Submissions for variant NM_014336.5(AIPL1):c.834G>A (p.Trp278Ter) (rs62637014)

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics	RCV000086235	SCV000338213	pathogenic	not provided	2017-04-05	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV000365317	SCV000405575	pathogenic	AIPL1-Related Disorders	2017-04-27	criteria provided, single submitter	clinical testing	Across a selection of the available literature, the AIPL1 c.834G>A p.Trp278Ter variant has been reported in at least four studies in association with Leber congenital amaurosis and is found in a total of at least 31 unrelated individuals including 19 in a homozygous state and 12 in a compound heterozygous state (Sohocki et al. 2000a; Sohocki et al. 2000b; Dharmaraj et al. 2004; Testa et al. 2011). Multiple pedigrees show segregation with disease in an autosomal recessive pattern (Sohocki et al. 2000a; Sohocki et al. 2000b). The p.Trp278Ter variant was absent from 305 controls and is reported at a frequency of 0.00093 in the European American population of the Exome Sequencing Project. Van der Spuy et al. (2004) co-transfected AIPL1 with GFP-NUB1-N and GFP-NUB1-C W278Ter to show the p.Trp278Ter variant formed non-functional SDS insoluble inclusions. Hidalgo-de-Quintana et al. (2015) used yeast two-hybrid analysis and showed the interaction of EB1 with AIPL1 harboring the p.Trp278Ter variant was severely compromised. Based on the collective evidence and potential impact of stop-gained variants, the p.Trp278Ter variant is classified as pathogenic for AIPL1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000005906	SCV000494234	pathogenic	Leber congenital amaurosis 4	2016-04-08	criteria provided, single submitter	clinical testing	The c.834G>A (p.Trp278*) nonsense variant in the AIPL1 gene has been previously reported as a common pathogenic variant associated with Leber congenital amaurosis (Sohocki et al., 2000a; Sohocki et al., 2000b; Aboshiha et al., 2015). This variant has been shown to co-segregate with disease in multiple affected members from at least 4 families (Sohocki et al., 2000a; Sohocki et al., 2000b). This nonsense variant introduces a stop codon in the last exon of AIPL1 and is expected to truncate the protein by 107 amino acids. This variant is often observed in trans with other pathogenic variants in affected individuals (Sohocki et al., 2000a; Sohocki et al., 2000b; Aboshiha et al., 2015). Functional studies have shown that this variant effects the subcellular localization of NUB1, a protein AIPL1 modulates and/or chaperones (van der Spuy et al., 2004). This variant is reported at low frequency in the population databases (Exome Sequencing Project = 0.093%; 1000 Genomes = 0%; and ExAC = 0.057%). Therefore, this collective evidence supports the classification of the c.834G>A (p.Trp278*) as a Pathogenic variant for Leber congenital amaurosis. We have confirmed this finding in our laboratory using Sanger sequencing.
GeneDx	RCV000086235	SCV000680497	pathogenic	not provided	2018-11-12	criteria provided, single submitter	clinical testing	The W278X variant in the AIPL1 gene has been reported previously in association with autosomal recessive Leber congenital amaurosis (Sohocki et al., 2000; Damji et al., 2001; Aboshiha et al., 2015). This variant is predicted to cause loss of normal protein function through protein truncation, as the last 107 amino acids are lost. Functional studies have shown that W278X has a detrimental effect on the AIPL1 protein (van der Spuy et al., 2004). The W278X variant is observed in 77/124,080 (0.0621%) alleles from individuals of non-Finnish European background in large population cohorts (Lek et al., 2016). We interpret W278X as a pathogenic variant.
Invitae	RCV000005906	SCV000833757	pathogenic	Leber congenital amaurosis 4	2019-12-26	criteria provided, single submitter	clinical testing	This sequence change results in a premature translational stop signal in the AIPL1 gene (p.Trp278*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 107 amino acids of the AIPL1 protein. This variant is present in population databases (rs62637014, ExAC 0.06%). This variant has been reported to segregate with Leber congenital amaurosis in several families (PMID: 10615133, 10873396) and is one of the most common variants associated with this disease (PMID: 15249368, 21474771, 22412862). ClinVar contains an entry for this variant (Variation ID: 5565). Experimental studies have shown that AIPL1 protein with this nonsense change forms non-functional inclusions and alters protein-protein interactions in cell culture (PMID: 15347646, 25799540). For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics	RCV001074840	SCV001240441	pathogenic	Retinal dystrophy	2019-07-23	criteria provided, single submitter	clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen	RCV000086235	SCV001246292	pathogenic	not provided	2017-10-01	criteria provided, single submitter	clinical testing
OMIM	RCV000005906	SCV000026088	pathogenic	Leber congenital amaurosis 4	2015-04-01	no assertion criteria provided	literature only
GeneReviews	RCV000005906	SCV000086966	pathologic	Leber congenital amaurosis 4	2013-05-02	no assertion criteria provided	curation	Converted during submission to Pathogenic.
Retina International	RCV000086235	SCV000118381	not provided	not provided		no assertion provided	not provided
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000505017	SCV000599074	pathogenic	Leber congenital amaurosis	2015-01-01	no assertion criteria provided	research
Medical Genetics Laboratory, Kennedy Center,Juliane Marie Center, Rigshospitalet	RCV000505017	SCV000926500	pathogenic	Leber congenital amaurosis	2018-04-01	no assertion criteria provided	research
Sharon lab,Hadassah-Hebrew University Medical Center	RCV000505017	SCV001160891	pathogenic	Leber congenital amaurosis	2019-06-23	no assertion criteria provided	research
Laboratory of Genetics in Ophthalmology,Institut Imagine	RCV000005906	SCV001335452	pathogenic	Leber congenital amaurosis 4		no assertion criteria provided	research