NM_000527.5(LDLR):c.1238C>T (p.Thr413Met) AND Hypercholesterolemia, familial, 1

Germline classification:: Likely pathogenic (11 submissions)
Last evaluated:: Jun 9, 2021
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:: RCV000211581.25

Allele description [Variation Report for NM_000527.5(LDLR):c.1238C>T (p.Thr413Met)]

NM_000527.5(LDLR):c.1238C>T (p.Thr413Met)

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.1238C>T (p.Thr413Met)

Other names:

NM_000527.5(LDLR):c.1238C>T

HGVS:

NC_000019.10:g.11113329C>T
NG_009060.1:g.28949C>T
NM_000527.5:c.1238C>TMANE SELECT
NM_001195798.2:c.1238C>T
NM_001195799.2:c.1115C>T
NM_001195800.2:c.734C>T
NM_001195803.2:c.857C>T
NP_000518.1:p.Thr413Met
NP_000518.1:p.Thr413Met
NP_001182727.1:p.Thr413Met
NP_001182728.1:p.Thr372Met
NP_001182729.1:p.Thr245Met
NP_001182732.1:p.Thr286Met
LRG_274t1:c.1238C>T
LRG_274:g.28949C>T
LRG_274p1:p.Thr413Met
NC_000019.9:g.11224005C>T
NM_000527.4:c.1238C>T
c.1238C>T

Protein change:

T245M

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000967; dbSNP: rs368562025

NCBI 1000 Genomes Browser:

rs368562025

Molecular consequence:

NM_000527.5:c.1238C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1238C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1115C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.734C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.857C>T - missense variant - [Sequence Ontology: SO:0001583]

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000266311	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, 2015)	germline	research	PubMed (1) [See all records that cite this PMID] Kullo Lab Assertion Criteria_01072016.pdf, Citation Link,
SCV000268607	Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	no assertion criteria provided	Pathogenic (Jun 5, 2008)	germline	clinical testing
SCV000295318	LDLR-LOVD, British Heart Foundation	criteria provided, single submitter (ACGS Guidelines, 2013)	Likely pathogenic (Mar 25, 2016)	germline	literature only	PubMed (3) [See all records that cite these PMIDs] 11857755, 15199436, 17539906 Citation Link,
SCV000503321	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)	Uncertain significance (Dec 16, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000540894	Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation See additional submitters Centre of Molecular Biology and Gene Therapy, University Hospital Brno	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 3, 2017)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000606368	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	no assertion criteria provided	Pathogenic	germline	research
SCV000839993	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Oct 23, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001960926	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	reviewed by expert panel (ClinGen FH ACMG Specifications v1-1)	Likely pathogenic (Jun 9, 2021)	germline	curation	Citation Link,
SCV002813855	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Dec 23, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004027629	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (May 8, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004820282	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (Jul 7, 2023)	germline	clinical testing	PubMed (14) [See all records that cite these PMIDs] 11668627, 11857755, 15015036, 15199436, 15576851, 17539906, 19843101, 22883975, 25487149, 25682026, 31993549, 32015373, 34029164, 25741868

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	3	not provided	not provided	108544	not provided	clinical testing, research, curation
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	6	not provided	not provided	2603	not provided	clinical testing, literature only
Caucasian	unknown	yes	1	1	not provided	3976	not provided	clinical testing
White	germline	no	not provided	not provided	not provided	1013	not provided	research

Citations

PubMed

Variability in assigning pathogenicity to incidental findings: insights from LDLR sequence linked to the electronic health record in 1013 individuals.

Safarova MS, Klee EW, Baudhuin LM, Winkler EM, Kluge ML, Bielinski SJ, Olson JE, Kullo IJ.

Eur J Hum Genet. 2017 Apr;25(4):410-415. doi: 10.1038/ejhg.2016.193. Epub 2017 Feb 1.

PubMed [citation]

PMID:: 28145427
PMCID:: PMC5386413

Low density lipoprotein receptor (LDLR) gene mutations in Canadian subjects with familial hypercholesterolemia, but not of French descent.

Wang J, Huff E, Janecka L, Hegele RA.

Hum Mutat. 2001 Oct;18(4):359.

PubMed [citation]

PMID:: 11668627

See all PubMed Citations (15)

Details of each submission

From Cardiovascular Biomarker Research Laboratory, Mayo Clinic - RIGHT, SCV000266311.2

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

Description

MAF =<0.3%, likely pathogenic based on the integrative in-silico score, previously reported as P/LP in the literature

#	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 Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital, SCV000268607.1

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

From LDLR-LOVD, British Heart Foundation, SCV000295318.2

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

#	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

From Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix, SCV000503321.1

#	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 / Software predictions: Conflicting

#	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 Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation, SCV000540894.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Caucasian	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	unknown	yes	3976	Whole blood	not provided		1	not provided	1	not provided

From Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum, SCV000606368.1

#	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 Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine, SCV000839993.1

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

Description

This c.1238C>T (p.Thr413Met) variant in the LDLR gene has been reported in multiple individuals with familial hypercholesterolemia (PMID: 11857755, 17539906, 19843101, 11668627, 15015036, 25682026) or myocardial infarction (PMID: 25487149). The p.Thr413Met variant occurs within the low-density lipoprotein receptor repeat class B domain of the LDLR protein (https://www.ncbi.nlm.nih.gov/Structure/cdd/wrpsb.cgi?seqinput=NP_001182729.1 ). The c.1238C>T variant is rare in the general population and threonine at position 413 of the LDLR protein is highly evolutionarily conserved. The c.1238C>T (p.Thr413Met) variant in the LDLR gene is classified as likely pathogenic.

#	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, SCV001960926.1

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

Description

NM_000527.5(LDLR):c.1238C>T (p.Thr413Met) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PS4_Moderate, PP1 and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM2 - PopMax MAF = 0.00006533 (0.007%) in South Asian (gnomAD v2.1.1). PS4_moderate - Variant meets PM2. Variant identified in 6 index cases. PP1 - Variant segregates with phenotype in 2 members of family (2 meiosis) from GeneDx laboratory. PP4 - Variant meets PM2. Variant identified in 6 index cases (2 cases from Center of molecular biology and gene therapy with Simon-Broome criteria; 1 case from GeneDx laboratory with Simon Broome criteria, 1 case from Color laboratory with DLCN criteria, 2 cases from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA) with DLCN criteria).

#	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, SCV002813855.1

#	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

From Institute of Human Genetics, University of Leipzig Medical Center, SCV004027629.1

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

Description

Criteria applied: PS4_MOD,PM2_SUP,PP1,PP3,PP4

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

From All of Us Research Program, National Institutes of Health, SCV004820282.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	not provided	not provided	clinical testing	PubMed (14)

Description

This missense variant replaces threonine with methionine at codon 413 in the LDLR type B repeat 1 of the EGF precursor homology domain of the LDLR protein. This variant is also known as p.Thr392Met in the mature protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have indicated no significant change in LDLR protein expression and function due to this variant (PMID: 32015373, 34029164). This variant has been reported in over twenty heterozygous individuals affected with familial hypercholesterolemia (PMID: 11668627, 11857755, 15015036, 15199436, 15576851, 17539906, 19843101, 22883975, 25682026, 31993549; ClinVar SCV001960926.1) and in an individual affected with myocardial infarction (PMID: 25487149). This variant has been observed in an individual with severe familial hypercholesterolemia who also carried a pathogenic truncation variant in the same gene (PMID: 34029164). This variant has been reported to segregate with disease in two members of a family (ClinVar SCV001960926.1). This variant has been identified in 7/251176 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		3	not provided	not provided	not provided

Last Updated: Aug 25, 2024

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