NM_000527.5(LDLR):c.1745T>C (p.Leu582Pro) AND Hypercholesterolemia, familial, 1

Germline classification:: Likely pathogenic (5 submissions)
Last evaluated:: Jan 8, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000211698.11

Allele description [Variation Report for NM_000527.5(LDLR):c.1745T>C (p.Leu582Pro)]

NM_000527.5(LDLR):c.1745T>C (p.Leu582Pro)

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.1745T>C (p.Leu582Pro)

Other names:

NP_000518.1:p.L582P

HGVS:

NC_000019.10:g.11116898T>C
NG_009060.1:g.32518T>C
NM_000527.5:c.1745T>CMANE SELECT
NM_001195798.2:c.1745T>C
NM_001195799.2:c.1622T>C
NM_001195800.2:c.1241T>C
NM_001195803.2:c.1364T>C
NP_000518.1:p.Leu582Pro
NP_000518.1:p.Leu582Pro
NP_001182727.1:p.Leu582Pro
NP_001182728.1:p.Leu541Pro
NP_001182729.1:p.Leu414Pro
NP_001182732.1:p.Leu455Pro
LRG_274t1:c.1745T>C
LRG_274:g.32518T>C
LRG_274p1:p.Leu582Pro
NC_000019.9:g.11227574T>C
NM_000527.4(LDLR):c.1745T>C
NM_000527.4:c.1745T>C
c.1745T>C

Protein change:

L414P

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000980; dbSNP: rs875989930

NCBI 1000 Genomes Browser:

rs875989930

Molecular consequence:

NM_000527.5:c.1745T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1745T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1622T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.1241T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.1364T>C - 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

Recent activity

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SA14
SA14

biosample
RecName: Full=NADH dehydrogenase [ubiquinone] 1 alpha subcomplex assembly factor...
RecName: Full=NADH dehydrogenase [ubiquinone] 1 alpha subcomplex assembly factor 3
gi|74733183|sp|Q9BU61.1|NDUF3_HUMAN

Protein
Hypospadias 1, X-linked
Hypospadias 1, X-linked

MedGen
C2678098[conceptid] (1)
MedGen

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000268635	Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	no assertion criteria provided	Pathogenic (Aug 7, 2012)	germline	clinical testing
SCV000295631	LDLR-LOVD, British Heart Foundation	criteria provided, single submitter (ACGS Guidelines, 2013)	Likely pathogenic (Mar 25, 2016)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 15199436, 11668627 Citation Link,
SCV000484721	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]
SCV000503406	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]
SCV004822493	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (Jan 8, 2024)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 11668627, 15199436, 15576851, 17353666, 27765764, 28161202, 34037665, 36325061, 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	2	not provided	not provided	108544	not provided	clinical testing
not provided	germline	yes	10	not provided	not provided	2602	not provided	clinical testing, literature only

Citations

PubMed

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

Application of molecular genetics for diagnosing familial hypercholesterolemia in Norway: results from a family-based screening program.

Leren TP, Manshaus T, Skovholt U, Skodje T, Nossen IE, Teie C, Sørensen S, Bakken KS.

Semin Vasc Med. 2004 Feb;4(1):75-85. Review.

PubMed [citation]

PMID:: 15199436

See all PubMed Citations (9)

Details of each submission

From Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital, SCV000268635.1

#	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, SCV000295631.2

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

From Robarts Research Institute, Western University, SCV000484721.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	5	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		5	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, SCV000503406.1

#	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 prediction damaging

#	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 All of Us Research Program, National Institutes of Health, SCV004822493.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (9)

Description

This missense variant replaces leucine with proline at codon 582 of the LDLR protein. This variant is also known as p.Leu561Pro in the mature protein. This variant alters a conserved AA1 residue in the fifth LDLR type B repeat of the EGF precursor homology domain of the LDLR protein (a.a. 572-615), where pathogenic missense variants are found enriched (ClinVar-LDLR). Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This LDLR variant has been reported in over 10 heterozygous individuals affected with familial hypercholesterolemia (PMID: 11668627, 15199436, 15576851, 17353666, 27765764, 28161202, 34037665; Color internal data; ClinVar SCV000268635.1, SCV000503406.1). This variant has also been observed in homozygous state in one individual affected with severe homozygous familial hypercholesterolemia (PMID: 36325061). This variant has not been identified 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		2	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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