Disrupt disulfide bridge between Cys204 and Cys222.
ClinVar Genomic variation as it relates to human health
NM_000527.5(LDLR):c.611G>T (p.Cys204Phe)
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.
(4)
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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.
Likely pathogenic
4
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000527.5(LDLR):c.611G>T (p.Cys204Phe)
Variation ID: 251322 Accession: VCV000251322.5
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19p13.2 19: 11105517 (GRCh38) [ NCBI UCSC ] 19: 11216193 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Jul 29, 2016 May 1, 2024 Oct 15, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000527.5:c.611G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000518.1:p.Cys204Phe missense NM_001195798.2:c.611G>T NP_001182727.1:p.Cys204Phe missense NM_001195799.2:c.488G>T NP_001182728.1:p.Cys163Phe missense NM_001195800.2:c.314-1875G>T intron variant NM_001195803.2:c.314-1048G>T intron variant NC_000019.10:g.11105517G>T NC_000019.9:g.11216193G>T NG_009060.1:g.21137G>T LRG_274:g.21137G>T LRG_274t1:c.611G>T LRG_274p1:p.Cys204Phe - Protein change
- C204F, C163F
- Other names
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- Canonical SPDI
- NC_000019.10:11105516:G:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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| HI score
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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. |
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| LDLR | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
4075 | 4351 | |
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. |
|---|---|---|---|---|
| Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Nov 5, 2016 | RCV000237647.2 | |
| Likely pathogenic (1) |
criteria provided, single submitter
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Aug 16, 2022 | RCV002356332.2 | |
| Likely pathogenic (1) |
criteria provided, single submitter
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Oct 15, 2023 | RCV003581605.2 |
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. |
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Likely pathogenic
(Mar 25, 2016)
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criteria provided, single submitter
Method: literature only
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Familial hypercholesterolemia
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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LDLR-LOVD, British Heart Foundation
Accession: SCV000294820.2
First in ClinVar: Jul 29, 2016 Last updated: Jul 29, 2016 |
Number of individuals with the variant: 1
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Likely pathogenic
(Nov 05, 2016)
|
criteria provided, single submitter
Method: clinical testing
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Hypercholesterolemia, familial, 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
inherited
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Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation
Additional submitter:
Centre of Molecular Biology and Gene Therapy, University Hospital Brno
Accession: SCV000540744.1
First in ClinVar: Jul 29, 2016 Last updated: Jul 29, 2016 |
Comment:
Disrupt disulfide bridge between Cys204 and Cys222.
Number of individuals with the variant: 6
Clinical Features:
Hypercholesterolemia (present) , Xanthelasma (present) , Tendon xanthoma (present) , Corneal arcus (present)
Family history: yes
Age: 6-48 years
Sex: mixed
Ethnicity/Population group: Caucasian
Geographic origin: Czech Republic
Tissue: Whole blood
Method: ADH Master kit (Multiplicom)
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Likely pathogenic
(Oct 15, 2023)
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criteria provided, single submitter
Method: clinical testing
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Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV004298327.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 204 of the LDLR protein … (more)
This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 204 of the LDLR protein (p.Cys204Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of familial hypercholesterolemia (PMID: 22881376). ClinVar contains an entry for this variant (Variation ID: 251322). 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.Cys204 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 12417285, 23375686, 30592178), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less)
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Likely pathogenic
(Aug 16, 2022)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002654398.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.C204F variant (also known as c.611G>T), located in coding exon 4 of the LDLR gene, results from a G to T substitution at nucleotide … (more)
The p.C204F variant (also known as c.611G>T), located in coding exon 4 of the LDLR gene, results from a G to T substitution at nucleotide position 611. The cysteine at codon 204 is replaced by phenylalanine, an amino acid with highly dissimilar properties. 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). This alteration, which is also known as p.C183F, has been reported in individuals with FH (Ambry internal data). Another alteration at the same codon, p.C204Y (c.611G>A), has been detected in a proband and son with FH, and in additional FH cohorts (Cefalù AB et al. Int. J. Mol. Med., 2006 Mar;17:539-46; Marduel M et al. Hum. Mutat., 2010 Nov;31:E1811-24; Bertolini S et al. Atherosclerosis, 2013 Apr;227:342-8). Internal structural analysis indicates this variant eliminates a disulfide bond critical for the structural integrity of the LDLR class A repeat 5 (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
|
Comment:
Comment:
This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 204 of the LDLR protein (p.Cys204Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of familial hypercholesterolemia (PMID: 22881376). ClinVar contains an entry for this variant (Variation ID: 251322). 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.Cys204 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 12417285, 23375686, 30592178), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Comment:
The p.C204F variant (also known as c.611G>T), located in coding exon 4 of the LDLR gene, results from a G to T substitution at nucleotide position 611. The cysteine at codon 204 is replaced by phenylalanine, an amino acid with highly dissimilar properties. 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). This alteration, which is also known as p.C183F, has been reported in individuals with FH (Ambry internal data). Another alteration at the same codon, p.C204Y (c.611G>A), has been detected in a proband and son with FH, and in additional FH cohorts (Cefalù AB et al. Int. J. Mol. Med., 2006 Mar;17:539-46; Marduel M et al. Hum. Mutat., 2010 Nov;31:E1811-24; Bertolini S et al. Atherosclerosis, 2013 Apr;227:342-8). Internal structural analysis indicates this variant eliminates a disulfide bond critical for the structural integrity of the LDLR class A repeat 5 (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be 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:
Disrupt disulfide bridge between Cys204 and Cys222.
Comment:
This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 204 of the LDLR protein (p.Cys204Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of familial hypercholesterolemia (PMID: 22881376). ClinVar contains an entry for this variant (Variation ID: 251322). 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.Cys204 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 12417285, 23375686, 30592178), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Comment:
The p.C204F variant (also known as c.611G>T), located in coding exon 4 of the LDLR gene, results from a G to T substitution at nucleotide position 611. The cysteine at codon 204 is replaced by phenylalanine, an amino acid with highly dissimilar properties. 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). This alteration, which is also known as p.C183F, has been reported in individuals with FH (Ambry internal data). Another alteration at the same codon, p.C204Y (c.611G>A), has been detected in a proband and son with FH, and in additional FH cohorts (Cefalù AB et al. Int. J. Mol. Med., 2006 Mar;17:539-46; Marduel M et al. Hum. Mutat., 2010 Nov;31:E1811-24; Bertolini S et al. Atherosclerosis, 2013 Apr;227:342-8). Internal structural analysis indicates this variant eliminates a disulfide bond critical for the structural integrity of the LDLR class A repeat 5 (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Limited-Variant Screening vs Comprehensive Genetic Testing for Familial Hypercholesterolemia Diagnosis. | Sturm AC | JAMA cardiology | 2021 | PMID: 34037665 |
| Genetic variations in familial hypercholesterolemia and cascade screening in East Asians. | Chan ML | Molecular genetics & genomic medicine | 2019 | PMID: 30592178 |
| Spectrum of mutations and phenotypic expression in patients with autosomal dominant hypercholesterolemia identified in Italy. | Bertolini S | Atherosclerosis | 2013 | PMID: 23375686 |
| Low-density lipoprotein receptor gene familial hypercholesterolemia variant database: update and pathological assessment. | Usifo E | Annals of human genetics | 2012 | PMID: 22881376 |
| Update and analysis of the University College London low density lipoprotein receptor familial hypercholesterolemia database. | Leigh SE | Annals of human genetics | 2008 | PMID: 18325082 |
| Six novel mutations of the LDL receptor gene in FH kindred of Sicilian and Paraguayan descent. | Cefalù AB | International journal of molecular medicine | 2006 | PMID: 16465405 |
| Molecular genetic analysis of familial hypercholesterolemia: spectrum and regional difference of LDL receptor gene mutations in Japanese population. | Yu W | Atherosclerosis | 2002 | PMID: 12417285 |
| 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 |
Text-mined citations for rs879254592 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 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.