ClinVar Miner

Submissions for variant NM_001122769.3(LCA5):c.835C>T (p.Gln279Ter) (rs121918165)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000190663 SCV000244103 pathogenic Inborn genetic diseases 2013-09-10 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000001019 SCV000465592 pathogenic Leber congenital amaurosis 5 2017-04-27 criteria provided, single submitter clinical testing 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.
Invitae RCV000812173 SCV000952477 pathogenic not provided 2018-12-13 criteria provided, single submitter clinical testing 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. This variant is present in population databases (rs121918165, ExAC 0.02%). This variant has been reported as homozygous or compound heterozygous in several individuals affected with Leber congenital amaurosis (PMID: 17546029, 23946133). ClinVar contains an entry for this variant (Variation ID: 968). Experimental studies have shown that this nonsense change abolishes interaction with intraflagellar transport components (PMID: 21606596). Loss-of-function variants in LCA5 are known to be pathogenic (PMID: 17546029, 23946133). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000001019 SCV000021169 pathogenic Leber congenital amaurosis 5 2007-07-01 no assertion criteria provided literature only
GeneReviews RCV000001019 SCV000087066 pathologic Leber congenital amaurosis 5 2013-05-02 no assertion criteria provided curation Converted during submission to Pathogenic.

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