ClinVar Genomic variation as it relates to human health
NM_000527.5(LDLR):c.223T>A (p.Cys75Ser)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000527.5(LDLR):c.223T>A (p.Cys75Ser)
Variation ID: 251079 Accession: VCV000251079.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19p13.2 19: 11102696 (GRCh38) [ NCBI UCSC ] 19: 11213372 (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 Oct 10, 2018 Feb 20, 2024 Oct 4, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000527.5:c.223T>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000518.1:p.Cys75Ser missense NM_001195798.2:c.223T>A NP_001182727.1:p.Cys75Ser missense NM_001195799.2:c.190+2351T>A intron variant NM_001195800.2:c.223T>A NP_001182729.1:p.Cys75Ser missense NM_001195803.2:c.223T>A NP_001182732.1:p.Cys75Ser missense NC_000019.10:g.11102696T>A NC_000019.9:g.11213372T>A NG_009060.1:g.18316T>A LRG_274:g.18316T>A LRG_274t1:c.223T>A LRG_274p1:p.Cys75Ser - Protein change
- C75S
- Other names
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- Canonical SPDI
- NC_000019.10:11102695:T:A
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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
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The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
The Genome Aggregation Database (gnomAD) 0.00001
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
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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 |
3897 | 4140 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Likely pathogenic (1) |
criteria provided, single submitter
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Mar 25, 2016 | RCV000237232.4 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Oct 4, 2023 | RCV000775026.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 17, 2021 | RCV001582800.3 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Sep 21, 2022 | RCV002429164.1 |
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
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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
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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
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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: SCV000294535.2
First in ClinVar: Jul 29, 2016 Last updated: Oct 10, 2018 |
Number of individuals with the variant: 1
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Pathogenic
(Feb 17, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001810974.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Comment:
Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Participates … (more)
Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Participates in disulfide bonding with another cysteine residue which is critical for correct protein structure, and is located in the LDL-receptor class A2 repeat domain which is necessary for ligand binding (Sudhof et al., 1985; Rudenko et al., 2002); Reported as a pathogenic/likely pathogenic variant by other clinical laboratories in ClinVar (ClinVar Variant ID#251079; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 10089940) (less)
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Likely pathogenic
(Mar 12, 2019)
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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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Color Diagnostics, LLC DBA Color Health
Accession: SCV000909123.3
First in ClinVar: May 20, 2019 Last updated: Jan 12, 2022 |
Comment:
This missense variant (also known as p.Cys54Ser in the mature protein) is located in the second LDLR type A repeat of the ligand binding domain … (more)
This missense variant (also known as p.Cys54Ser in the mature protein) is located in the second LDLR type A repeat of the ligand binding domain of LDLR protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. Although functional assays have not been performed for this variant, it 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 identified in an individual diagnosed with familial hypercholesterolemia in U.S. (PMID: 10089940). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Likely Pathogenic. (less)
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Likely pathogenic
(Sep 21, 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: SCV002727963.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.C75S variant (also known as c.223T>A), located in coding exon 3 of the LDLR gene, results from a T to A substitution at nucleotide … (more)
The p.C75S variant (also known as c.223T>A), located in coding exon 3 of the LDLR gene, results from a T to A substitution at nucleotide position 223. The cysteine at codon 75 is replaced by serine, an amino acid with 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 et al. Hum Mutat. 2002;20(2):81-7). This particular cysteine alteration (also referred to as C54S) has been described in a proband with LDL-C level of 298mg/dL, in a Slovenian pediatric hypercholesterolemia cohort, and in additional probands referred for FH genetic testing (Emi M et al. Jpn Heart J. 1998;39(6):785-789; Klanar G et al. J. Am. Coll. Cardiol. 2015;66(11):1250-1257; Invitae pers.comm.). Internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of LDLR class A repeat 2 (Ambry internal data). Other variants affecting this codon (p.C75W, c.225T>G and p.C75R, c.223T>C) have also been reported in association with FH (Tosi I et al. Atherosclerosis. 2007;194(1):102-11; Hori M et al. Atherosclerosis. 2019 10;289:101-108). 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)
Number of individuals with the variant: 1
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Pathogenic
(Oct 04, 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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Invitae
Accession: SCV000627031.7
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 75 of the LDLR protein … (more)
This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 75 of the LDLR protein (p.Cys75Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypercholesterolemia (PMID: 10089940; Invitae). This variant is also known as C54S. ClinVar contains an entry for this variant (Variation ID: 251079). 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.Cys75 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 9676383, 10089940, 12124988, 17094996; Invitae), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. (less)
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Impact of LDLR and PCSK9 pathogenic variants in Japanese heterozygous familial hypercholesterolemia patients. | Hori M | Atherosclerosis | 2019 | PMID: 31491741 |
Universal Screening for Familial Hypercholesterolemia in Children. | Klančar G | Journal of the American College of Cardiology | 2015 | PMID: 26361156 |
Update and analysis of the University College London low density lipoprotein receptor familial hypercholesterolemia database. | Leigh SE | Annals of human genetics | 2008 | PMID: 18325082 |
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 |
The UMD-LDLR database: additions to the software and 490 new entries to the database. | Villéger L | Human mutation | 2002 | PMID: 12124988 |
Familial hypercholesterolemia kindred in Utah with novel C54S mutations of the LDL receptor gene. | Emi M | Japanese heart journal | 1998 | PMID: 10089940 |
Mutation analysis of exon 3 of the LDL receptor gene in patients with severe hypercholesterolemia. | Geisel J | Clinical chemistry and laboratory medicine | 1998 | PMID: 9676383 |
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 rs879254439 ...
HelpRecord last updated Feb 28, 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.