NM_000527.5(LDLR):c.1897C>T (p.Arg633Cys) AND Hypercholesterolemia, familial, 1

Germline classification:: Pathogenic/Likely pathogenic (16 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:: RCV000211568.31

Allele description [Variation Report for NM_000527.5(LDLR):c.1897C>T (p.Arg633Cys)]

NM_000527.5(LDLR):c.1897C>T (p.Arg633Cys)

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.1897C>T (p.Arg633Cys)

Other names:

NP_000518.1:p.R633C

HGVS:

NC_000019.10:g.11120143C>T
NG_009060.1:g.35763C>T
NM_000527.5:c.1897C>TMANE SELECT
NM_001195798.2:c.1897C>T
NM_001195799.2:c.1774C>T
NM_001195800.2:c.1393C>T
NM_001195803.2:c.1516C>T
NP_000518.1:p.Arg633Cys
NP_000518.1:p.Arg633Cys
NP_001182727.1:p.Arg633Cys
NP_001182728.1:p.Arg592Cys
NP_001182729.1:p.Arg465Cys
NP_001182732.1:p.Arg506Cys
LRG_274t1:c.1897C>T
LRG_274:g.35763C>T
LRG_274p1:p.Arg633Cys
NC_000019.9:g.11230819C>T
NM_000527.4:c.1897C>T
NM_000527.5:c.1897C>T
P01130:p.Arg633Cys
c.1897C>T

Protein change:

R465C

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001544; UniProtKB: P01130#VAR_005405

Molecular consequence:

NM_000527.5:c.1897C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1897C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1774C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.1393C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.1516C>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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Homo sapiens mRNA; cDNA DKFZp686A19191 (from clone DKFZp686A19191)
Homo sapiens mRNA; cDNA DKFZp686A19191 (from clone DKFZp686A19191)
gi|34367536|emb|BX648377.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000268648	Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	no assertion criteria provided	Pathogenic (Jan 9, 2015)	germline	clinical testing
SCV000295745	LDLR-LOVD, British Heart Foundation	criteria provided, single submitter (ACGS Guidelines, 2013)	Likely pathogenic (Mar 25, 2016)	germline	literature only	PubMed (6) [See all records that cite these PMIDs] 15241806, 9259195, 9452078, 22698793, 19446849, 20538126 Citation Link,
SCV000484757	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]
SCV000540848	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
SCV000583906	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]
SCV000588622	Laboratory of Genetics and Molecular Cardiology, University of São Paulo - HipercolBrasil	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 1, 2016)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV000606552	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	no assertion criteria provided	Pathogenic	germline	research
SCV000607653	Fundacion Hipercolesterolemia Familiar - SAFEHEART	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 1, 2016)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV000839998	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 14, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000914827	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Pathogenic (Apr 28, 2017)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 19446849, 19538517, 22698793, 23375686, 20538126, 17539906, 15241806, 9259195 Citation Link,
SCV002017133	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 2, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002564559	Arcensus	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 1, 2013)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003799113	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 11, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004231906	Clinical Genomics Laboratory, Stanford Medicine	no assertion criteria provided	Pathogenic (Sep 23, 2021)	germline	clinical testing
SCV004818464	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 8, 2024)	germline	clinical testing	PubMed (18) [See all records that cite these PMIDs] 9259195, 15241806, 16159606, 17094996, 17539906, 19446849, 19538517, 19843101, 20538126, 22698793, 23375686, 27765764, 27784735, 28028493, 28235710, 31491741, 32015373, 25741868
SCV005061045	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	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	germline	yes	11	2	not provided	6	not provided	clinical testing, literature only
not provided	germline	unknown	8	not provided	not provided	108544	not provided	clinical testing, research
Caucasian	unknown	yes	1	1	not provided	3964	not provided	clinical testing

Citations

PubMed

Identification of three new mutations of the low density lipoprotein receptor gene in Dutch familial hypercholesterolemic patients.

Lombardi P, Sijbrands EJ, Kamerling S, Smelt AH, Havekes LM.

Hum Mutat. 1998;Suppl 1:S172-4. No abstract available.

PubMed [citation]

PMID:: 9452078

Spectrum of LDL receptor gene mutations in heterozygous familial hypercholesterolemia.

Day IN, Whittall RA, O'Dell SD, Haddad L, Bolla MK, Gudnason V, Humphries SE.

Hum Mutat. 1997;10(2):116-27.

PubMed [citation]

PMID:: 9259195

See all PubMed Citations (19)

Details of each submission

From Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital, SCV000268648.1

#	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, SCV000295745.2

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

#	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

From Robarts Research Institute, Western University, SCV000484757.1

#	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 Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation, SCV000540848.1

#	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, SCV000583906.1

#	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 : Probable 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	2	not provided

From Laboratory of Genetics and Molecular Cardiology, University of São Paulo - HipercolBrasil, SCV000588622.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	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 Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum, SCV000606552.1

#	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, SCV000607653.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	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 Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine, SCV000839998.1

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

Description

The c.1897C>T (p.Arg633Cys) variant in the LDLR gene has been reported in several unrelated individuals with familial hypercholesterolemia (PMID: 9259195, 15241806, 19446849, 19843101, 21376320, 22698793, 23375686). Moreover, two other variants at the same residue (p.Arg633His, and p.Arg633Leu) have also been described in multiple individuals with familial hypercholesterolemia (PMID: 16250003, 22390909) suggesting that the Arg633 residue is critical for normal functioning of the LDLR protein. In light of the currently available data this variant in the LDLR gene is classified likely pathogenic

#	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 Illumina Laboratory Services, Illumina, SCV000914827.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

The LDLR c.1897C>T (p.Arg633Cys) variant has been reported in at least eight studies and is found in a total of at least 11 individuals with familial hypercholesterolemia, including one who carried the variant in a compound heterozygous state along with a deletion and in a heterozygous state in ten individuals (Day et al. 1997; Mozas et al. 2004; Taylor et al. 2007; Guardamagna et al. 2009; Taylor et al. 2009; Chiou et al. 2010; TichÃ½ et al. 2012; Bertolini et al. 2013). The p.Arg633Cys variant was absent from 100 controls, and is not found in the 1000 Genomes Project, the Exome Sequencing Project, or the Exome Aggregation Consortium, in a region of good sequence coverage, and hence is presumed to be rare. Based on the evidence, the p.Arg633Cys variant is classified as pathogenic for familial hypercholesterolemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

#	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 Revvity Omics, Revvity, SCV002017133.3

#	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 Arcensus, SCV002564559.1

#	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 Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center, SCV003799113.2

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

Description

PS3, PM1, PM2, PM5, PP1

#	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 Clinical Genomics Laboratory, Stanford Medicine, SCV004231906.1

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

Description

The p.Arg633Cys variant in the LDLR gene has been reported in at least 10 unrelated individuals with familial hypercholesterolemia (Day et al., 1997; Mozas et al., 2004; Graham et al., 2005; Tosi et al., 2007; Guardamagna et al., 2009; Tichý et al., 2012; Hori et al., 2019; Xiang et al., 2019). Additionally, this variant was found in the compound heterozygous state with a multi-exon deletion in an individual with suspected homozygous familial hypercholesterolemia (Taylor et al., 2009). This variant is also referred to as R612C in the literature. Notably, two different amino acid changes (p.Arg633Leu, p.Arg633His) at this residue have been previously reported in multiple unrelated individuals. This variant has been identified in 3/251,490 chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Although this variant has been seen in the general population, its frequency is low enough to be consistent with the prevalence of familial hypercholesterolemia. A functional study of p.Arg633Cys showed reduced LDLR expression and reduced LDL binding activity, supporting a deleterious effect to the protein (Galicia-Garcia et al., 2020). Computational tools predict that this variant is deleterious; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Arg633Cys variant as pathogenic for autosomal dominant familial hypercholesterolemia based on the information above. [ACMG evidence codes used: PS4; PM2; PM3; PS3_Supporting; PP3]

#	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 All of Us Research Program, National Institutes of Health, SCV004818464.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	8	not provided	not provided	clinical testing	PubMed (18)

Description

This missense variant (also known as p.Arg612Cys in the mature protein) replaces arginine with cysteine at codon 633 in the LDLR type B repeat 6 of the LDLR protein. 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). A functional study using transfected LDLR-deficient CHO-ldlA7 cells has shown that this variant causes a significant reduction in LDLR expression and activity (PMID: 32015373). This variant has been reported in over 10 individuals affected with familial hypercholesterolemia (PMID: 9259195, 15241806, 16159606, 17094996, 17539906, 19446849, 19843101, 20538126, 22698793, 23375686, 27765764, 28028493, 28235710, 31491741). This variant has also been observed in compound heterozygous and homozygous state in individuals affected with homozygous familial hypercholesterolemia (PMID: 17094996, 19538517, 27784735), indicating that this variant contributes to disease. This variant has been identified in 3/251490 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Arg633His, is considered to be disease-causing (ClinVar variation ID: 226380), suggesting that arginine at this position is important for LDLR protein function. 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		8	not provided	not provided	not provided

From Neuberg Centre For Genomic Medicine, NCGM, SCV005061045.1

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

Description

#	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

Last Updated: Oct 13, 2024

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