This missense variant (also known as p.Cys113Phe in the mature protein and as FH Alessandria) is located in the third LDLR type A repeat of the ligand binding domain of the 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 reported in three individuals with hypercholesterolemia in Italy, Germany, and Japan (PMID: 10978268 11462246 18718593, 23375686). 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.
ClinVar Genomic variation as it relates to human health
NM_000527.5(LDLR):c.401G>T (p.Cys134Phe)
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.
(5)
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
5
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.401G>T (p.Cys134Phe)
Variation ID: 251204 Accession: VCV000251204.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19p13.2 19: 11105307 (GRCh38) [ NCBI UCSC ] 19: 11215983 (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 May 19, 2018 Feb 14, 2024 Sep 11, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000527.5:c.401G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000518.1:p.Cys134Phe missense NM_001195798.2:c.401G>T NP_001182727.1:p.Cys134Phe missense NM_001195799.2:c.278G>T NP_001182728.1:p.Cys93Phe missense NM_001195800.2:c.314-2085G>T intron variant NM_001195803.2:c.314-1258G>T intron variant NC_000019.10:g.11105307G>T NC_000019.9:g.11215983G>T NG_009060.1:g.20927G>T LRG_274:g.20927G>T LRG_274t1:c.401G>T LRG_274p1:p.Cys134Phe P01130:p.Cys134Phe - Protein change
- C134F, C93F
- Other names
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FH Alessandria
- Canonical SPDI
- NC_000019.10:11105306: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
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. |
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| 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. |
|---|---|---|---|---|
| Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Mar 25, 2016 | RCV000237376.4 | |
| Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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May 29, 2020 | RCV000775037.13 | |
| Likely pathogenic (1) |
criteria provided, single submitter
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Sep 11, 2023 | RCV003148692.2 |
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
|
LDLR-LOVD, British Heart Foundation
Accession: SCV000294687.2
First in ClinVar: Jul 29, 2016 Last updated: May 19, 2018 |
Observation 1:
Number of individuals with the variant: 1
Observation 2:
Number of individuals with the variant: 1
|
|
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Likely pathogenic
(Mar 01, 2016)
|
criteria provided, single submitter
Method: research
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Familial hypercholesterolemia
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
Iberoamerican FH Network
Accession: SCV000748130.1
First in ClinVar: May 19, 2018 Last updated: May 19, 2018
Comment:
Variant present in the database from Uruguay
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Likely pathogenic
(Mar 12, 2019)
|
criteria provided, single submitter
Method: clinical testing
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Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000909134.3
First in ClinVar: May 20, 2019 Last updated: Jan 12, 2022 |
Comment:
This missense variant (also known as p.Cys113Phe in the mature protein and as FH Alessandria) is located in the third LDLR type A repeat of … (more)
This missense variant (also known as p.Cys113Phe in the mature protein and as FH Alessandria) is located in the third LDLR type A repeat of the ligand binding domain of the 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 reported in three individuals with hypercholesterolemia in Italy, Germany, and Japan (PMID: 10978268 11462246 18718593, 23375686). 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 11, 2023)
|
criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV003836811.2
First in ClinVar: Mar 11, 2023 Last updated: Sep 22, 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.(C113F); This variant is associated with the following publications: (PMID: 30583242, 34906454, 2988123, 12459547, 23375686, 31491741, 32331935, 34037665, 11462246, 10978268, 18718593) (less)
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Pathogenic
(May 29, 2020)
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criteria provided, single submitter
Method: clinical testing
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Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001212401.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with phenylalanine at codon 134 of the LDLR protein … (more)
This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with phenylalanine at codon 134 of the LDLR protein (p.Cys134Phe). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and phenylalanine. This variant has been observed in individual(s) with familial hypercholesterolemia (PMID: 10978268, 11462246, 18718593). This variant is also known as C113F in the literature. ClinVar contains an entry for this variant (Variation ID: 251204). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic. 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: 23375686, 11462246, 25921077, 10735632), which suggests that this may be a clinically significant amino acid residue. 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). (less)
|
Comment:
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.(C113F); This variant is associated with the following publications: (PMID: 30583242, 34906454, 2988123, 12459547, 23375686, 31491741, 32331935, 34037665, 11462246, 10978268, 18718593)
Comment:
This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with phenylalanine at codon 134 of the LDLR protein (p.Cys134Phe). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and phenylalanine. This variant has been observed in individual(s) with familial hypercholesterolemia (PMID: 10978268, 11462246, 18718593). This variant is also known as C113F in the literature. ClinVar contains an entry for this variant (Variation ID: 251204). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic. 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: 23375686, 11462246, 25921077, 10735632), which suggests that this may be a clinically significant amino acid residue. 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).
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:
This missense variant (also known as p.Cys113Phe in the mature protein and as FH Alessandria) is located in the third LDLR type A repeat of the ligand binding domain of the 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 reported in three individuals with hypercholesterolemia in Italy, Germany, and Japan (PMID: 10978268 11462246 18718593, 23375686). 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.
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.(C113F); This variant is associated with the following publications: (PMID: 30583242, 34906454, 2988123, 12459547, 23375686, 31491741, 32331935, 34037665, 11462246, 10978268, 18718593)
Comment:
This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with phenylalanine at codon 134 of the LDLR protein (p.Cys134Phe). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and phenylalanine. This variant has been observed in individual(s) with familial hypercholesterolemia (PMID: 10978268, 11462246, 18718593). This variant is also known as C113F in the literature. ClinVar contains an entry for this variant (Variation ID: 251204). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic. 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: 23375686, 11462246, 25921077, 10735632), which suggests that this may be a clinically significant amino acid residue. 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).
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| 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 of Japanese common LDLR gene mutations and their phenotypes: Mild type mutation L547V might predominate in the Japanese population. | Miyake Y | Atherosclerosis | 2009 | PMID: 18718593 |
| Update and analysis of the University College London low density lipoprotein receptor familial hypercholesterolemia database. | Leigh SE | Annals of human genetics | 2008 | PMID: 18325082 |
| Identification of recurrent and novel mutations in the LDL receptor gene in German patients with familial hypercholesterolemia. | Nauck MS | Human mutation | 2001 | PMID: 11462246 |
| Clinical expression of familial hypercholesterolemia in clusters of mutations of the LDL receptor gene that cause a receptor-defective or receptor-negative phenotype. | Bertolini S | Arteriosclerosis, thrombosis, and vascular biology | 2000 | PMID: 10978268 |
| 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 |
Text-mined citations for rs879254514 ...
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.