Variant summary: The LDLR c.1897C>T (p.Arg633Cys) variant, alternatively also known as R612C, is located in EGF precursor homology domain of the LDLR protein (Mozas_2004, Bertolini_2013) and 4/4 in silico tools predict a damaging outcome for this substitution. This variant is absent in 121614 control chromosomes including broad and large populations from ExAC. In literature, this variant is widely reported as a pathogenic variant and is found in several FH patients. Other missense variants in this codon, p.Arg633Leu and p.Arg633His, have been reported as FH patients and are classified as pathogenic/likely pathogenic in ClinVar, suggesting that the codon p.Arg633 is mutational hot-spot. In addition, multiple clinical diagnostic laboratories/reputable databases have classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000527.5(LDLR):c.1897C>T (p.Arg633Cys)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(26)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic/Likely pathogenic
26
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000527.5(LDLR):c.1897C>T (p.Arg633Cys)
Variation ID: 226379 Accession: VCV000226379.57
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 19p13.2 19: 11120143 (GRCh38) [ NCBI UCSC ] 19: 11230819 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline May 22, 2016 Oct 8, 2024 Apr 3, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000527.5:c.1897C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000518.1:p.Arg633Cys missense NM_001195798.2:c.1897C>T NP_001182727.1:p.Arg633Cys missense NM_001195799.2:c.1774C>T NP_001182728.1:p.Arg592Cys missense NM_001195800.2:c.1393C>T NP_001182729.1:p.Arg465Cys missense NM_001195803.2:c.1516C>T NP_001182732.1:p.Arg506Cys missense NC_000019.10:g.11120143C>T NC_000019.9:g.11230819C>T NG_009060.1:g.35763C>T LRG_274:g.35763C>T LRG_274t1:c.1897C>T LRG_274p1:p.Arg633Cys P01130:p.Arg633Cys - Protein change
- R633C, R465C, R592C, R506C
- Other names
-
NP_000518.1:p.R633C
- Canonical SPDI
- NC_000019.10:11120142:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| LDLR | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
4076 | 4352 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (16) |
criteria provided, multiple submitters, no conflicts
|
Jan 8, 2024 | RCV000211568.31 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Feb 21, 2022 | RCV000486101.4 | |
| Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Jan 2, 2024 | RCV000590441.14 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Mar 4, 2019 | RCV000826210.4 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Apr 3, 2024 | RCV002408918.4 | |
|
LDLR-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
Jul 22, 2024 | RCV003407739.6 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Likely pathogenic
(Mar 25, 2016)
|
criteria provided, single submitter
Method: literature only
|
Familial hypercholesterolemia
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
LDLR-LOVD, British Heart Foundation
Accession: SCV000295745.2
First in ClinVar: Jul 29, 2016 Last updated: Dec 26, 2017 |
Observation 1:
Number of individuals with the variant: 1
Observation 2:
Number of individuals with the variant: 1
Observation 3:
Number of individuals with the variant: 1
Observation 4:
Number of individuals with the variant: 1
Observation 5:
Number of individuals with the variant: 1
Observation 6:
Number of individuals with the variant: 1
|
|
|
Likely pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Robarts Research Institute, Western University
Accession: SCV000484757.1
First in ClinVar: Dec 17, 2016 Last updated: Dec 17, 2016 |
Number of individuals with the variant: 1
|
|
|
Likely pathogenic
(Nov 05, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown
|
Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation
Additional submitter:
Centre of Molecular Biology and Gene Therapy, University Hospital Brno
Accession: SCV000540848.1
First in ClinVar: Dec 17, 2016 Last updated: Dec 17, 2016 |
Number of individuals with the variant: 1
Clinical Features:
Hypercholesterolemia (present)
Age: 40-49 years
Sex: female
Ethnicity/Population group: Caucasian
Geographic origin: Czech Republic
Tissue: Whole blood
|
|
|
Pathogenic
(Mar 30, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Familial Hypercholesterolemia
Affected status: yes
Allele origin:
germline
|
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille
Accession: SCV000583906.1
First in ClinVar: Apr 16, 2017 Last updated: Apr 16, 2017
Comment:
ACMG Guidelines: Pathogenic (ii)
|
Number of individuals with the variant: 2
Clinical Features:
Hyperbetalipoproteinemia (present) , Hypercholesterolemia (present)
Indication for testing: Familial Hypercholesterolemia
Sex: mixed
Geographic origin: France
Comment on evidence:
Dutch Lipid Clinic Scoring : Probable FH
Secondary finding: no
|
|
|
Likely pathogenic
(Mar 01, 2016)
|
criteria provided, single submitter
Method: research
|
Familial hypercholesterolemia
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
Laboratory of Genetics and Molecular Cardiology, University of São Paulo
Study: HipercolBrasil
Accession: SCV000588622.1 First in ClinVar: Aug 13, 2017 Last updated: Aug 13, 2017 |
|
|
|
Likely pathogenic
(Mar 01, 2016)
|
criteria provided, single submitter
Method: research
|
Familial hypercholesterolemia
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
Fundacion Hipercolesterolemia Familiar
Study: SAFEHEART
Accession: SCV000607653.1 First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017 |
|
|
|
Pathogenic
(Nov 08, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000697214.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Comment:
Variant summary: The LDLR c.1897C>T (p.Arg633Cys) variant, alternatively also known as R612C, is located in EGF precursor homology domain of the LDLR protein (Mozas_2004, Bertolini_2013) … (more)
Variant summary: The LDLR c.1897C>T (p.Arg633Cys) variant, alternatively also known as R612C, is located in EGF precursor homology domain of the LDLR protein (Mozas_2004, Bertolini_2013) and 4/4 in silico tools predict a damaging outcome for this substitution. This variant is absent in 121614 control chromosomes including broad and large populations from ExAC. In literature, this variant is widely reported as a pathogenic variant and is found in several FH patients. Other missense variants in this codon, p.Arg633Leu and p.Arg633His, have been reported as FH patients and are classified as pathogenic/likely pathogenic in ClinVar, suggesting that the codon p.Arg633 is mutational hot-spot. In addition, multiple clinical diagnostic laboratories/reputable databases have classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as pathogenic. (less)
|
|
|
Likely pathogenic
(Jan 14, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
Affected status: unknown
Allele origin:
germline
|
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine
Accession: SCV000839998.1
First in ClinVar: Dec 26, 2017 Last updated: Dec 26, 2017 |
Comment:
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, … (more)
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 (less)
|
|
|
Pathogenic
(Apr 28, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000914827.1
First in ClinVar: May 24, 2019 Last updated: May 24, 2019 |
Comment:
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 … (more)
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; Tichý 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. (less)
|
|
|
Likely pathogenic
(Mar 04, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Homozygous familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000967775.2
First in ClinVar: Aug 26, 2019 Last updated: Aug 26, 2019 |
Comment:
The p.Arg633Cys variant in LDLR has been reported in at least 11 individuals with familial hypercholesterolemia (FH), including one homozygote (Day 1997, Mozas 2004, Guardamagna … (more)
The p.Arg633Cys variant in LDLR has been reported in at least 11 individuals with familial hypercholesterolemia (FH), including one homozygote (Day 1997, Mozas 2004, Guardamagna 2009, Taylor 2009, Chiou 2011, Tichy 2012, Bertolini 2013, Xiang 2017, Medieros 2017). This variant has been reported in ClinVar (Variation ID: 226379) and has also been identified in 1/30782 South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that the p.Arg833Cys variant may impact the protein. Two other variants at this amino acid position have been reported in at least 4 individuals with FH (p.Arg633Leu and p.Arg633His). In summary, although additional studies are required to fully establish its clinical significance, the p.Arg633Cys variant is likely pathogenic. ACMG/AMP Criteria applied: PS4_Moderate, PM2, PM5_Supporting, PP3. (less)
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Feb 21, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: yes
Allele origin:
germline
|
AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002502727.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 3
Secondary finding: no
|
|
|
Pathogenic
(Feb 01, 2013)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
Affected status: yes
Allele origin:
germline
|
Arcensus
Accession: SCV002564559.1
First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022 |
|
|
|
Pathogenic
(Jan 26, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000567421.5
First in ClinVar: Apr 27, 2017 Last updated: Mar 04, 2023 |
Comment:
Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein … (more)
Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies suggest a damaging effect as Western blotting showed decreased expression and reduced LDL uptake suggesting a negative effect on LDLR receptor recycling (Galicia-Garcia et al., 2020); Reported in ClinVar but additional evidence is not available (ClinVar Variant ID#226379; ClinVar); Also reported as R612C due to alternate nomenclature; This variant is associated with the following publications: (PMID: 28349888, 27680772, 9259195, 15241806, 27578128, 28235710, 19843101, 16159606, 20538126, 23375686, 19446849, 18700895, 17539906, 22698793, 21376320, 19538517, 17094996, 32015373, 31447099, 31491741, 30586733, 31589614, 34037665, 33087929, 32041611, 32719484) (less)
|
|
|
Pathogenic
(Aug 02, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002017133.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Jan 02, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000544682.8
First in ClinVar: Apr 16, 2017 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 633 of the LDLR protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 633 of the LDLR protein (p.Arg633Cys). This variant is present in population databases (rs746118995, gnomAD 0.003%). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 9259195, 15241806, 19446849, 19538517, 19843101, 21376320, 22698793, 23375686). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as p.Arg612Cys. ClinVar contains an entry for this variant (Variation ID: 226379). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Apr 27, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000909183.4
First in ClinVar: May 20, 2019 Last updated: Feb 14, 2024 |
Comment:
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 … (more)
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. (less)
|
|
|
Pathogenic
(Oct 11, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
Affected status: yes
Allele origin:
germline
|
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV003799113.2
First in ClinVar: Feb 13, 2023 Last updated: Mar 04, 2023 |
Comment:
PS3, PM1, PM2, PM5, PP1
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
HYPERCHOLESTEROLEMIA, FAMILIAL
Affected status: yes
Allele origin:
germline
|
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV004046251.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
Comment:
This variant is also referred to as p.Arg612Cys in the literature. This variant has been reported as a heterozygous change in individuals with features of … (more)
This variant is also referred to as p.Arg612Cys in the literature. This variant has been reported as a heterozygous change in individuals with features of familial hypercholesterolemia (PMID: 28349888, 27680772, 9259195, 15241806, 27578128, 21376320, 28235710). Functional studies have shown that the c.1897C>T (p.Arg633Cys) variant results in abnormal function of the LDLR protein (PMID: 32015373). The c.1897C>T (p.Arg633Cys) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.001% (3/251490). It affects a moderately conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Different missense variants involving the same residue (p.Arg633His and p.Arg633Leu) have been previously reported in individuals with familial hypercholesterolemia (ClinVar Variation ID: 226380, 252107). Based on the available evidence, the c.1897C>T (p.Arg633Cys) variant is classified as Pathogenic. (less)
|
|
|
Pathogenic
(Jan 08, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
(Semidominant inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004818464.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
|
Comment:
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 … (more)
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. (less)
Number of individuals with the variant: 8
|
|
|
Pathogenic
(Aug 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
familial hypercholesterolemia
Affected status: unknown
Allele origin:
unknown
|
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine
Accession: SCV005045753.1
First in ClinVar: Jun 02, 2024 Last updated: Jun 02, 2024 |
Comment:
The c.1897C>T (p.Arg633Cys) variant in the LDLR gene is located on the exon 13 and is predicted to replace arginine with cysteine at codon 633 … (more)
The c.1897C>T (p.Arg633Cys) variant in the LDLR gene is located on the exon 13 and is predicted to replace arginine with cysteine at codon 633 (p.Arg633Cys). The variant has been identified in more than 10 unrelated individuals with familial hypercholesterolemia (FH) (PMID: 27680772, 28235710, 28349888, 31893465, 21376320, 22698793, 15241806, 17094996). Other variants disrupting the same amino acid (p.Arg633Leu, p.Arg633His) have been interpreted as likely pathogenic (ClinVar ID: 252107, 226380). The variant is rare in the general population according to gnomAD (3/251490). Computational prediction algorithms suggest a deleterious impact for this variant (REVEL score 0.845). Therefore, the c.1897C>T (p.Arg633Cys) variant of LDLR has been classified as pathogenic. (less)
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV005061045.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
Comment:
NA
|
|
|
Pathogenic
(Apr 03, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002722562.4
First in ClinVar: Nov 29, 2022 Last updated: Aug 11, 2024 |
Comment:
The c.1897C>T (p.R633C) alteration is located in exon 13 (coding exon 13) of the LDLR gene. This alteration results from a C to T substitution … (more)
The c.1897C>T (p.R633C) alteration is located in exon 13 (coding exon 13) of the LDLR gene. This alteration results from a C to T substitution at nucleotide position 1897, causing the arginine (R) at amino acid position 633 to be replaced by a cysteine (C). Based on data from gnomAD, the T allele has an overall frequency of 0.001% (3/251490) total alleles studied. The highest observed frequency was 0.003% (1/30616) of South Asian alleles. This variant (also known as p.R612C) has been reported in numerous individuals and cohorts with familial hypercholesterolemia (FH) (Day, 1997; Sánchez-Hernández, 2016; Wang, 2016). Alternate amino acid substitutions at this codon, p.R633L and p.R633H, have also been reported in individuals with FH (Fouchier, 2005). Based on the available evidence, this alteration is classified as pathogenic. (less)
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Pathogenic
(Jan 09, 2015)
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no assertion criteria provided
Method: clinical testing
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Familial hypercholesterolemia
Affected status: yes
Allele origin:
germline
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Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital
Accession: SCV000268648.1
First in ClinVar: May 22, 2016 Last updated: May 22, 2016 |
Number of individuals with the variant: 1
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Pathogenic
(-)
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no assertion criteria provided
Method: research
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Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum
Accession: SCV000606552.1
First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017 |
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Pathogenic
(Sep 23, 2021)
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no assertion criteria provided
Method: clinical testing
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Hypercholesterolemia, familial, 1
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Clinical Genomics Laboratory, Stanford Medicine
Accession: SCV004231906.1
First in ClinVar: Feb 28, 2024 Last updated: Feb 28, 2024 |
Comment:
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 … (more)
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] (less)
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Pathogenic
(Jul 22, 2024)
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no assertion criteria provided
Method: clinical testing
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LDLR-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004113889.2
First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024 |
Comment:
The LDLR c.1897C>T variant is predicted to result in the amino acid substitution p.Arg633Cys. This variant (also reported as c.Arg612Cys in the literature) has been … (more)
The LDLR c.1897C>T variant is predicted to result in the amino acid substitution p.Arg633Cys. This variant (also reported as c.Arg612Cys in the literature) has been reported in many unrelated individuals with familial hypercholesterolemia (Mozas et al. 2004. PubMed ID: 15241806; Chiou et al. 2011. PubMed ID: 21376320; Tichý et al. 2012. PubMed ID: 22698793; Day et al. 1997. PubMed ID: 9259195, referred to as R612C; Bertolini et al. 2013. PubMed ID: 23375686, supplementary data; Di Taranto et al. 2019. PubMed ID: 30710474, supplementary data; Dron et al. 2020. PubMed ID: 32041611; Sturm et al. 2021. PubMed ID: 34037665, supplementary data; Futema et al. 2017. PubMed ID: 28349888). In vitro analysis of this variant indicated that this variant results in diminished LDLR expression and activity (Galicia-Garcia et al. 2020. PubMed ID: 32015373). This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD. This variant has been reported in ClinVar by many outside laboratories as likely pathogenic or pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/226379/). Two other amino acid substitutions at this position (p.Arg633His and p.Arg633Leu) have also been reported in individuals with hypercholesterolemia (Fouchier et al. 2005. PubMed ID: 16250003; Di Taranto et al. 2021. PubMed ID: 34297352). In summary, we categorize c.1897C>T (p.Arg633Cys) as pathogenic. (less)
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Comment:
Comment:
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
Comment:
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; Tichý 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.
Comment:
The p.Arg633Cys variant in LDLR has been reported in at least 11 individuals with familial hypercholesterolemia (FH), including one homozygote (Day 1997, Mozas 2004, Guardamagna 2009, Taylor 2009, Chiou 2011, Tichy 2012, Bertolini 2013, Xiang 2017, Medieros 2017). This variant has been reported in ClinVar (Variation ID: 226379) and has also been identified in 1/30782 South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that the p.Arg833Cys variant may impact the protein. Two other variants at this amino acid position have been reported in at least 4 individuals with FH (p.Arg633Leu and p.Arg633His). In summary, although additional studies are required to fully establish its clinical significance, the p.Arg633Cys variant is likely pathogenic. ACMG/AMP Criteria applied: PS4_Moderate, PM2, PM5_Supporting, PP3.
Comment:
Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies suggest a damaging effect as Western blotting showed decreased expression and reduced LDL uptake suggesting a negative effect on LDLR receptor recycling (Galicia-Garcia et al., 2020); Reported in ClinVar but additional evidence is not available (ClinVar Variant ID#226379; ClinVar); Also reported as R612C due to alternate nomenclature; This variant is associated with the following publications: (PMID: 28349888, 27680772, 9259195, 15241806, 27578128, 28235710, 19843101, 16159606, 20538126, 23375686, 19446849, 18700895, 17539906, 22698793, 21376320, 19538517, 17094996, 32015373, 31447099, 31491741, 30586733, 31589614, 34037665, 33087929, 32041611, 32719484)
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 633 of the LDLR protein (p.Arg633Cys). This variant is present in population databases (rs746118995, gnomAD 0.003%). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 9259195, 15241806, 19446849, 19538517, 19843101, 21376320, 22698793, 23375686). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as p.Arg612Cys. ClinVar contains an entry for this variant (Variation ID: 226379). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Comment:
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.
Comment:
PS3, PM1, PM2, PM5, PP1
Comment:
This variant is also referred to as p.Arg612Cys in the literature. This variant has been reported as a heterozygous change in individuals with features of familial hypercholesterolemia (PMID: 28349888, 27680772, 9259195, 15241806, 27578128, 21376320, 28235710). Functional studies have shown that the c.1897C>T (p.Arg633Cys) variant results in abnormal function of the LDLR protein (PMID: 32015373). The c.1897C>T (p.Arg633Cys) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.001% (3/251490). It affects a moderately conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Different missense variants involving the same residue (p.Arg633His and p.Arg633Leu) have been previously reported in individuals with familial hypercholesterolemia (ClinVar Variation ID: 226380, 252107). Based on the available evidence, the c.1897C>T (p.Arg633Cys) variant is classified as Pathogenic.
Comment:
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.
Comment:
The c.1897C>T (p.Arg633Cys) variant in the LDLR gene is located on the exon 13 and is predicted to replace arginine with cysteine at codon 633 (p.Arg633Cys). The variant has been identified in more than 10 unrelated individuals with familial hypercholesterolemia (FH) (PMID: 27680772, 28235710, 28349888, 31893465, 21376320, 22698793, 15241806, 17094996). Other variants disrupting the same amino acid (p.Arg633Leu, p.Arg633His) have been interpreted as likely pathogenic (ClinVar ID: 252107, 226380). The variant is rare in the general population according to gnomAD (3/251490). Computational prediction algorithms suggest a deleterious impact for this variant (REVEL score 0.845). Therefore, the c.1897C>T (p.Arg633Cys) variant of LDLR has been classified as pathogenic.
Comment:
NA
Comment:
The c.1897C>T (p.R633C) alteration is located in exon 13 (coding exon 13) of the LDLR gene. This alteration results from a C to T substitution at nucleotide position 1897, causing the arginine (R) at amino acid position 633 to be replaced by a cysteine (C). Based on data from gnomAD, the T allele has an overall frequency of 0.001% (3/251490) total alleles studied. The highest observed frequency was 0.003% (1/30616) of South Asian alleles. This variant (also known as p.R612C) has been reported in numerous individuals and cohorts with familial hypercholesterolemia (FH) (Day, 1997; Sánchez-Hernández, 2016; Wang, 2016). Alternate amino acid substitutions at this codon, p.R633L and p.R633H, have also been reported in individuals with FH (Fouchier, 2005). Based on the available evidence, this alteration is classified as pathogenic.
Comment:
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]
Comment:
The LDLR c.1897C>T variant is predicted to result in the amino acid substitution p.Arg633Cys. This variant (also reported as c.Arg612Cys in the literature) has been reported in many unrelated individuals with familial hypercholesterolemia (Mozas et al. 2004. PubMed ID: 15241806; Chiou et al. 2011. PubMed ID: 21376320; Tichý et al. 2012. PubMed ID: 22698793; Day et al. 1997. PubMed ID: 9259195, referred to as R612C; Bertolini et al. 2013. PubMed ID: 23375686, supplementary data; Di Taranto et al. 2019. PubMed ID: 30710474, supplementary data; Dron et al. 2020. PubMed ID: 32041611; Sturm et al. 2021. PubMed ID: 34037665, supplementary data; Futema et al. 2017. PubMed ID: 28349888). In vitro analysis of this variant indicated that this variant results in diminished LDLR expression and activity (Galicia-Garcia et al. 2020. PubMed ID: 32015373). This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD. This variant has been reported in ClinVar by many outside laboratories as likely pathogenic or pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/226379/). Two other amino acid substitutions at this position (p.Arg633His and p.Arg633Leu) have also been reported in individuals with hypercholesterolemia (Fouchier et al. 2005. PubMed ID: 16250003; Di Taranto et al. 2021. PubMed ID: 34297352). In summary, we categorize c.1897C>T (p.Arg633Cys) as pathogenic.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
Variant summary: The LDLR c.1897C>T (p.Arg633Cys) variant, alternatively also known as R612C, is located in EGF precursor homology domain of the LDLR protein (Mozas_2004, Bertolini_2013) and 4/4 in silico tools predict a damaging outcome for this substitution. This variant is absent in 121614 control chromosomes including broad and large populations from ExAC. In literature, this variant is widely reported as a pathogenic variant and is found in several FH patients. Other missense variants in this codon, p.Arg633Leu and p.Arg633His, have been reported as FH patients and are classified as pathogenic/likely pathogenic in ClinVar, suggesting that the codon p.Arg633 is mutational hot-spot. In addition, multiple clinical diagnostic laboratories/reputable databases have classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as pathogenic.
Comment:
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
Comment:
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; Tichý 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.
Comment:
The p.Arg633Cys variant in LDLR has been reported in at least 11 individuals with familial hypercholesterolemia (FH), including one homozygote (Day 1997, Mozas 2004, Guardamagna 2009, Taylor 2009, Chiou 2011, Tichy 2012, Bertolini 2013, Xiang 2017, Medieros 2017). This variant has been reported in ClinVar (Variation ID: 226379) and has also been identified in 1/30782 South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that the p.Arg833Cys variant may impact the protein. Two other variants at this amino acid position have been reported in at least 4 individuals with FH (p.Arg633Leu and p.Arg633His). In summary, although additional studies are required to fully establish its clinical significance, the p.Arg633Cys variant is likely pathogenic. ACMG/AMP Criteria applied: PS4_Moderate, PM2, PM5_Supporting, PP3.
Comment:
Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies suggest a damaging effect as Western blotting showed decreased expression and reduced LDL uptake suggesting a negative effect on LDLR receptor recycling (Galicia-Garcia et al., 2020); Reported in ClinVar but additional evidence is not available (ClinVar Variant ID#226379; ClinVar); Also reported as R612C due to alternate nomenclature; This variant is associated with the following publications: (PMID: 28349888, 27680772, 9259195, 15241806, 27578128, 28235710, 19843101, 16159606, 20538126, 23375686, 19446849, 18700895, 17539906, 22698793, 21376320, 19538517, 17094996, 32015373, 31447099, 31491741, 30586733, 31589614, 34037665, 33087929, 32041611, 32719484)
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 633 of the LDLR protein (p.Arg633Cys). This variant is present in population databases (rs746118995, gnomAD 0.003%). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 9259195, 15241806, 19446849, 19538517, 19843101, 21376320, 22698793, 23375686). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as p.Arg612Cys. ClinVar contains an entry for this variant (Variation ID: 226379). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Comment:
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.
Comment:
PS3, PM1, PM2, PM5, PP1
Comment:
This variant is also referred to as p.Arg612Cys in the literature. This variant has been reported as a heterozygous change in individuals with features of familial hypercholesterolemia (PMID: 28349888, 27680772, 9259195, 15241806, 27578128, 21376320, 28235710). Functional studies have shown that the c.1897C>T (p.Arg633Cys) variant results in abnormal function of the LDLR protein (PMID: 32015373). The c.1897C>T (p.Arg633Cys) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.001% (3/251490). It affects a moderately conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Different missense variants involving the same residue (p.Arg633His and p.Arg633Leu) have been previously reported in individuals with familial hypercholesterolemia (ClinVar Variation ID: 226380, 252107). Based on the available evidence, the c.1897C>T (p.Arg633Cys) variant is classified as Pathogenic.
Comment:
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.
Comment:
The c.1897C>T (p.Arg633Cys) variant in the LDLR gene is located on the exon 13 and is predicted to replace arginine with cysteine at codon 633 (p.Arg633Cys). The variant has been identified in more than 10 unrelated individuals with familial hypercholesterolemia (FH) (PMID: 27680772, 28235710, 28349888, 31893465, 21376320, 22698793, 15241806, 17094996). Other variants disrupting the same amino acid (p.Arg633Leu, p.Arg633His) have been interpreted as likely pathogenic (ClinVar ID: 252107, 226380). The variant is rare in the general population according to gnomAD (3/251490). Computational prediction algorithms suggest a deleterious impact for this variant (REVEL score 0.845). Therefore, the c.1897C>T (p.Arg633Cys) variant of LDLR has been classified as pathogenic.
Comment:
NA
Comment:
The c.1897C>T (p.R633C) alteration is located in exon 13 (coding exon 13) of the LDLR gene. This alteration results from a C to T substitution at nucleotide position 1897, causing the arginine (R) at amino acid position 633 to be replaced by a cysteine (C). Based on data from gnomAD, the T allele has an overall frequency of 0.001% (3/251490) total alleles studied. The highest observed frequency was 0.003% (1/30616) of South Asian alleles. This variant (also known as p.R612C) has been reported in numerous individuals and cohorts with familial hypercholesterolemia (FH) (Day, 1997; Sánchez-Hernández, 2016; Wang, 2016). Alternate amino acid substitutions at this codon, p.R633L and p.R633H, have also been reported in individuals with FH (Fouchier, 2005). Based on the available evidence, this alteration is classified as pathogenic.
Comment:
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]
Comment:
The LDLR c.1897C>T variant is predicted to result in the amino acid substitution p.Arg633Cys. This variant (also reported as c.Arg612Cys in the literature) has been reported in many unrelated individuals with familial hypercholesterolemia (Mozas et al. 2004. PubMed ID: 15241806; Chiou et al. 2011. PubMed ID: 21376320; Tichý et al. 2012. PubMed ID: 22698793; Day et al. 1997. PubMed ID: 9259195, referred to as R612C; Bertolini et al. 2013. PubMed ID: 23375686, supplementary data; Di Taranto et al. 2019. PubMed ID: 30710474, supplementary data; Dron et al. 2020. PubMed ID: 32041611; Sturm et al. 2021. PubMed ID: 34037665, supplementary data; Futema et al. 2017. PubMed ID: 28349888). In vitro analysis of this variant indicated that this variant results in diminished LDLR expression and activity (Galicia-Garcia et al. 2020. PubMed ID: 32015373). This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD. This variant has been reported in ClinVar by many outside laboratories as likely pathogenic or pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/226379/). Two other amino acid substitutions at this position (p.Arg633His and p.Arg633Leu) have also been reported in individuals with hypercholesterolemia (Fouchier et al. 2005. PubMed ID: 16250003; Di Taranto et al. 2021. PubMed ID: 34297352). In summary, we categorize c.1897C>T (p.Arg633Cys) as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Mutation type classification and pathogenicity assignment of sixteen missense variants located in the EGF-precursor homology domain of the LDLR. | Galicia-Garcia U | Scientific reports | 2020 | PMID: 32015373 |
| Impact of LDLR and PCSK9 pathogenic variants in Japanese heterozygous familial hypercholesterolemia patients. | Hori M | Atherosclerosis | 2019 | PMID: 31491741 |
| Harmonizing Clinical Sequencing and Interpretation for the eMERGE III Network. | eMERGE Consortium. Electronic address: agibbs@bcm.edu | American journal of human genetics | 2019 | PMID: 31447099 |
| Whole-Genome Sequencing to Characterize Monogenic and Polygenic Contributions in Patients Hospitalized With Early-Onset Myocardial Infarction. | Khera AV | Circulation | 2019 | PMID: 30586733 |
| The genetic spectrum of familial hypercholesterolemia in the central south region of China. | Xiang R | Atherosclerosis | 2017 | PMID: 28235710 |
| Mutation detection in Chinese patients with familial hypercholesterolemia. | Du R | SpringerPlus | 2016 | PMID: 28028493 |
| Homozygous Familial Hypercholesterolemia in Spain: Prevalence and Phenotype-Genotype Relationship. | Sánchez-Hernández RM | Circulation. Cardiovascular genetics | 2016 | PMID: 27784735 |
| Polygenic Versus Monogenic Causes of Hypercholesterolemia Ascertained Clinically. | Wang J | Arteriosclerosis, thrombosis, and vascular biology | 2016 | PMID: 27765764 |
| Spectrum of mutations and phenotypic expression in patients with autosomal dominant hypercholesterolemia identified in Italy. | Bertolini S | Atherosclerosis | 2013 | PMID: 23375686 |
| The molecular basis of familial hypercholesterolemia in the Czech Republic: spectrum of LDLR mutations and genotype-phenotype correlations. | Tichý L | Atherosclerosis | 2012 | PMID: 22698793 |
| Array-based resequencing for mutations causing familial hypercholesterolemia. | Chiou KR | Atherosclerosis | 2011 | PMID: 21376320 |
| Detection of mutations and large rearrangements of the low-density lipoprotein receptor gene in Taiwanese patients with familial hypercholesterolemia. | Chiou KR | The American journal of cardiology | 2010 | PMID: 20538126 |
| Mutation screening in patients for familial hypercholesterolaemia (ADH). | Taylor A | Clinical genetics | 2010 | PMID: 19843101 |
| Multiplex ligation-dependent probe amplification analysis to screen for deletions and duplications of the LDLR gene in patients with familial hypercholesterolaemia. | Taylor A | Clinical genetics | 2009 | PMID: 19538517 |
| The type of LDLR gene mutation predicts cardiovascular risk in children with familial hypercholesterolemia. | Guardamagna O | The Journal of pediatrics | 2009 | PMID: 19446849 |
| Multiplex MassARRAY spectrometry (iPLEX) produces a fast and economical test for 56 familial hypercholesterolaemia-causing mutations. | Wright WT | Clinical genetics | 2008 | PMID: 18700895 |
| Multiplex ARMS analysis to detect 13 common mutations in familial hypercholesterolaemia. | Taylor A | Clinical genetics | 2007 | PMID: 17539906 |
| Genetic defects causing familial hypercholesterolaemia: identification of deletions and duplications in the LDL-receptor gene and summary of all mutations found in patients attending the Hammersmith Hospital Lipid Clinic. | Tosi I | Atherosclerosis | 2007 | PMID: 17094996 |
| Update of the molecular basis of familial hypercholesterolemia in The Netherlands. | Fouchier SW | Human mutation | 2005 | PMID: 16250003 |
| Genetic screening protocol for familial hypercholesterolemia which includes splicing defects gives an improved mutation detection rate. | Graham CA | Atherosclerosis | 2005 | PMID: 16159606 |
| Molecular characterization of familial hypercholesterolemia in Spain: identification of 39 novel and 77 recurrent mutations in LDLR. | Mozas P | Human mutation | 2004 | PMID: 15241806 |
| Identification of three new mutations of the low density lipoprotein receptor gene in Dutch familial hypercholesterolemic patients. | Lombardi P | Human mutation | 1998 | PMID: 9452078 |
| Spectrum of LDL receptor gene mutations in heterozygous familial hypercholesterolemia. | Day IN | Human mutation | 1997 | PMID: 9259195 |
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Text-mined citations for this variant ...
HelpRecord last updated Oct 13, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.