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

Total submissions: 9

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	2019-12-24	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.
Blueprint Genetics	RCV001073263	SCV001238799	pathogenic	Retinal dystrophy	2018-09-26	criteria provided, single submitter	clinical testing
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.
Sharon lab,Hadassah-Hebrew University Medical Center	RCV001003073	SCV001161130	pathogenic	Leber congenital amaurosis	2019-06-23	no assertion criteria provided	research
Laboratory of Genetics in Ophthalmology,Institut Imagine	RCV000001019	SCV001433630	pathogenic	Leber congenital amaurosis 5		no assertion criteria provided	research
Natera, Inc.	RCV001003073	SCV001453528	pathogenic	Leber congenital amaurosis	2020-09-16	no assertion criteria provided	clinical testing