NM_000527.5(LDLR):c.2177C>T (p.Thr726Ile) AND Hypercholesterolemia, familial, 1
- Germline classification:
- Benign (15 submissions)
- Last evaluated:
- May 24, 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:
- RCV000030134.35
Allele description [Variation Report for NM_000527.5(LDLR):c.2177C>T (p.Thr726Ile)]
NM_000527.5(LDLR):c.2177C>T (p.Thr726Ile)
- 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.2177C>T (p.Thr726Ile)
- Other names:
- FH Paris-9; NM_000527.5(LDLR):c.2177C>T
- HGVS:
- NC_000019.10:g.11123210C>T
- NG_009060.1:g.38830C>T
- NM_000527.5:c.2177C>TMANE SELECT
- NM_001195798.2:c.2177C>T
- NM_001195799.2:c.2054C>T
- NM_001195800.2:c.1673C>T
- NM_001195803.2:c.1643C>T
- NP_000518.1:p.Thr726Ile
- NP_000518.1:p.Thr726Ile
- NP_001182727.1:p.Thr726Ile
- NP_001182728.1:p.Thr685Ile
- NP_001182729.1:p.Thr558Ile
- NP_001182732.1:p.Thr548Ile
- LRG_274t1:c.2177C>T
- LRG_274:g.38830C>T
- LRG_274p1:p.Thr726Ile
- NC_000019.9:g.11233886C>T
- NM_000527.4:c.2177C>T
- P01130:p.Thr726Ile
- c.2177C>T
This HGVS expression did not pass validation- Protein change:
- T548I
- Links:
- LDLR-LOVD, British Heart Foundation: LDLR_001613; UniProtKB: P01130#VAR_005413
- Molecular consequence:
- NM_000527.5:c.2177C>T - missense variant - [Sequence Ontology: SO:0001583]
- NM_001195798.2:c.2177C>T - missense variant - [Sequence Ontology: SO:0001583]
- NM_001195799.2:c.2054C>T - missense variant - [Sequence Ontology: SO:0001583]
- NM_001195800.2:c.1673C>T - missense variant - [Sequence Ontology: SO:0001583]
- NM_001195803.2:c.1643C>T - missense variant - [Sequence Ontology: SO:0001583]
- Functional consequence:
- no known functional consequence - Comment(s)
- non-disruptive missense
- Observations:
- 25
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 |
---|---|---|---|---|---|---|
SCV000212141 | Institute for Integrative and Experimental Genomics, University of Luebeck | criteria provided, single submitter (Submitter's publication) | Likely benign | germline | research | |
SCV000295909 | LDLR-LOVD, British Heart Foundation | criteria provided, single submitter (ACGS Guidelines, 2013) | Benign (Mar 25, 2016) | germline | literature only | |
SCV000296927 | Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia | criteria provided, single submitter (DGD Variant Analysis Guidelines) | Benign (Jul 20, 2015) | unknown | clinical testing | DGD_Variant_Analysis_Guidelines.docx, |
SCV000323004 | Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge | criteria provided, single submitter (ACMG Guidelines, 2015) | Benign (Mar 1, 2016) | germline | research | |
SCV000323104 | 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) Kullo Lab Assertion Criteria_01072016.pdf, |
SCV000503472 | 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 | |
SCV000540902 | Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation
| criteria provided, single submitter (ACMG Guidelines, 2015) | Benign (Mar 23, 2017) | unknown | clinical testing | |
SCV000588642 | Laboratory of Genetics and Molecular Cardiology, University of São Paulo - HipercolBrasil | criteria provided, single submitter (ACMG Guidelines, 2015) | Benign (Mar 1, 2016) | germline | research | |
SCV000606613 | Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum | no assertion criteria provided | Benign | germline | research | |
SCV000607682 | Fundacion Hipercolesterolemia Familiar - SAFEHEART | criteria provided, single submitter (ACMG Guidelines, 2015) | Benign (Mar 1, 2016) | germline | research | |
SCV000733831 | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus | no assertion criteria provided | Benign | germline | clinical testing | |
SCV000748059 | Iberoamerican FH Network | criteria provided, single submitter (ACMG Guidelines, 2015) | Benign (Mar 1, 2016) | germline | research | |
SCV000782936 | Robarts Research Institute, Western University | criteria provided, single submitter (ACMG Guidelines, 2015) | Benign (Jan 2, 2018) | germline | clinical testing | |
SCV001286052 | Illumina Laboratory Services, Illumina | criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) | Benign (Apr 10, 2018) | germline | clinical testing | |
SCV002817169 | ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel | reviewed by expert panel (ClinGen FH ACMG Specifications v1-2) | Benign (May 24, 2022) | germline | curation |
Summary from all submissions
Ethnicity | Origin | Affected | Individuals | Families | Chromosomes tested | Number Tested | Family history | Method |
---|---|---|---|---|---|---|---|---|
not provided | germline | no | 6 | 6 | not provided | 6 | not provided | research, literature only |
not provided | unknown | unknown | not provided | not provided | not provided | not provided | not provided | clinical testing |
not provided | germline | yes | 21 | not provided | not provided | 2604 | 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 |
Caucasian | unknown | yes | 25 | 25 | not provided | 3976 | not provided | clinical testing |
White | germline | no | not provided | not provided | not provided | 1013 | not provided | research |
Citations
PubMed
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.
- PMID:
- 26036859
- PMCID:
- PMC4717192
Ebhardt M, Schmidt H, Doerk T, Tietge U, Haas R, Manns MP, Schmidtke J, Stuhrmann M.
Hum Mutat. 1999;13(3):257.
- PMID:
- 10090484
Details of each submission
From Institute for Integrative and Experimental Genomics, University of Luebeck, SCV000212141.1
# | 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 | no | not provided | not provided | not provided | not provided | not provided | 6 | not provided |
From LDLR-LOVD, British Heart Foundation, SCV000295909.2
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | 1 | not provided | not provided | literature only | PubMed (10) |
2 | not provided | 1 | not provided | not provided | literature only | PubMed (10) |
3 | not provided | 1 | not provided | not provided | literature only | PubMed (10) |
4 | not provided | 1 | not provided | not provided | literature only | PubMed (10) |
5 | not provided | 1 | not provided | not provided | literature only | PubMed (10) |
6 | not provided | 1 | not provided | not provided | literature only | PubMed (10) |
7 | not provided | 1 | not provided | not provided | literature only | PubMed (10) |
8 | not provided | 1 | not provided | not provided | literature only | PubMed (10) |
9 | not provided | 1 | not provided | not provided | literature only | PubMed (10) |
10 | not provided | 1 | not provided | not provided | literature only | PubMed (10) |
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | germline | no | 1 | not provided | not provided | 1 | not provided | not provided | not provided | |
2 | germline | no | 1 | not provided | not provided | 1 | not provided | not provided | not provided | |
3 | germline | no | 1 | not provided | not provided | 1 | not provided | not provided | not provided | |
4 | germline | no | 1 | not provided | not provided | 1 | not provided | not provided | not provided | |
5 | germline | no | 1 | not provided | not provided | 1 | not provided | not provided | not provided | |
6 | germline | no | 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 | |
9 | germline | yes | 1 | not provided | not provided | 1 | not provided | not provided | not provided | |
10 | 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, SCV000296927.3
# | 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, SCV000323004.1
# | 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
%MAF (ExAC):0.6261
Description
1Hmz + 1Htz/100 normolipidemic individuals; 0/200 non-FH alleles
# | 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, SCV000323104.1
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | White | not provided | not provided | not provided | research | PubMed (1) |
Description
does not meet required criteria. "Little/No effect" on the LDL receptor activity based on experimental validation.
# | 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, SCV000503472.1
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | 17 | not provided | not provided | clinical testing | PubMed (1) |
Description
subjects mutated among 2600 FH index cases screened = 17/Software predictions: Benign
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | germline | yes | 2600 | not provided | not provided | 17 | not provided | not provided | not provided |
From Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation, SCV000540902.1
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | Caucasian | 25 | 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 | yes | 3976 | Whole blood | not provided | 25 | not provided | 25 | not provided |
From Laboratory of Genetics and Molecular Cardiology, University of São Paulo - HipercolBrasil, SCV000588642.1
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | not provided | not provided | not provided | research | PubMed (1) |
2 | not provided | not provided | not provided | not provided | research | PubMed (1) |
Description
%MAF(ExAC):0.6261
Assay description:Heterologous cells (CHO), FACS assays
# | 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, SCV000606613.1
# | 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, SCV000607682.1
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | not provided | not provided | not provided | research | PubMed (1) |
2 | not provided | not provided | not provided | not provided | research | PubMed (1) |
Description
%MAF(ExAC):0.6261
Heterologous cells (CHO), FACS assays
# | 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, SCV000733831.1
# | 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, SCV000748059.1
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | not provided | not provided | not provided | research | PubMed (1) |
2 | not provided | not provided | not provided | not provided | research | PubMed (1) |
Description
%MAF(ExAC):0.6261
Assay Description:Heterologous cells (CHO), FACS assays
# | 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, SCV000782936.1
# | 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, SCV001286052.1
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (1) |
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, SCV002817169.1
# | 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.2177C>T (p.Thr726Ile) variant is classified as Benign for Familial Hypercholesterolemia by applying evidence codes BA1 and BP4 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 - FAF = 0.008138 (0.8138%) in European (non-Finnish) exomes (gnomAD v2.1.1), so BA1 is Met. BP4 - REVEL = 0.454, it is below 0.50, so splicing evaluation is required. Functional data on splicing not available. A) variant not on limits B) does not create AG C) variant is exonic and there 1 an AG nearby MES scores: variant cryptic = -1.90, wt cryptic = -1.77, canonical acceptor = 8.76. Ratio variant cryptic/wt cryptic: -1.90/-1.77 = 1.07 --- it is not above 1.1 Ratio variant cryptic/canonical acceptor: -1.90/8.76 --- it is not above 0.9 --- BP4 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 |
Last Updated: Sep 8, 2024
PubMed [ID: 1301956]