identified by sequencing. PMID: 19208450: Heterozygous patients' Epstein Barr virus transformed lymphocytes, RNA assays - result - Normal LDLR transcripts, 43% of mutant transcripts (from total transcripts) in htz cells. ---- Aberrant transcripts are not detected, so BS3_Supporting is Met. PP1_moderate - Variant segregates with FH phenotype in at least 5 informative meiosis from 2 families from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge: 5 affected family members have the variant, so PP1_Moderate is Met. Variant has 1 Strong plus 1 Supporting evidence codes towards Benign, enough to classify as Likely benign and only 1 Moderate evidence code towards Pathogenic, not enough for Likely pathogenic, so we are confident in classifying this variant as Likely 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 Fulgent Genetics, Fulgent Genetics, SCV002804653.1

#	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

Flagged submissions

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000296925	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	flagged submission Reason: Conflicts with expert reviewed submission without evidence to support different classification Notes: None (DGD Variant Analysis Guidelines)	Uncertain significance (Sep 2, 2015)	unknown	clinical testing	DGD_Variant_Analysis_Guidelines.docx Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000296925

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

flagged submission

Reason: Conflicts with expert reviewed submission without evidence to support different classification

Notes: None

(DGD Variant Analysis Guidelines)

Uncertain significance
(Sep 2, 2015)

unknown

clinical testing

DGD_Variant_Analysis_Guidelines.docx

Citation Link

Last Updated: Oct 20, 2024

Relating variation to medicine