ClinVar Miner

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

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Total submissions: 10
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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 2018-01-05 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.
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

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