NM_000527.5(LDLR):c.1241T>G (p.Leu414Arg) AND Hypercholesterolemia, familial, 1

Germline classification:: Uncertain significance (5 submissions)
Last evaluated:: Mar 7, 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:: RCV000238583.8

Allele description [Variation Report for NM_000527.5(LDLR):c.1241T>G (p.Leu414Arg)]

NM_000527.5(LDLR):c.1241T>G (p.Leu414Arg)

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.1241T>G (p.Leu414Arg)

Other names:

NP_000518.1:p.L414R; NM_000527.5(LDLR):c.1241T>G

HGVS:

NC_000019.10:g.11113332T>G
NG_009060.1:g.28952T>G
NM_000527.5:c.1241T>GMANE SELECT
NM_001195798.2:c.1241T>G
NM_001195799.2:c.1118T>G
NM_001195800.2:c.737T>G
NM_001195803.2:c.860T>G
NP_000518.1:p.Leu414Arg
NP_000518.1:p.Leu414Arg
NP_001182727.1:p.Leu414Arg
NP_001182728.1:p.Leu373Arg
NP_001182729.1:p.Leu246Arg
NP_001182732.1:p.Leu287Arg
LRG_274t1:c.1241T>G
LRG_274:g.28952T>G
LRG_274p1:p.Leu414Arg
NC_000019.9:g.11224008T>G
NM_000527.4:c.1241T>G
P01130:p.Leu414Arg
c.1241T>G

Protein change:

L246R

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000372; UniProtKB: P01130#VAR_005379; dbSNP: rs748554592

NCBI 1000 Genomes Browser:

rs748554592

Molecular consequence:

NM_000527.5:c.1241T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1241T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1118T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.737T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.860T>G - 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
SCV000295319	LDLR-LOVD, British Heart Foundation	criteria provided, single submitter (ACGS Guidelines, 2013)	Likely pathogenic (Mar 25, 2016)	germline	literature only	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000484747	Robarts Research Institute, Western University	criteria provided, single submitter (Wang et al. (Arterioscler Thromb Vasc Biol. 2016))	Likely pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000606369	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	no assertion criteria provided	Pathogenic	germline	research
SCV001432554	Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 13, 2019)	germline	research	PubMed (2) [See all records that cite these PMIDs] 25741868, 31345425
SCV002506354	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	reviewed by expert panel (ClinGen FH ACMG Specifications v1-2)	Uncertain significance (Mar 7, 2022)	germline	curation	Citation Link

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	5	not provided	not provided	4	not provided	clinical testing, literature only, research
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	research, curation

Citations

PubMed

Mutations in the low-density lipoprotein receptor gene in Chinese familial hypercholesterolemia patients.

Mak YT, Pang CP, Tomlinson B, Zhang J, Chan YS, Mak TW, Masarei JR.

Arterioscler Thromb Vasc Biol. 1998 Oct;18(10):1600-5.

PubMed [citation]

PMID:: 9763532

Polygenic Versus Monogenic Causes of Hypercholesterolemia Ascertained Clinically.

Wang J, Dron JS, Ban MR, Robinson JF, McIntyre AD, Alazzam M, Zhao PJ, Dilliott AA, Cao H, Huff MW, Rhainds D, Low-Kam C, Dubé MP, Lettre G, Tardif JC, Hegele RA.

Arterioscler Thromb Vasc Biol. 2016 Dec;36(12):2439-2445. Epub 2016 Oct 20.

PubMed [citation]

PMID:: 27765764

See all PubMed Citations (4)

Details of each submission

From LDLR-LOVD, British Heart Foundation, SCV000295319.2

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

#	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 Robarts Research Institute, Western University, SCV000484747.1

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

From Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum, SCV000606369.1

#	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 Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia, SCV001432554.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	research	PubMed (2)
2	not provided	1	not provided	not provided	research	PubMed (2)
3	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
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 ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel, SCV002506354.1

#	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.1241T>G (p.Leu414Arg) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PS4_supporting, PP3 and 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: PM2 - PopMax MAF = 0.0001088 (0.01088%) in East Asian exomes+genomes (gnomAD v2.1.1). PP3 - REVEL = 0.822. PS4_supporting - Variant meets PM2. Variant identified in 4 unrelated index cases (3 cases with Simon-Broome published in PMID: 9763532; 1 case with DLCN criteria from Robarts Research Institute. PP4 - Variant meets PM2. Variant identified in 4 FH cases (3 cases with Simon-Broome Definite published in PMID: 9763532; 1 case with DLCN criteria = > 6 from Robarts Research Institute.

#	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: Jul 23, 2024

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