ClinVar Genomic variation as it relates to human health
NM_000527.5(LDLR):c.938G>A (p.Cys313Tyr)
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.938G>A (p.Cys313Tyr)
Variation ID: 226339 Accession: VCV000226339.14
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19p13.2 19: 11107512 (GRCh38) [ NCBI UCSC ] 19: 11218188 (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 22, 2016 Feb 14, 2024 May 8, 2020 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000527.5:c.938G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000518.1:p.Cys313Tyr missense NM_001195798.2:c.938G>A NP_001182727.1:p.Cys313Tyr missense NM_001195799.2:c.815G>A NP_001182728.1:p.Cys272Tyr missense NM_001195800.2:c.434G>A NP_001182729.1:p.Cys145Tyr missense NM_001195803.2:c.557G>A NP_001182732.1:p.Cys186Tyr missense NC_000019.10:g.11107512G>A NC_000019.9:g.11218188G>A NG_009060.1:g.23132G>A LRG_274:g.23132G>A LRG_274t1:c.938G>A LRG_274p1:p.Cys313Tyr P01130:p.Cys313Tyr - Protein change
- C313Y, C272Y, C145Y, C186Y
- Other names
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- Canonical SPDI
- NC_000019.10:11107511:G: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
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 |
3896 | 4139 |
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
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
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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. |
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Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Apr 25, 2018 | RCV000211642.9 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Mar 3, 2019 | RCV000826175.5 | |
Likely pathogenic (1) |
criteria provided, single submitter
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May 8, 2020 | RCV002223822.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 29, 2018 | RCV002229197.5 |
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: SCV000295072.2
First in ClinVar: Jul 29, 2016 Last updated: Oct 10, 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
Observation 4:
Number of individuals with the variant: 1
Observation 5:
Number of individuals with the variant: 1
Observation 6:
Number of individuals with the variant: 1
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Likely pathogenic
(Mar 01, 2016)
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criteria provided, single submitter
Method: research
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Familial hypercholesterolemia
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Fundacion Hipercolesterolemia Familiar
Study: SAFEHEART
Accession: SCV000607528.1 First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017 |
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Likely pathogenic
(Apr 25, 2018)
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criteria provided, single submitter
Method: clinical testing
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Hypercholesterolemia, familial, 1
Affected status: unknown
Allele origin:
germline
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Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine
Accession: SCV000840001.1
First in ClinVar: Oct 10, 2018 Last updated: Oct 10, 2018 |
Comment:
This c.938G>A (p.Cys313Tyr) variant in the LDLR gene has been reported in multiple familial hypercholesterolemia patients [PMID: 9259195, 11857755, 11810272] but not observed in general … (more)
This c.938G>A (p.Cys313Tyr) variant in the LDLR gene has been reported in multiple familial hypercholesterolemia patients [PMID: 9259195, 11857755, 11810272] but not observed in general population according to gnomad database. This variant has been reported by multiple clinical test center as disease-causing according to ClinVar database. Multiple in silico predictions suggest this cysteine to tyrosine is deleterious. Multiple variants causing cysteine at amino acid position 313 change to other amino acids have been reported as disease-causing in literature [PMID: 19318025, 15823288, 11257257]. Based upon above evidences, c.938G>A (p.Cys313Tyr) variant in the LDLR gene is classified as likely pathogenic. (less)
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Likely pathogenic
(Mar 03, 2019)
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criteria provided, single submitter
Method: clinical testing
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Homozygous familial hypercholesterolemia
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000967714.2
First in ClinVar: Aug 26, 2019 Last updated: Jul 03, 2020 |
Comment:
The p.Cys313Tyr variant in LDLR (also described as p.Cys292Tyr in the literature) has been reported in >10 individuals with familial hypercholesterolemia (FH), of which 2 … (more)
The p.Cys313Tyr variant in LDLR (also described as p.Cys292Tyr in the literature) has been reported in >10 individuals with familial hypercholesterolemia (FH), of which 2 are in the compound heterozygous state (Day 1997, Thiart 2000, Fouchier 2001, Bunn 2002, Van der Graaf 2011, Martin 2016). It has also been reported in ClinVar (Variation ID: 226339) and was absent from large population studies. Computational prediction tools and conservation analysis suggest that the p.Cys131Tyr variant may impact the protein. This variant is located in the last three bases of the exon, which is part of the 5’ splice region. Computational tools do not suggest an impact to splicing. Additionally, other missense variants at this amino acid position (p.Cys313Arg, p.Cys313Gly and p.Cys313Trp) have been reported in individuals with familial hypercholesterolemia (Human Gene Mutation Database: Stenson 2017), suggesting that changes at this position may not be tolerated. In summary, although additional studies are required to fully establish its clinical significance, the p.Cys313Tyr variant is likely pathogenic. The ACMG/AMP Criteria applied (Richards 2015): PS4_Moderate, PM2, PP3, PM5_Supporting. (less)
Number of individuals with the variant: 1
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Likely pathogenic
(May 08, 2020)
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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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AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002502951.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 1
Secondary finding: no
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Pathogenic
(Jan 29, 2018)
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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: SCV000752418.5
First in ClinVar: May 03, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces cysteine with tyrosine at codon 313 of the LDLR protein (p.Cys313Tyr). The cysteine residue is highly conserved and there is a … (more)
This sequence change replaces cysteine with tyrosine at codon 313 of the LDLR protein (p.Cys313Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. For these reasons, this variant has been classified as Pathogenic. This variant affects a cysteine residue located within an LDLRA domain 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 domains affecting cysteine residues are overrepresented among patients with hypercholesterolemia (PMID: 18325082). Other missense substitutions at this codon (p.Cys313Arg) have been reported in individuals affected with hypercholesterolemia (PMID: 19318025). 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. This variant has been reported in several individuals affected with hypercholesterolemia (PMID: 9259195, 9698020, 11810272, 11857755). This variant is also known as p.Cys292Tyr in the literature. ClinVar contains an entry for this variant (Variation ID: 226339). This variant is not present in population databases (ExAC no frequency). (less)
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Pathogenic
(Mar 18, 2010)
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no assertion criteria provided
Method: clinical testing
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Familial hypercholesterolemia
Affected status: yes
Allele origin:
germline
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Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital
Accession: SCV000268591.1
First in ClinVar: May 22, 2016 Last updated: May 22, 2016 |
Number of individuals with the variant: 1
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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: SCV000606274.1
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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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 |
Genetic diagnosis of familial hypercholesterolaemia using a rapid biochip array assay for 40 common LDLR, APOB and PCSK9 mutations. | Martin R | Atherosclerosis | 2016 | PMID: 27680772 |
Molecular basis of autosomal dominant hypercholesterolemia: assessment in a large cohort of hypercholesterolemic children. | van der Graaf A | Circulation | 2011 | PMID: 21382890 |
Genetic diagnosis of familial hypercholesterolemia using a DNA-array based platform. | Alonso R | Clinical biochemistry | 2009 | PMID: 19318025 |
Update and analysis of the University College London low density lipoprotein receptor familial hypercholesterolemia database. | Leigh SE | Annals of human genetics | 2008 | PMID: 18325082 |
Comparison of SSCP and DHPLC for the detection of LDLR mutations in a New Zealand cohort. | Bunn CF | Human mutation | 2002 | PMID: 11857755 |
The molecular basis of familial hypercholesterolemia in The Netherlands. | Fouchier SW | Human genetics | 2001 | PMID: 11810272 |
Mutation analysis in a small cohort of New Zealand patients originating from the United Kingdom demonstrates genetic heterogeneity in familial hypercholesterolemia. | Thiart R | Molecular and cellular probes | 2000 | PMID: 11040093 |
Spectrum of LDL receptor gene mutations in heterozygous familial hypercholesterolemia. | Day IN | Human mutation | 1997 | PMID: 9259195 |
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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Text-mined citations for rs875989911 ...
HelpRecord last updated Feb 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.