NM_000527.5(LDLR):c.718G>A (p.Glu240Lys) AND Hypercholesterolemia, familial, 1

Germline classification:: Pathogenic (12 submissions)
Last evaluated:: Feb 14, 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:: RCV000211564.24

Allele description [Variation Report for NM_000527.5(LDLR):c.718G>A (p.Glu240Lys)]

NM_000527.5(LDLR):c.718G>A (p.Glu240Lys)

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.718G>A (p.Glu240Lys)

Other names:

FH Charlotte; NM_000527.5(LDLR):c.718G>A

HGVS:

NC_000019.10:g.11106588G>A
NG_009060.1:g.22208G>A
NM_000527.5:c.718G>AMANE SELECT
NM_001195798.2:c.718G>A
NM_001195799.2:c.595G>A
NM_001195800.2:c.314-804G>A
NM_001195803.2:c.337G>A
NP_000518.1:p.Glu240Lys
NP_000518.1:p.Glu240Lys
NP_001182727.1:p.Glu240Lys
NP_001182728.1:p.Glu199Lys
NP_001182732.1:p.Glu113Lys
LRG_274t1:c.718G>A
LRG_274:g.22208G>A
NC_000019.9:g.11217264G>A
NM_000527.4(LDLR):c.718G>A
NM_000527.4:c.718G>A
NM_000527.5:c.718G>A
P01130:p.Glu240Lys
c.718G>A
p.(Glu240Lys)
p.E240K

Protein change:

E113K

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001828; UniProtKB: P01130#VAR_005343; dbSNP: rs768563000

NCBI 1000 Genomes Browser:

rs768563000

Molecular consequence:

NM_001195800.2:c.314-804G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.718G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.718G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.595G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.337G>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
SCV000268584	Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 5, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 11052664, 1301956, 25741868
SCV000294938	LDLR-LOVD, British Heart Foundation	criteria provided, single submitter (ACGS Guidelines, 2013)	Likely pathogenic (Mar 25, 2016)	germline	literature only	PubMed (4) [See all records that cite these PMIDs] 1301956, 16250003, 23375686, 25463123 Citation Link,
SCV000503229	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 benign (Dec 16, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000583731	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]
SCV000606209	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	no assertion criteria provided	Pathogenic	germline	research
SCV000782952	Robarts Research Institute, Western University	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jan 2, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001423087	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jan 22, 2020)	germline	curation	PubMed (6) [See all records that cite these PMIDs] 16250003, 24956927, 1301956, 25463123, 10704205, 25741868 Citation Link,
SCV001432576	Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 6, 2018)	germline	research	PubMed (2) [See all records that cite these PMIDs] 25741868, 31345425
SCV001653607	Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 24, 2021)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 1301956, 23375686, 28965616, 30241732, 31447099, 32977124, 32041611, 32719484, 25741868
SCV002022676	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Aug 23, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002506368	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	reviewed by expert panel (ClinGen FH ACMG Specifications v1-2)	Pathogenic (Feb 14, 2022)	germline	curation	Citation Link,
SCV002814853	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Oct 2, 2021)	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	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	7	1	not provided	2605	not provided	clinical testing, literature only, research
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, research, curation
Caucasian	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Evidence that familial hypercholesterolemia mutations of the LDL receptor cause limited local misfolding in an LDL-A module pair.

North CL, Blacklow SC.

Biochemistry. 2000 Oct 31;39(43):13127-35.

PubMed [citation]

PMID:: 11052664

Update of the molecular basis of familial hypercholesterolemia in The Netherlands.

Fouchier SW, Kastelein JJ, Defesche JC.

Hum Mutat. 2005 Dec;26(6):550-6.

PubMed [citation]

PMID:: 16250003

See all PubMed Citations (15)

Details of each submission

From Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital, SCV000268584.2

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

Description

The LDLR p.Glu240Lys (originally p.Glu219Lys, FH Charlotte) missense variant is likely pathogenic for familial hypercholesterolaemia (FH). In silico algorithms (PolyPhen2, SIFT, MutationTaster) predict p.Glu240Lys to be pathogenic. It has previously been identified in multiple cohorts of FH patients worldwide and is present at a very low frequency (2/121,396 alleles) in the gnomAD population database. In vitro studies demonstrated that LDLR p.Glu240Lys affected protein folding (PMID:11052664) and resulted in decreased LDL-receptor activity (PMID: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

From LDLR-LOVD, British Heart Foundation, SCV000294938.2

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

#	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

From Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix, SCV000503229.1

#	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 / previously described in association with FH / 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 U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille, SCV000583731.1

#	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 : 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		1	not provided	1	not provided

From Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum, SCV000606209.1

#	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 Robarts Research Institute, Western University, SCV000782952.1

#	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 Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001423087.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (6)

Description

The p.Glu240Lys variant in LDLR has been reported in 7 individuals with Familial Hypercholesterolemia, segregated with disease in 4 affected relatives from 2 families (PMID: 16250003, 25463123, 24956927), and has been identified in 0.005418% (7/129192) of European (non-Finnish) chromosomes, 0.005012% (1/19954) of East Asian chromosomes, and 0.004005% (1/24968) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs768563000). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported as a likely benign variant, VUS, likely pathogenic variant, and pathogenic variant in ClinVar (Variation ID: 200920). In vitro functional studies with protein imaging provide some evidence that the p.Glu240Lys variant may slightly impact protein folding (PMID: 10704205). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS3_supporting, PP3, PP1, PS4_Supporting (Richards 2015).

#	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 Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia, SCV001432576.1

#	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 Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II, SCV001653607.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Caucasian	1	not provided	not provided	clinical testing	PubMed (9)

#	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 Revvity Omics, Revvity, SCV002022676.3

#	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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel, SCV002506368.1

#	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.718G>A (p.Glu240Lys) variant is classified as U Pathogenic for Familial Hypercholesterolemia by applying evidence codes PP3, PM2, PS4, PM3, PP4 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: PP3 - REVEL = 0.865. It is above 0.75, so PP3 is Met. PM2 - PopMax MAF = 0.00005418 (0.005418%) in European (non-Finnish) exomes+genomes (gnomAD v2.1.1), so PM2 is Met. PS4 - Variant meets PM2 and is identified in at least 11 unrelated index cases: 2 index cases with Simon Broome possible from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière); 1 index case with DLCN>6 from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA); 2 index cases with DLCN>6 from Robarts Research Institute; 2 index cases with DLCN>6 from Color Health, Inc; 2 index cases fulfilling the following criteria: children with a) TC >200 mg/dl or LDL >120 mg/dl and b) presence of primary hypercholesterolemia in 1st degree relatives with autosomal dominant mode of inheritance or c) family history of pCHD or d) presence of xanthomas in proband or in parents, from Greece (PMID: 25463123); at least 1 index case with Simon Broome criteria from China (PMID: 28235710); 1 index case with Definite FH (LDL >13 mmol/l and presence of xanthomas and hypercholesterolemia in both parents) from Italy (PMID: 32977124), so PS4 is Met. PM3 - Variant meets PM2 and is identified in an italian index case with homozygous FH phenotype (LDL>13 mmol/l) with another LDLR variant, in trans (PMID: 32977124). In PMID: 28965616 is identified an italian index case (phenotype not reported) with LDLR variant c.304C>T (p.Gln102*), classified as Pathogenic by these guidelines, but cannot determine if the variants are in trans (PMID: 28965616). Assuming that is the same homozygous index case (same lab), PM3 is Met. PP4 - Variant meets PM2 and is identified in at least 11 unrelated index cases as reported above, so PP4 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

From Fulgent Genetics, Fulgent Genetics, SCV002814853.1

#	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

Last Updated: Sep 29, 2024

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