ClinVar Genomic variation as it relates to human health
NM_000527.5(LDLR):c.265T>C (p.Cys89Arg)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000527.5(LDLR):c.265T>C (p.Cys89Arg)
Variation ID: 251102 Accession: VCV000251102.6
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19p13.2 19: 11102738 (GRCh38) [ NCBI UCSC ] 19: 11213414 (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 15, 2016 Feb 4, 2024 Mar 25, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000527.5:c.265T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000518.1:p.Cys89Arg missense NM_001195798.2:c.265T>C NP_001182727.1:p.Cys89Arg missense NM_001195799.2:c.190+2393T>C intron variant NM_001195800.2:c.265T>C NP_001182729.1:p.Cys89Arg missense NM_001195803.2:c.265T>C NP_001182732.1:p.Cys89Arg missense NC_000019.10:g.11102738T>C NC_000019.9:g.11213414T>C NG_009060.1:g.18358T>C LRG_274:g.18358T>C LRG_274t1:c.265T>C LRG_274p1:p.Cys89Arg - Protein change
- C89R
- Other names
- FH Catanzaro
- NM_000527.5(LDLR):c.265T>C
- p.Cys89Arg
- Canonical SPDI
- NC_000019.10:11102737:T:C
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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.
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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 |
4017 | 4288 |
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 (6) |
reviewed by expert panel
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Mar 25, 2022 | RCV000237985.11 |
Submissions - Germline
Classification
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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, 2022)
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reviewed by expert panel
Method: curation
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Hypercholesterolemia, familial, 1
(Semidominant inheritance)
Affected status: unknown
Allele origin:
germline
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ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel
FDA Recognized Database
Accession: SCV002506374.1 First in ClinVar: May 07, 2022 Last updated: May 07, 2022 |
Comment:
The NM_000527.5(LDLR):c.265T>C (p.Cys89Arg) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PM1, PM2, PM3, PS4_Supporting, PP1, PP3 and PP4 as … (more)
The NM_000527.5(LDLR):c.265T>C (p.Cys89Arg) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PM1, PM2, PM3, PS4_Supporting, PP1, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM1 - Variant meets PM2 and alters Cys89, one of the cysteine residues listed, so PM1 is Met. PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is Met. PM3 - Variant meets PM2 and is identified in an index case with homozygous FH phenotype (LDL = 18.05 mmol/L) and LDLR variant c.1775G>A/p.(Gly592Glu), classified as Pathogenic by these guidelines, in trans, from ltaly (PMID: 9974426), so PM3 is Met. PS4_Supporting - Variant meets PM2 and is identified in 5 unrelated index cases: 1 index case with possible FH (Simon-Broome criteria) from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge, at least 1 index case with definite heterozygous FH from The Netherlands (PMID: 16250003), 1 index case fulfilling MedPed criteria for FH from Spain (PMID: 16627557), 2 index cases fulfilling WHO criteria for FH from Poland (PMID: 20145306), so PS4_Supporting is Met. PP1 - Variant segregates with FH phenotype in 3 informative meiosis from 1 family from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge: 2 affected family members have the variant and 1 non-affected family member does not have the variant, so PP1 is Met. PP3 - REVEL = 0.973. It is above 0.75, so PP3 is Met. PP4 - Variant meets PM2 and is identified in 5 unrelated index cases fulfilling clinical criteria for FH from several labs (see PS4 for details), so PP4 is Met. (less)
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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: SCV000294565.2
First in ClinVar: Jul 29, 2016 Last updated: May 30, 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
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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: yes
Allele origin:
germline
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Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge
Accession: SCV000322883.1
First in ClinVar: Oct 15, 2016 Last updated: Oct 15, 2016 |
Comment:
0/208 non-FH alleles
Observation 1: Observation 2:
Comment on evidence:
Compound Heterozygous (with p.(Gly592Glu)) patient fibroblast, 125I-LDL assays
Result:
<5% LDLR activity
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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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Laboratory of Genetics and Molecular Cardiology, University of São Paulo
Study: HipercolBrasil
Accession: SCV000588492.1 First in ClinVar: Aug 13, 2017 Last updated: Aug 13, 2017 |
Observation 1: Observation 2:
Comment on evidence:
Assay description:Comp htz (with p.(Gly592Glu)) patient fibroblast, 125I-LDL assays
Result:
<5% LDLR activity
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Pathogenic
(Nov 14, 2022)
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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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Revvity Omics, Revvity
Accession: SCV003819465.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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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: SCV000606055.1
First in ClinVar: Aug 13, 2017 Last updated: Aug 13, 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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Molecular characterization of Polish patients with familial hypercholesterolemia: novel and recurrent LDLR mutations. | Chmara M | Journal of applied genetics | 2010 | PMID: 20145306 |
Familial hypercholesterolaemia in Portugal. | Bourbon M | Atherosclerosis | 2008 | PMID: 17765246 |
Analysis of sequence variations in the LDL receptor gene in Spain: general gene screening or search for specific alterations? | Blesa S | Clinical chemistry | 2006 | PMID: 16627557 |
Update of the molecular basis of familial hypercholesterolemia in The Netherlands. | Fouchier SW | Human mutation | 2005 | PMID: 16250003 |
Analysis of LDL receptor gene mutations in Italian patients with homozygous familial hypercholesterolemia. | Bertolini S | Arteriosclerosis, thrombosis, and vascular biology | 1999 | PMID: 9974426 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/7f250f74-e4cd-4624-ad04-72229035c1dc | - | - | - | - |
Text-mined citations for this variant ...
HelpRecord last updated Mar 17, 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.