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 starsreviewed by expert panel
- Somatic classification
of clinical impact: - None
- Review status:
- (0/4) 0 stars out of maximum of 4 starsno assertion criteria provided
- Somatic classification
of oncogenicity: - None
- Review status:
- (0/4) 0 stars out of maximum of 4 starsno assertion criteria provided
- Record status:
- current
- Accession:
- RCV000211645.33
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
This HGVS expression did not pass validation- 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:
- 1
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
Assertion and evidence details
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 | |
SCV000295599 | LDLR-LOVD, British Heart Foundation | criteria provided, single submitter (ACGS Guidelines, 2013) | Likely benign (Mar 25, 2016) | germline | literature only | |
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 | |
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) Kullo Lab Assertion Criteria_01072016.pdf, |
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 | |
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 | |
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 | |
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 | |
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 | |
SCV000782923 | Robarts Research Institute, Western University | criteria provided, single submitter (ACMG Guidelines, 2015) | Likely benign (Jan 2, 2018) | germline | clinical testing | |
SCV001281863 | Illumina Laboratory Services, Illumina | criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) | Uncertain significance (Aug 28, 2018) | germline | clinical testing | |
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 | |
SCV002804653 | Fulgent Genetics, Fulgent Genetics | criteria provided, single submitter (ACMG Guidelines, 2015) | Likely benign (Apr 28, 2022) | unknown | clinical testing |
Summary from all submissions
Ethnicity | Origin | Affected | Individuals | Families | Chromosomes tested | Number Tested | Family history | Method |
---|---|---|---|---|---|---|---|---|
not provided | germline | yes | 10 | 1 | not provided | 2607 | not provided | clinical testing, research, literature only |
not provided | germline | unknown | not provided | not provided | not provided | not provided | not provided | clinical testing, research, 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
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.
- 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.
- PMID:
- 15200491
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
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
# | 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
# | 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
# | 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 |
Last Updated: May 12, 2024
PubMed [ID: 26020417]