NM_000527.5(LDLR):c.1747C>T (p.His583Tyr) AND Hypercholesterolemia, familial, 1

Germline classification:: Pathogenic/Likely pathogenic (12 submissions)
Last evaluated:: Jan 4, 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:: RCV000211604.22

Allele description [Variation Report for NM_000527.5(LDLR):c.1747C>T (p.His583Tyr)]

NM_000527.5(LDLR):c.1747C>T (p.His583Tyr)

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.1747C>T (p.His583Tyr)

Other names:

p.H583Y:CAC>TAC; NP_000518.1:p.H583Y

HGVS:

NC_000019.10:g.11116900C>T
NG_009060.1:g.32520C>T
NM_000527.5:c.1747C>TMANE SELECT
NM_001195798.2:c.1747C>T
NM_001195799.2:c.1624C>T
NM_001195800.2:c.1243C>T
NM_001195803.2:c.1366C>T
NP_000518.1:p.His583Tyr
NP_000518.1:p.His583Tyr
NP_001182727.1:p.His583Tyr
NP_001182728.1:p.His542Tyr
NP_001182729.1:p.His415Tyr
NP_001182732.1:p.His456Tyr
LRG_274t1:c.1747C>T
LRG_274:g.32520C>T
LRG_274p1:p.His583Tyr
NC_000019.9:g.11227576C>T
NM_000527.4:c.1747C>T
c.1747C>T

Protein change:

H415Y

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000234; dbSNP: rs730882109

NCBI 1000 Genomes Browser:

rs730882109

Molecular consequence:

NM_000527.5:c.1747C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1747C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1624C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.1243C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.1366C>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

Recent activity

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RecName: Full=Bis(monoacylglycero)phosphate synthase CLN5; Short=BMP synthase CL...
RecName: Full=Bis(monoacylglycero)phosphate synthase CLN5; Short=BMP synthase CLN5; AltName: Full=Ceroid-lipofuscinosis neuronal protein 5; Short=Protein CLN5; AltName: Full=Palmitoyl protein thioesterase CLN5; AltName: Full=S-depalmitoylase CLN5; Contains: RecName: Full=Bis(monoacylglycero)phosphate synthase CLN5, secreted form
gi|187608866|sp|O75503.2|CLN5_HUMAN

Protein
Homo sapiens thymocyte nuclear protein 1, mRNA (cDNA clone MGC:12187 IMAGE:36823...
Homo sapiens thymocyte nuclear protein 1, mRNA (cDNA clone MGC:12187 IMAGE:3682324), complete cds
gi|13937762|gb|BC006978.1|

Nucleotide
SUCLA2 [Pelecanus crispus]
SUCLA2 [Pelecanus crispus]
Gene ID:104031395

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000268636	Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	no assertion criteria provided	Pathogenic (Oct 19, 2010)	germline	clinical testing
SCV000295633	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] 16205024, 7903864, 20538126 Citation Link,
SCV000484707	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]
SCV000583880	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]
SCV000599392	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 1, 2016)	germline, not applicable	curation, literature only	PubMed (3) [See all records that cite these PMIDs] 25741868, 21511053, 7903864
SCV000606503	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	no assertion criteria provided	Pathogenic	germline	research
SCV000778597	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology - AGHI-GT-HudsonAlpha	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 23, 2018)	unknown	research	PubMed (1) [See all records that cite this PMID]
SCV001432592	Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jun 5, 2019)	germline	research	PubMed (2) [See all records that cite these PMIDs] 25741868, 31345425
SCV002017115	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 5, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002516655	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2019)	Pathogenic (May 4, 2022)	germline	clinical testing	Citation Link,
SCV004822494	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 4, 2024)	germline	clinical testing	PubMed (16) [See all records that cite these PMIDs] 7903864, 15494314, 15741231, 16205024, 20538126, 22353362, 23155708, 29233637, 30949068, 32695144, 32759540, 33418990, 33746137, 36011335, 36172582, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	12	1	not provided	2604	not provided	clinical testing, literature only, research
not provided	germline	unknown	3	not provided	not provided	108544	not provided	clinical testing, research, curation
not provided	not applicable	not applicable	not provided	not provided	not provided	not provided	not provided	literature only
not provided	unknown	yes	1	not provided	not provided	1	not provided	research
not provided	unknown	unknown	1	not provided	not provided	1	not provided	research

Citations

PubMed

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

Role of an intramolecular contact on lipoprotein uptake by the LDL receptor.

Zhao Z, Michaely P.

Biochim Biophys Acta. 2011 Jun;1811(6):397-408. doi: 10.1016/j.bbalip.2011.04.002. Epub 2011 Apr 9.

PubMed [citation]

PMID:: 21511053
PMCID:: PMC3092732

See all PubMed Citations (19)

Details of each submission

From Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital, SCV000268636.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	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		3	not provided	not provided	not provided

From LDLR-LOVD, British Heart Foundation, SCV000295633.2

#	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 Robarts Research Institute, Western University, SCV000484707.1

#	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 Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix, SCV000503407.1

#	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, SCV000583880.1

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

From Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge, SCV000599392.1

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

Description

%MAF(ExAC):0.009061

"Assay Description:Retrovirus transfected LDLR-/- fibroblasts, FACS and 125I-LDL assays / Heterologous cells (COS), immunoblot"

PubMed [ID: 21511053]

#	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	not applicable	not applicable	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum, SCV000606503.1

#	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 HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology - AGHI-GT-HudsonAlpha, SCV000778597.1

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

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

From Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia, SCV001432592.1

#	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 Revvity Omics, Revvity, SCV002017115.3

#	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 Mendelics, SCV002516655.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	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	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, SCV004822494.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	not provided	not provided	clinical testing	PubMed (16)

Description

This missense variant replaces histidine with tyrosine at codon 583 of the LDLR protein. This variant is also known as p.His562Tyr in the mature protein. This variant alters a conserved histidine 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 tool suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >=0.7, PMID: 27666373). Functional studies have shown that this variant causes partially defective protein processing and trafficking to the plasma membrane (PMID: 7903864, 32695144), decrease in LDL internalization (PMID: 32695144), and reduction in recycling of LDLR when bound to LDL (PMID: 15494314, 15741231). This variant has been observed in over fifty individuals affected with familial hypercholesterolemia, mostly of East Asian ancestry (PMID: 7903864, 16205024, 20538126, 22353362, 23155708, 29233637, 30949068, 32759540, 33418990, 33746137, 36011335, 36172582; Color internal data). This variant has been reported to segregate with disease in two families (PMID: 22353362, 23155708). Individuals who were compound heterozygous for this variant and other pathogenic variant in the same gene have shown a more severe phenotype than heterozygous carriers of this variant (PMID: 7903864, 20538126, 23155708, 29233637, 36011335). This variant has been identified in 29/282882 chromosomes (24/19952 East Asian chromosomes) 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		3	not provided	not provided	not provided

Flagged submissions

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000503407	Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	flagged submission Reason: Older and outlier claim with insufficient supporting evidence Notes: None (ACMG Guidelines, 2015)	Likely benign (Dec 16, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000503407

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

flagged submission

Reason: Older and outlier claim with insufficient supporting evidence

Notes: None

(ACMG Guidelines, 2015)

Likely benign
(Dec 16, 2016)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Last Updated: Sep 29, 2024

Relating variation to medicine