NM_000527.5(LDLR):c.1222G>A (p.Glu408Lys) AND Hypercholesterolemia, familial, 1

Germline classification:: Likely pathogenic (13 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:: RCV000030125.33

Allele description [Variation Report for NM_000527.5(LDLR):c.1222G>A (p.Glu408Lys)]

NM_000527.5(LDLR):c.1222G>A (p.Glu408Lys)

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.1222G>A (p.Glu408Lys)

Other names:

FH Algeria-1; FH Osaka; NM_000527.5(LDLR):c.1222G>A

HGVS:

NC_000019.10:g.11113313G>A
NG_009060.1:g.28933G>A
NM_000527.5:c.1222G>AMANE SELECT
NM_001195798.2:c.1222G>A
NM_001195799.2:c.1099G>A
NM_001195800.2:c.718G>A
NM_001195803.2:c.841G>A
NP_000518.1:p.Glu408Lys
NP_000518.1:p.Glu408Lys
NP_001182727.1:p.Glu408Lys
NP_001182728.1:p.Glu367Lys
NP_001182729.1:p.Glu240Lys
NP_001182732.1:p.Glu281Lys
LRG_274t1:c.1222G>A
LRG_274:g.28933G>A
LRG_274p1:p.Glu408Lys
NC_000019.9:g.11223989G>A
NM_000527.4:c.1222G>A
P01130:p.Glu408Lys
c.1222G>A

Protein change:

E240K

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001379; UniProtKB: P01130#VAR_005378; dbSNP: rs137943601

NCBI 1000 Genomes Browser:

rs137943601

Molecular consequence:

NM_000527.5:c.1222G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1222G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1099G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.718G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.841G>A - 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
SCV000268606	Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	no assertion criteria provided	Pathogenic (Aug 25, 2011)	germline	clinical testing
SCV000295310	LDLR-LOVD, British Heart Foundation	criteria provided, single submitter (ACGS Guidelines, 2013)	Likely pathogenic (Mar 25, 2016)	germline	literature only	PubMed (9) [See all records that cite these PMIDs] 12436241, 1301956, 16250003, 9026534, 15199436, 9698020, 17765246, 19318025, 22698793 Citation Link,
SCV000322938	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 1, 2016)	germline	research	PubMed (3) [See all records that cite these PMIDs] 25741868, 1301956, 9026534
SCV000503319	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)	Likely pathogenic (Dec 16, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000540803	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 (Nov 5, 2016)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25741868, 22698793
SCV000583809	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 30, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000606366	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	no assertion criteria provided	Pathogenic	germline	research
SCV000607577	Fundacion Hipercolesterolemia Familiar - SAFEHEART	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 1, 2016)	germline	research	PubMed (3) [See all records that cite these PMIDs] 25741868, 1301956, 9026534
SCV001429020	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 23, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001432552	Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Nov 29, 2018)	germline	research	PubMed (2) [See all records that cite these PMIDs] 25741868, 31345425
SCV001960925	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,
SCV002789095	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 12, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004820280	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 28, 2023)	germline	clinical testing	PubMed (19) [See all records that cite these PMIDs] 1301956, 2153120, 9026534, 9698020, 12436241, 14974088, 15199436, 16250003, 17094996, 17347910, 17765246, 18022922, 19026292, 19843101, 22698793, 29353225, 29396260, 30415195, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	39	14	not provided	2610	not provided	clinical testing, research, literature only
not provided	germline	unknown	1	not provided	not provided	108544	not provided	clinical testing, research, curation
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
Caucasian	unknown	yes	1	1	not provided	3964	not provided	clinical testing

Citations

PubMed

Genetic diagnosis of familial hypercholesterolemia using a DNA-array based platform.

Alonso R, Defesche JC, Tejedor D, Castillo S, Stef M, Mata N, Gomez-Enterria P, Martinez-Faedo C, Forga L, Mata P.

Clin Biochem. 2009 Jun;42(9):899-903. doi: 10.1016/j.clinbiochem.2009.01.017. Epub 2009 Feb 6.

PubMed [citation]

PMID:: 19318025

Risk of Premature Atherosclerotic Disease in Patients With Monogenic Versus Polygenic Familial Hypercholesterolemia.

Trinder M, Li X, DeCastro ML, Cermakova L, Sadananda S, Jackson LM, Azizi H, Mancini GBJ, Francis GA, Frohlich J, Brunham LR.

J Am Coll Cardiol. 2019 Jul 30;74(4):512-522. doi: 10.1016/j.jacc.2019.05.043.

PubMed [citation]

PMID:: 31345425

See all PubMed Citations (21)

Details of each submission

From Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital, SCV000268606.1

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

From LDLR-LOVD, British Heart Foundation, SCV000295310.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	literature only	PubMed (9)
2	not provided	1	not provided	not provided	literature only	PubMed (9)
3	not provided	1	not provided	not provided	literature only	PubMed (9)
4	not provided	1	not provided	not provided	literature only	PubMed (9)
5	not provided	1	not provided	not provided	literature only	PubMed (9)
6	not provided	1	not provided	not provided	literature only	PubMed (9)
7	not provided	1	not provided	not provided	literature only	PubMed (9)
8	not provided	1	not provided	not provided	literature only	PubMed (9)
9	not provided	1	not provided	not provided	literature only	PubMed (9)

#	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
9	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, SCV000322938.1

#	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):0.000831

"Homozygous patients' fibroblasts / Epstein-Barr virus-transformed lymphoblasts, 125I-LDL assays"

PubMed [ID: 1301956]

Description

0/208 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 Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix, SCV000503319.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	10	not provided	not provided	clinical testing	PubMed (1)

Description

subjects mutated among 2600 FH index cases screened = 10 , family members = 5 with co-segregation / FH-AlgÃ©rie-1/Osaka, <2% LDLR Activity / 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		10	not provided	not provided	not provided

From Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation, SCV000540803.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Caucasian	1	not provided	not provided	clinical testing	PubMed (2)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	3964	Whole blood	not provided		1	not provided	1	not provided

From U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille, SCV000583809.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	16	not provided	not provided	clinical testing	PubMed (1)

Description

Dutch Lipid Clinic Scoring : Definite 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		16	not provided	14	not provided

From Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum, SCV000606366.1

#	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, SCV000607577.1

#	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):0.000831

"Hmz patients' fibroblasts / Epstein-Barr virus-transformed lymphoblasts, 125I-LDL assays"

PubMed [ID: 1301956]

#	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 Institute of Human Genetics, University of Leipzig Medical Center, SCV001429020.1

#	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 Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia, SCV001432552.1

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

#	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

From ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel, SCV001960925.1

#	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.1222G>A (p.Glu408Lys) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PS3_Moderate, PS4_Moderate, PP1, PP3 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 = 0.00001763 (0.0018%) in European non-Finnish exomes (gnomAD v2.1.1). PS3_moderate - Level 2 assay: PMID:1301956 - study on hmz patient's fibroblasts, 125I-LDL assay, effect value reported as <2%; Level 2 assay: PMID: 9026534 - Epstein-Barr virus-transformed lymphoblasts from hmz patient, 125I-LDL assays - Results - 5-10% LDLR activity. PS4_moderate - Variant meets PM2. Variant identified in 8 index cases (1 case 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 Simon Broome criteria, 1 case from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA) with Simon Broome criteria, 1 case from University of British Columbia with DLCN criteria, 1 case from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge with Simon-Broome criteria, 2 cases from Ambry Genetics with Simon-Broome criteria). PP1 - Variant segregates with phenotype in 2 members of family (2 meiosis) from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge. PP3 - REVEL: 0,879. Score is above 0,75. PP4 - Variant meets PM2. Variant identified in 8 index cases (see PS4_Moderate).

#	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, SCV002789095.1

#	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 All of Us Research Program, National Institutes of Health, SCV004820280.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (19)

Description

This missense variant (also known as p.Glu387Lys in the mature protein and as FH-Algeria-1) replaces glutamic acid with lysine at codon 408 in the EGF precursor homology domain of the LDLR protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant causes a significant decrease in LDLR function due to impaired LDLR recycling and increased protein degradation in lysosomes (PMID: 9026534, 1301956, 19026292, 2153120). This variant has been reported in many unrelated individuals affected with familial hypercholesterolemia (PMID: 1301956, 9026534, 9698020, 12436241, 14974088, 15199436, 16250003, 17094996, 17347910, 17765246, 18022922, 19843101, 22698793, 29353225, 29396260, 30415195). This variant has also been reported in two unrelated individuals affected with homozygous familial hypercholesterolemia (PMID: 9026534, 19026292). This variant has been identified in 2/251104 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as 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		1	not provided	not provided	not provided

Last Updated: Nov 3, 2024

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