Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(C113R); This variant is associated with the following publications: (PMID: 26582918, 25921077, 7548065, 18325082, 23375686, 12459547, 2988123, 7603991, 29233637, 15256764, 12417285, 31447099, 10735632, 32759540, 32770674, 12730724, 30415195, 11462246, 34037665, 28179607, 7979249, 28349240)
ClinVar Genomic variation as it relates to human health
NM_000527.5(LDLR):c.400T>C (p.Cys134Arg)
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.
(10)
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
10
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.400T>C (p.Cys134Arg)
Variation ID: 226322 Accession: VCV000226322.27
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 19p13.2 19: 11105306 (GRCh38) [ NCBI UCSC ] 19: 11215982 (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 20, 2024 Aug 1, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000527.5:c.400T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000518.1:p.Cys134Arg missense NM_001195798.2:c.400T>C NP_001182727.1:p.Cys134Arg missense NM_001195799.2:c.277T>C NP_001182728.1:p.Cys93Arg missense NM_001195800.2:c.314-2086T>C intron variant NM_001195803.2:c.314-1259T>C intron variant NC_000019.10:g.11105306T>C NC_000019.9:g.11215982T>C NG_009060.1:g.20926T>C LRG_274:g.20926T>C LRG_274t1:c.400T>C LRG_274p1:p.Cys134Arg - Protein change
- C134R, C93R
- Other names
- -
- Canonical SPDI
- NC_000019.10:11105305:T:C
-
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.
-
The Genome Aggregation Database (gnomAD), exomes 0.00000
- 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 (4) |
criteria provided, multiple submitters, no conflicts
|
Mar 9, 2023 | RCV000211566.12 | |
| Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Aug 1, 2024 | RCV000494460.6 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Oct 10, 2023 | RCV000775036.11 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Aug 15, 2017 | RCV000844756.4 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Mar 9, 2023 | RCV002372212.3 |
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
(Jun 12, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000582589.7
First in ClinVar: Jul 02, 2017 Last updated: Jun 24, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(C113R); This variant is associated with the following publications: (PMID: 26582918, 25921077, 7548065, 18325082, 23375686, 12459547, 2988123, 7603991, 29233637, 15256764, 12417285, 31447099, 10735632, 32759540, 32770674, 12730724, 30415195, 11462246, 34037665, 28179607, 7979249, 28349240) (less)
|
|
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Pathogenic
(Mar 09, 2023)
|
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: SCV004820162.1
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 replaces cysteine with arginine at codon 134 in the third LDLR type A repeat of the ligand binding domain of the LDLR … (more)
This missense variant replaces cysteine with arginine at codon 134 in the third LDLR type A repeat of the ligand binding domain of the LDLR protein. This variant is also known as p.Cys113Arg in the mature protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Although functional studies have not been reported, this variant changes one of the functionally critical cysteine residues that form intra-repeat disulfide bonds in the ligand binding domain (PMID: 15952897) and is expected to have deleterious impact on the LDLR protein folding and stability. This variant has been reported in over ten individuals affected with familial hypercholesterolemia (PMID: 10735632, 11462246, 12417285, 12730724, 15256764, 25921077, 29233637, 32143996, 32759540). It has also been observed to segregate with high LDL-C levels and xanthomas in three related individuals (PMID: 25921077). This variant has been identified in 1/251176 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Pathogenic. (less)
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Mar 09, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002624552.3
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.C134R pathogenic mutation (also known as c.400T>C), located in coding exon 4 of the LDLR gene, results from a T to C substitution at … (more)
The p.C134R pathogenic mutation (also known as c.400T>C), located in coding exon 4 of the LDLR gene, results from a T to C substitution at nucleotide position 400. The cysteine at codon 134 is replaced by arginine, an amino acid with highly dissimilar properties. This variant has been described in patients with familial hypercholesterolemia (FH) from various ethnic groups (Lombardi MP et al. Clin Genet. 2000;57:116-24; Nauck MS et al. Hum Mutat. 2001;18:165-6; El Messal M et al. J Hum Genet. 2003;48:199-203; Han Y et al. Int J Pediatr Otorhinolaryngol. 2015;79:1148-51). Other alterations involving the same amino acid, p.C134F (c.401G>T), p.C134W (c.402C>G), and p.C134Y (c.401G>A), have also been reported in FH cohorts (Bertolini S et al. Atherosclerosis. 2013;227(2):342-8). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Pathogenic LDLR mutations that result in the substitution or generation of cysteine residues within the cysteine-rich LDLR class A repeats and EGF-like domains are common in familial hypercholesterolemia (FH) (Villéger L. Hum Mutat. 2002;20(2):81-7). Internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of the LDLR class A repeat 3 (Ambry internal data). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
|
|
|
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: SCV000294685.2
First in ClinVar: Jul 29, 2016 Last updated: May 03, 2018 |
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
|
|
|
Likely pathogenic
(Aug 15, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Homozygous familial hypercholesterolemia
(Autosomal dominant inheritance)
Affected status: not provided
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000711781.2
First in ClinVar: Apr 09, 2018 Last updated: Aug 31, 2019 |
Comment:
The p.Cys134Arg (previously p.Cys113Arg) variant in LDLR has been reported in >4 individuals with familial hypercholesterolemia (FH) and segregated with disease with 2 affected relatives … (more)
The p.Cys134Arg (previously p.Cys113Arg) variant in LDLR has been reported in >4 individuals with familial hypercholesterolemia (FH) and segregated with disease with 2 affected relatives from 1 family (Lombardi 2000, Nauck 2001, El Messal 2 003, Han 2015, ClinVar: Variation ID 226322). It has also been identified in 1/1 11580 European chromosomes by the Genome Aggregation Database (gnomAD, http://gn omad.broadinstitute.org/; dbSNP rs875989900). Computational prediction tools and conservation analysis suggest that the p.Cys134Arg variant may impact the prote in. Additionally, other missense variants at this position (p.Cys134Tyr, p.Cys13 4Phe, p.Cys134Gly and p.Cys134Trp) have been reported in individuals with famili al hypercholesterolemia (Human Gene Mutation Database: Stenson et al., 2017), In summary, although additional studies are required to fully establish its clinic al significance, the p.Cys134Arg variant is likely pathogenic for autosomal domi nant FH. ACMG/AMP criteria applied: PS4_Moderate, PM2, PM5_Supporting, PP3. (less)
Number of individuals with the variant: 7
|
|
|
Pathogenic
(Oct 10, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000752410.7
First in ClinVar: May 03, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 134 of the LDLR protein … (more)
This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 134 of the LDLR protein (p.Cys134Arg). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 10735632, 11462246, 12730724, 25921077). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Cys113Arg. ClinVar contains an entry for this variant (Variation ID: 226322). 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. This variant affects a cysteine residue located within an LDLRA or epidermal-growth-factor (EGF)-like domains of the LDLR protein. Cysteine residues in these domains have been shown to be involved in the formation of disulfide bridges, which are critical for protein structure and stability (PMID: 7548065, 7603991, 7979249). In addition, missense substitutions within the LDLRA and EGF-like domains affecting cysteine residues are overrepresented among patients with hypercholesterolemia (PMID: 18325082). This variant disrupts the p.Cys134 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 11462246, 23375686), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Oct 24, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000909133.4
First in ClinVar: May 20, 2019 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces cysteine with arginine at codon 134 in the third LDLR type A repeat of the ligand binding domain of the LDLR … (more)
This missense variant replaces cysteine with arginine at codon 134 in the third LDLR type A repeat of the ligand binding domain of the LDLR protein. This variant is also known as p.Cys113Arg in the mature protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Although functional studies have not been reported, this variant changes one of the functionally critical cysteine residues that form intra-repeat disulfide bonds in the ligand binding domain (PMID: 15952897) and is expected to have deleterious impact on the LDLR protein folding and stability. Different missense variants occurring at the same codon (p.Cys134Tyr, p.Cys134Phe, p.Cys134Trp) are known to be disease-causing (ClinVar variation ID: 251203, 251204, 251205). This p.Cys134Arg variant has been reported in over ten individuals affected with familial hypercholesterolemia (PMID: 10735632, 11462246, 12417285, 12730724, 15256764, 25921077, 29233637, 32143996, 32759540). It has also been observed to segregate with high LDL-C levels and xanthomas in three related individuals (PMID: 25921077). This variant has been identified in 1/251176 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Pathogenic. (less)
|
|
|
Pathogenic
(Aug 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV005330403.2
First in ClinVar: Oct 08, 2024 Last updated: Oct 20, 2024 |
Comment:
LDLR: PM1, PM2, PM5, PP4:Moderate, PS4:Moderate
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Mar 24, 2016)
|
no assertion criteria provided
Method: clinical testing
|
Familial hypercholesterolemia
Affected status: yes
Allele origin:
germline
|
Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital
Accession: SCV000268561.1
First in ClinVar: May 22, 2016 Last updated: May 22, 2016 |
Number of individuals with the variant: 1
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: research
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum
Accession: SCV000606104.1
First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017 |
|
Comment:
Comment:
This missense variant replaces cysteine with arginine at codon 134 in the third LDLR type A repeat of the ligand binding domain of the LDLR protein. This variant is also known as p.Cys113Arg in the mature protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Although functional studies have not been reported, this variant changes one of the functionally critical cysteine residues that form intra-repeat disulfide bonds in the ligand binding domain (PMID: 15952897) and is expected to have deleterious impact on the LDLR protein folding and stability. This variant has been reported in over ten individuals affected with familial hypercholesterolemia (PMID: 10735632, 11462246, 12417285, 12730724, 15256764, 25921077, 29233637, 32143996, 32759540). It has also been observed to segregate with high LDL-C levels and xanthomas in three related individuals (PMID: 25921077). This variant has been identified in 1/251176 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Pathogenic.
Comment:
The p.C134R pathogenic mutation (also known as c.400T>C), located in coding exon 4 of the LDLR gene, results from a T to C substitution at nucleotide position 400. The cysteine at codon 134 is replaced by arginine, an amino acid with highly dissimilar properties. This variant has been described in patients with familial hypercholesterolemia (FH) from various ethnic groups (Lombardi MP et al. Clin Genet. 2000;57:116-24; Nauck MS et al. Hum Mutat. 2001;18:165-6; El Messal M et al. J Hum Genet. 2003;48:199-203; Han Y et al. Int J Pediatr Otorhinolaryngol. 2015;79:1148-51). Other alterations involving the same amino acid, p.C134F (c.401G>T), p.C134W (c.402C>G), and p.C134Y (c.401G>A), have also been reported in FH cohorts (Bertolini S et al. Atherosclerosis. 2013;227(2):342-8). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Pathogenic LDLR mutations that result in the substitution or generation of cysteine residues within the cysteine-rich LDLR class A repeats and EGF-like domains are common in familial hypercholesterolemia (FH) (Villéger L. Hum Mutat. 2002;20(2):81-7). Internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of the LDLR class A repeat 3 (Ambry internal data). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Comment:
The p.Cys134Arg (previously p.Cys113Arg) variant in LDLR has been reported in >4 individuals with familial hypercholesterolemia (FH) and segregated with disease with 2 affected relatives from 1 family (Lombardi 2000, Nauck 2001, El Messal 2 003, Han 2015, ClinVar: Variation ID 226322). It has also been identified in 1/1 11580 European chromosomes by the Genome Aggregation Database (gnomAD, http://gn omad.broadinstitute.org/; dbSNP rs875989900). Computational prediction tools and conservation analysis suggest that the p.Cys134Arg variant may impact the prote in. Additionally, other missense variants at this position (p.Cys134Tyr, p.Cys13 4Phe, p.Cys134Gly and p.Cys134Trp) have been reported in individuals with famili al hypercholesterolemia (Human Gene Mutation Database: Stenson et al., 2017), In summary, although additional studies are required to fully establish its clinic al significance, the p.Cys134Arg variant is likely pathogenic for autosomal domi nant FH. ACMG/AMP criteria applied: PS4_Moderate, PM2, PM5_Supporting, PP3.
Comment:
This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 134 of the LDLR protein (p.Cys134Arg). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 10735632, 11462246, 12730724, 25921077). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Cys113Arg. ClinVar contains an entry for this variant (Variation ID: 226322). 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. This variant affects a cysteine residue located within an LDLRA or epidermal-growth-factor (EGF)-like domains of the LDLR protein. Cysteine residues in these domains have been shown to be involved in the formation of disulfide bridges, which are critical for protein structure and stability (PMID: 7548065, 7603991, 7979249). In addition, missense substitutions within the LDLRA and EGF-like domains affecting cysteine residues are overrepresented among patients with hypercholesterolemia (PMID: 18325082). This variant disrupts the p.Cys134 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 11462246, 23375686), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Comment:
This missense variant replaces cysteine with arginine at codon 134 in the third LDLR type A repeat of the ligand binding domain of the LDLR protein. This variant is also known as p.Cys113Arg in the mature protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Although functional studies have not been reported, this variant changes one of the functionally critical cysteine residues that form intra-repeat disulfide bonds in the ligand binding domain (PMID: 15952897) and is expected to have deleterious impact on the LDLR protein folding and stability. Different missense variants occurring at the same codon (p.Cys134Tyr, p.Cys134Phe, p.Cys134Trp) are known to be disease-causing (ClinVar variation ID: 251203, 251204, 251205). This p.Cys134Arg variant has been reported in over ten individuals affected with familial hypercholesterolemia (PMID: 10735632, 11462246, 12417285, 12730724, 15256764, 25921077, 29233637, 32143996, 32759540). It has also been observed to segregate with high LDL-C levels and xanthomas in three related individuals (PMID: 25921077). This variant has been identified in 1/251176 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Pathogenic.
Comment:
LDLR: PM1, PM2, PM5, PP4:Moderate, PS4:Moderate
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:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(C113R); This variant is associated with the following publications: (PMID: 26582918, 25921077, 7548065, 18325082, 23375686, 12459547, 2988123, 7603991, 29233637, 15256764, 12417285, 31447099, 10735632, 32759540, 32770674, 12730724, 30415195, 11462246, 34037665, 28179607, 7979249, 28349240)
Comment:
This missense variant replaces cysteine with arginine at codon 134 in the third LDLR type A repeat of the ligand binding domain of the LDLR protein. This variant is also known as p.Cys113Arg in the mature protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Although functional studies have not been reported, this variant changes one of the functionally critical cysteine residues that form intra-repeat disulfide bonds in the ligand binding domain (PMID: 15952897) and is expected to have deleterious impact on the LDLR protein folding and stability. This variant has been reported in over ten individuals affected with familial hypercholesterolemia (PMID: 10735632, 11462246, 12417285, 12730724, 15256764, 25921077, 29233637, 32143996, 32759540). It has also been observed to segregate with high LDL-C levels and xanthomas in three related individuals (PMID: 25921077). This variant has been identified in 1/251176 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Pathogenic.
Comment:
The p.C134R pathogenic mutation (also known as c.400T>C), located in coding exon 4 of the LDLR gene, results from a T to C substitution at nucleotide position 400. The cysteine at codon 134 is replaced by arginine, an amino acid with highly dissimilar properties. This variant has been described in patients with familial hypercholesterolemia (FH) from various ethnic groups (Lombardi MP et al. Clin Genet. 2000;57:116-24; Nauck MS et al. Hum Mutat. 2001;18:165-6; El Messal M et al. J Hum Genet. 2003;48:199-203; Han Y et al. Int J Pediatr Otorhinolaryngol. 2015;79:1148-51). Other alterations involving the same amino acid, p.C134F (c.401G>T), p.C134W (c.402C>G), and p.C134Y (c.401G>A), have also been reported in FH cohorts (Bertolini S et al. Atherosclerosis. 2013;227(2):342-8). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Pathogenic LDLR mutations that result in the substitution or generation of cysteine residues within the cysteine-rich LDLR class A repeats and EGF-like domains are common in familial hypercholesterolemia (FH) (Villéger L. Hum Mutat. 2002;20(2):81-7). Internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of the LDLR class A repeat 3 (Ambry internal data). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Comment:
The p.Cys134Arg (previously p.Cys113Arg) variant in LDLR has been reported in >4 individuals with familial hypercholesterolemia (FH) and segregated with disease with 2 affected relatives from 1 family (Lombardi 2000, Nauck 2001, El Messal 2 003, Han 2015, ClinVar: Variation ID 226322). It has also been identified in 1/1 11580 European chromosomes by the Genome Aggregation Database (gnomAD, http://gn omad.broadinstitute.org/; dbSNP rs875989900). Computational prediction tools and conservation analysis suggest that the p.Cys134Arg variant may impact the prote in. Additionally, other missense variants at this position (p.Cys134Tyr, p.Cys13 4Phe, p.Cys134Gly and p.Cys134Trp) have been reported in individuals with famili al hypercholesterolemia (Human Gene Mutation Database: Stenson et al., 2017), In summary, although additional studies are required to fully establish its clinic al significance, the p.Cys134Arg variant is likely pathogenic for autosomal domi nant FH. ACMG/AMP criteria applied: PS4_Moderate, PM2, PM5_Supporting, PP3.
Comment:
This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 134 of the LDLR protein (p.Cys134Arg). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 10735632, 11462246, 12730724, 25921077). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Cys113Arg. ClinVar contains an entry for this variant (Variation ID: 226322). 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. This variant affects a cysteine residue located within an LDLRA or epidermal-growth-factor (EGF)-like domains of the LDLR protein. Cysteine residues in these domains have been shown to be involved in the formation of disulfide bridges, which are critical for protein structure and stability (PMID: 7548065, 7603991, 7979249). In addition, missense substitutions within the LDLRA and EGF-like domains affecting cysteine residues are overrepresented among patients with hypercholesterolemia (PMID: 18325082). This variant disrupts the p.Cys134 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 11462246, 23375686), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Comment:
This missense variant replaces cysteine with arginine at codon 134 in the third LDLR type A repeat of the ligand binding domain of the LDLR protein. This variant is also known as p.Cys113Arg in the mature protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Although functional studies have not been reported, this variant changes one of the functionally critical cysteine residues that form intra-repeat disulfide bonds in the ligand binding domain (PMID: 15952897) and is expected to have deleterious impact on the LDLR protein folding and stability. Different missense variants occurring at the same codon (p.Cys134Tyr, p.Cys134Phe, p.Cys134Trp) are known to be disease-causing (ClinVar variation ID: 251203, 251204, 251205). This p.Cys134Arg variant has been reported in over ten individuals affected with familial hypercholesterolemia (PMID: 10735632, 11462246, 12417285, 12730724, 15256764, 25921077, 29233637, 32143996, 32759540). It has also been observed to segregate with high LDL-C levels and xanthomas in three related individuals (PMID: 25921077). This variant has been identified in 1/251176 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Pathogenic.
Comment:
LDLR: PM1, PM2, PM5, PP4:Moderate, PS4:Moderate
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Targeted Genetic Analysis in a Chinese Cohort of 208 Patients Related to Familial Hypercholesterolemia. | Wang H | Journal of atherosclerosis and thrombosis | 2020 | PMID: 32759540 |
| Patient acceptance of genetic testing for familial hypercholesterolemia in the CASCADE FH Registry. | Gidding SS | Journal of clinical lipidology | 2020 | PMID: 32143996 |
| Compound heterozygous familial hypercholesterolemia in a Chinese boy with a de novo and transmitted low-density lipoprotein receptor mutation. | Ma Y | Journal of clinical lipidology | 2018 | PMID: 29233637 |
| The Human Gene Mutation Database: towards a comprehensive repository of inherited mutation data for medical research, genetic diagnosis and next-generation sequencing studies. | Stenson PD | Human genetics | 2017 | PMID: 28349240 |
| Clinical features of bilateral temporal bone xanthoma with LDLR gene mutation. | Han Y | International journal of pediatric otorhinolaryngology | 2015 | PMID: 25921077 |
| Spectrum of mutations and phenotypic expression in patients with autosomal dominant hypercholesterolemia identified in Italy. | Bertolini S | Atherosclerosis | 2013 | PMID: 23375686 |
| Update and analysis of the University College London low density lipoprotein receptor familial hypercholesterolemia database. | Leigh SE | Annals of human genetics | 2008 | PMID: 18325082 |
| Structure and physiologic function of the low-density lipoprotein receptor. | Jeon H | Annual review of biochemistry | 2005 | PMID: 15952897 |
| Mutations in Japanese subjects with primary hyperlipidemia--results from the Research Committee of the Ministry of Health and Welfare of Japan since 1996--. | Maruyama T | Journal of atherosclerosis and thrombosis | 2004 | PMID: 15256764 |
| Familial hypercholesterolemia in Morocco: first report of mutations in the LDL receptor gene. | El Messal M | Journal of human genetics | 2003 | PMID: 12730724 |
| Molecular genetic analysis of familial hypercholesterolemia: spectrum and regional difference of LDL receptor gene mutations in Japanese population. | Yu W | Atherosclerosis | 2002 | PMID: 12417285 |
| Identification of recurrent and novel mutations in the LDL receptor gene in German patients with familial hypercholesterolemia. | Nauck MS | Human mutation | 2001 | PMID: 11462246 |
| Molecular genetic testing for familial hypercholesterolemia: spectrum of LDL receptor gene mutations in The Netherlands. | Lombardi MP | Clinical genetics | 2000 | PMID: 10735632 |
| Three-dimensional structure of a cysteine-rich repeat from the low-density lipoprotein receptor. | Daly NL | Proceedings of the National Academy of Sciences of the United States of America | 1995 | PMID: 7603991 |
| Disulfide bridges of a cysteine-rich repeat of the LDL receptor ligand-binding domain. | Bieri S | Biochemistry | 1995 | PMID: 7548065 |
| Structures and functions of multiligand lipoprotein receptors: macrophage scavenger receptors and LDL receptor-related protein (LRP). | Krieger M | Annual review of biochemistry | 1994 | PMID: 7979249 |
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Record last updated Oct 20, 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.