ClinVar Genomic variation as it relates to human health
NM_000527.5(LDLR):c.1056C>G (p.Cys352Trp)
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.1056C>G (p.Cys352Trp)
Variation ID: 251622 Accession: VCV000251622.5
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19p13.2 19: 11110767 (GRCh38) [ NCBI UCSC ] 19: 11221443 (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 May 24, 2021 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000527.5:c.1056C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000518.1:p.Cys352Trp missense NM_001195798.2:c.1056C>G NP_001182727.1:p.Cys352Trp missense NM_001195799.2:c.933C>G NP_001182728.1:p.Cys311Trp missense NM_001195800.2:c.552C>G NP_001182729.1:p.Cys184Trp missense NM_001195803.2:c.675C>G NP_001182732.1:p.Cys225Trp missense NC_000019.10:g.11110767C>G NC_000019.9:g.11221443C>G NG_009060.1:g.26387C>G LRG_274:g.26387C>G LRG_274t1:c.1056C>G LRG_274p1:p.Cys352Trp - Protein change
- C352W, C184W, C225W, C311W
- Other names
- FH Avellino-1
- Canonical SPDI
- NC_000019.10:11110766:C:G
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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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0.00120 (T)
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Allele frequency
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The frequency of the allele represented by this VCV record.
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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 | ||
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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 |
4017 | 4288 |
Conditions - Germline
Condition
Help
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
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
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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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Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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May 24, 2021 | RCV000237561.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 26, 2017 | RCV000586287.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 23, 2019 | RCV002401933.2 |
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: SCV000295171.2
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
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Pathogenic
(Mar 01, 2016)
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criteria provided, single submitter
Method: curation, literature only
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Familial hypercholesterolemia
(Autosomal dominant inheritance)
Affected status: not applicable, unknown
Allele origin:
germline,
not applicable
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Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge
Accession: SCV000599358.1
First in ClinVar: Jul 29, 2016 Last updated: Jul 29, 2016 |
Observation 1: Observation 2:
Comment on evidence:
Assay Description:Hmz patients' fibrolbasts, 125I-LDL assays
Result:
9% LDLR activity
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Pathogenic
(Jul 26, 2017)
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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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000697183.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Comment:
Variant summary: The LDLR c.1056C>G (p.Cys352Trp) variant involves the alteration of a non-conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. … (more)
Variant summary: The LDLR c.1056C>G (p.Cys352Trp) variant involves the alteration of a non-conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. The variant of interest has not been found in a large, broad control population, ExAC in 120928 control chromosomes. This variant was reported in multiple patients with familial hypercholesterolemia (FH), including a homozygous patient whose phenotype was more severe than the heterozygous patients (Bertolini_Atherosclerosis_2013, Fouchier_HG_2001), including . A functional study suggested that the variant causes a defective LDL receptor, though the data was not provided for independent assessment (Bertolini_Atherosclerosis_2013). In addition, one clinical diagnostic laboratory classified this variant as likely pathogenic. Taken together, this variant is classified as pathogenic. (less)
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Pathogenic
(Jan 23, 2019)
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criteria provided, single submitter
Method: research
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Hypercholesterolemia, familial, 1
Affected status: yes
Allele origin:
germline
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Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia
Accession: SCV001432585.1
First in ClinVar: Sep 19, 2020 Last updated: Sep 19, 2020 |
Number of individuals with the variant: 1
Clinical Features:
Dutch Lipid Clinic Network Criteria score (present) , low-density lipoprotein cholesterol level (present)
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Likely pathogenic
(May 24, 2021)
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criteria provided, single submitter
Method: clinical testing
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Hypercholesterolemia, familial, 1
Affected status: yes
Allele origin:
germline
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Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II
Accession: SCV001653617.1
First in ClinVar: Jun 08, 2021 Last updated: Jun 08, 2021 |
Number of individuals with the variant: 1
Ethnicity/Population group: Caucasian
Geographic origin: Italy
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Pathogenic
(Sep 23, 2019)
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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: SCV002712277.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.C352W pathogenic mutation (also known as c.1056C>G), located in coding exon 7 of the LDLR gene, results from a C to G substitution at … (more)
The p.C352W pathogenic mutation (also known as c.1056C>G), located in coding exon 7 of the LDLR gene, results from a C to G substitution at nucleotide position 1056. The cysteine at codon 352 is replaced by tryptophan, an amino acid with highly dissimilar properties, and is located in an EGF-like domain. 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 particular cysteine alteration (also referred to as C331W and FH Avellino-1) has been reported in the homozygous state in a pediatric patient reported to have a clinical diagnosis of homozygous familial hypercholesterolemia (FH) and significantly reduced LDL-receptor activity; however, experimental data were not shown (Bertolini S et al. Arterioscler. Thromb. Vasc. Biol., 1999;19:408-18). This variant has been detected in additional individuals from FH cohorts (Lombardi MP et al. Clin. Genet., 2000;57:116-24; Van Gaal LF et al. Mol. Cell. Probes, 2001;15:329-36; Bertolini S et al. Atherosclerosis, 2013;227:342-8; Gabová D et al. Physiol Res, 2017;66:75-84). Internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of the EGF-like 1 domain (Ambry internal data). In addition, other variants affecting this codon (e.g., p.C352Y and p.C352S) have also been reported in association with FH (Magaña Torres MT et al. J Clin Lipidol. 2014;8:525-7; Medeiros AM et al. Genet. Med. 2016;18:316-24). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: research
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Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
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Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum
Accession: SCV000606302.1
First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017 |
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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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Homozygous familial hypercholesterolemia in Italy: Clinical and molecular features. | Bertolini S | Atherosclerosis | 2020 | PMID: 32977124 |
Lipid profile and genetic status in a familial hypercholesterolemia pediatric population: exploring the LDL/HDL ratio. | Di Taranto MD | Clinical chemistry and laboratory medicine | 2019 | PMID: 30710474 |
Validation of LDLr Activity as a Tool to Improve Genetic Diagnosis of Familial Hypercholesterolemia: A Retrospective on Functional Characterization of LDLr Variants. | Benito-Vicente A | International journal of molecular sciences | 2018 | PMID: 29874871 |
The molecular genetic background of familial hypercholesterolemia: data from the Slovak nation-wide survey. | Gabčová D | Physiological research | 2017 | PMID: 27824480 |
Individual analysis of patients with HoFH participating in a phase 3 trial with lomitapide: The Italian cohort. | Averna M | Nutrition, metabolism, and cardiovascular diseases : NMCD | 2016 | PMID: 26723464 |
Mutational analysis of a cohort with clinical diagnosis of familial hypercholesterolemia: considerations for genetic diagnosis improvement. | Medeiros AM | Genetics in medicine : official journal of the American College of Medical Genetics | 2016 | PMID: 26020417 |
Spectrum of mutations and phenotypic expression in patients with autosomal dominant hypercholesterolemia identified in Italy. | Bertolini S | Atherosclerosis | 2013 | PMID: 23375686 |
Autosomal recessive hypercholesterolemia (ARH) and homozygous familial hypercholesterolemia (FH): a phenotypic comparison. | Pisciotta L | Atherosclerosis | 2006 | PMID: 16343504 |
Effect of low-density lipoprotein receptor mutation on lipoproteins and cardiovascular disease risk: a parent-offspring study. | Koeijvoets KC | Atherosclerosis | 2005 | PMID: 15823280 |
Low-density lipoprotein receptor gene mutation analysis and clinical correlation in Belgian hypercholesterolaemics. | Van Gaal LF | Molecular and cellular probes | 2001 | PMID: 11851376 |
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 |
Analysis of LDL receptor gene mutations in Italian patients with homozygous familial hypercholesterolemia. | Bertolini S | Arteriosclerosis, thrombosis, and vascular biology | 1999 | PMID: 9974426 |
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Text-mined citations for rs13306515 ...
HelpRecord last updated Jun 23, 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.