ClinVar Genomic variation as it relates to human health
NM_001122769.3(LCA5):c.835C>T (p.Gln279Ter)
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_001122769.3(LCA5):c.835C>T (p.Gln279Ter)
Variation ID: 968 Accession: VCV000000968.26
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 6q14.1 6: 79493636 (GRCh38) [ NCBI UCSC ] 6: 80203353 (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 1, 2013 Feb 20, 2024 Jan 16, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001122769.3:c.835C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001116241.1:p.Gln279Ter nonsense NM_181714.4:c.835C>T NP_859065.2:p.Gln279Ter nonsense NC_000006.12:g.79493636G>A NC_000006.11:g.80203353G>A NG_016011.1:g.48795C>T - Protein change
- Q279*
- Other names
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- Canonical SPDI
- NC_000006.12:79493635: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
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00006
Trans-Omics for Precision Medicine (TOPMed) 0.00008
Exome Aggregation Consortium (ExAC) 0.00012
The Genome Aggregation Database (gnomAD), exomes 0.00012
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
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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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LCA5 | - | - |
GRCh38 GRCh37 |
794 | 817 |
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. |
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Pathogenic (8) |
criteria provided, multiple submitters, no conflicts
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Oct 6, 2023 | RCV000001019.16 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 10, 2013 | RCV000190663.4 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 16, 2024 | RCV000812173.9 | |
Pathogenic (2) |
no assertion criteria provided
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Sep 16, 2020 | RCV001003073.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 26, 2018 | RCV001073263.1 |
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
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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Pathogenic
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Leber congenital amaurosis 5
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000465592.3
First in ClinVar: Dec 06, 2016 Last updated: May 27, 2019 |
Comment:
The LCA5 c.835C>T (p.Gln279Ter) variant is a stop-gained variant that is described in four studies, in which it was found in a homozygous state in … (more)
The LCA5 c.835C>T (p.Gln279Ter) variant is a stop-gained variant that is described in four studies, in which it was found in a homozygous state in five patients with Leber congenital amaurosis (LCA) and in a compound heterozygous state in three patients with LCA (den Hollander et al. 2007; Jacobson et al. 2009; MacKay et al. 2013; Farwell et al. 2015). The variant was absent from 180 total controls but is reported at a frequency of 0.00035 in the European American population of the Exome Sequencing Project. Functional studies by Boldt et al. (2011) showed that the p.Gln279Ter variant resulted in a total loss of the protein interactions shown by wild type libercilin with the intraflagellar transport (IFT) machinery. IFT-dependent protein transport is an evolutionarily conserved basic mechanism found in all cilia. The variant also caused a loss of additional protein binding capabilities. Based on the collective evidence, the p.Gln279Ter variant is classified as pathogenic for Leber congenital amaurosis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Pathogenic
(Sep 26, 2018)
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criteria provided, single submitter
Method: clinical testing
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Retinal dystrophy
Affected status: yes
Allele origin:
germline
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Blueprint Genetics
Accession: SCV001238799.1
First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020 |
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Pathogenic
(Nov 30, 2021)
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criteria provided, single submitter
Method: clinical testing
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Leber congenital amaurosis 5
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV003827069.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Pathogenic
(Sep 10, 2013)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000244103.6
First in ClinVar: Sep 14, 2015 Last updated: Dec 07, 2020 |
Number of individuals with the variant: 1
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Pathogenic
(Apr 08, 2021)
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criteria provided, single submitter
Method: research
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Leber congenital amaurosis 5
Affected status: yes
Allele origin:
germline
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Ocular Genomics Institute, Massachusetts Eye and Ear
Accession: SCV001573600.1
First in ClinVar: May 10, 2021 Last updated: May 10, 2021 |
Comment:
The LCA5 c.835C>T variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we … (more)
The LCA5 c.835C>T variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PVS1, PM2, PM3, PP1-S. Based on this evidence we have classified this variant as Pathogenic. (less)
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Pathogenic
(Jun 03, 2019)
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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: SCV001805283.1
First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published … (more)
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate a total loss of protein interaction with intraflagellar transport machinery (Boldt et al., 2011); This variant is associated with the following publications: (PMID: 31456290, 23946133, 25356970, 19503738, 17546029, 25525159, 21606596) (less)
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Pathogenic
(Feb 22, 2022)
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criteria provided, single submitter
Method: clinical testing
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Leber congenital amaurosis 5
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002816559.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Oct 06, 2023)
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criteria provided, single submitter
Method: clinical testing
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Leber congenital amaurosis 5
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004190598.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Jan 16, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000952477.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Gln279*) in the LCA5 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Gln279*) in the LCA5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LCA5 are known to be pathogenic (PMID: 17546029, 23946133). This variant is present in population databases (rs121918165, gnomAD 0.2%), including at least one homozygous and/or hemizygous individual. This premature translational stop signal has been observed in individuals with Leber congenital amaurosis (PMID: 17546029, 23946133). ClinVar contains an entry for this variant (Variation ID: 968). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jun 23, 2019)
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no assertion criteria provided
Method: research
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leber congenital amaurosis
Affected status: yes
Allele origin:
inherited
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Sharon lab, Hadassah-Hebrew University Medical Center
Accession: SCV001161130.1
First in ClinVar: Feb 16, 2020 Last updated: Feb 16, 2020 |
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Pathogenic
(-)
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no assertion criteria provided
Method: research
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Leber congenital amaurosis 5
Affected status: yes
Allele origin:
inherited
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Laboratory of Genetics in Ophthalmology, Institut Imagine
Accession: SCV001433630.1
First in ClinVar: Sep 27, 2020 Last updated: Sep 27, 2020 |
Number of individuals with the variant: 1
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Pathogenic
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
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Leber congenital amaurosis
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001453528.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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Pathogenic
(Jul 01, 2007)
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no assertion criteria provided
Method: literature only
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LEBER CONGENITAL AMAUROSIS 5
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000021169.3
First in ClinVar: Apr 04, 2013 Last updated: Mar 19, 2021 |
Comment on evidence:
In a patient with Leber congenital amaurosis-5 (LCA5; 604537) from a nonconsanguineous family of Ashkenazi Jewish descent, den Hollander et al. (2007) identified homozygosity for … (more)
In a patient with Leber congenital amaurosis-5 (LCA5; 604537) from a nonconsanguineous family of Ashkenazi Jewish descent, den Hollander et al. (2007) identified homozygosity for an 835C-T transition in exon 5 of the LCA5 gene, resulting in a gln279-to-ter (Q279X) substitution. The mutation was not found in 180 control individuals. (less)
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not provided
(-)
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no classification provided
Method: literature only
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Leber congenital amaurosis 5
Affected status: not provided
Allele origin:
unknown
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GeneReviews
Accession: SCV000087066.2
First in ClinVar: Oct 01, 2013 Last updated: Oct 01, 2022 |
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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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Enhanced utility of family-centered diagnostic exome sequencing with inheritance model-based analysis: results from 500 unselected families with undiagnosed genetic conditions. | Farwell KD | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25356970 |
Screening of a large cohort of leber congenital amaurosis and retinitis pigmentosa patients identifies novel LCA5 mutations and new genotype-phenotype correlations. | Mackay DS | Human mutation | 2013 | PMID: 23946133 |
Leber Congenital Amaurosis – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY. | Adam MP | - | 2013 | PMID: 20301475 |
Disruption of intraflagellar protein transport in photoreceptor cilia causes Leber congenital amaurosis in humans and mice. | Boldt K | The Journal of clinical investigation | 2011 | PMID: 21606596 |
Leber congenital amaurosis caused by Lebercilin (LCA5) mutation: retained photoreceptors adjacent to retinal disorganization. | Jacobson SG | Molecular vision | 2009 | PMID: 19503738 |
Mutations in LCA5, encoding the ciliary protein lebercilin, cause Leber congenital amaurosis. | den Hollander AI | Nature genetics | 2007 | PMID: 17546029 |
Text-mined citations for rs121918165 ...
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.