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

gnomAD frequency: 0.00038  dbSNP: rs62637014

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000086235	SCV000338213	pathogenic	not provided	2017-04-05	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, 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	2022-10-11	criteria provided, single submitter	clinical testing	Published functional studies demonstrate that W278X has a detrimental effect on the AIPL1 protein (van der Spuy and Cheetham, 2004); Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 107 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); This variant is associated with the following publications: (PMID: 11548141, 20702822, 16205573, 22412862, 21474771, 15249368, 20065226, 29068479, 10873396, 20301475, 29053603, 31429209, 32531858, 35456422, 25596619, 12374762, 21900377, 16505055, 16123401, 15024725, 17724218, 25799540, 10615133, 29178642, 30576320, 30718709, 31456290, 31980526, 32552793, 32581362, 33067476, 31589614, 34426522, 32783370, 32865313, 15347646, 24077912)
Invitae	RCV000005906	SCV000833757	pathogenic	Leber congenital amaurosis 4	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp278*) in the AIPL1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 107 amino acid(s) of the AIPL1 protein. This variant is present in population databases (rs62637014, gnomAD 0.06%). This premature translational stop signal has been observed in individual(s) with Leber congenital amaurosis (PMID: 10615133, 10873396, 15249368, 21474771, 22412862). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5565). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects AIPL1 function (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 Center for Human Genetics Tuebingen	RCV000086235	SCV001246292	pathogenic	not provided	2017-10-01	criteria provided, single submitter	clinical testing
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV000005906	SCV001573248	pathogenic	Leber congenital amaurosis 4	2021-04-08	criteria provided, single submitter	research	The AIPL1 c.834G>A 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: PP1, PM3, PS3, PM2, PM4. Based on this evidence we have classified this variant as Pathogenic.
Revvity Omics, Revvity	RCV000005906	SCV002024140	pathogenic	Leber congenital amaurosis 4	2022-07-11	criteria provided, single submitter	clinical testing
3billion	RCV000005906	SCV002058854	pathogenic	Leber congenital amaurosis 4	2022-01-03	criteria provided, single submitter	clinical testing	Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by more than 10% (PVS1_S). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000005565, PMID:10615133, 3billion dataset). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000335, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Genetics and Molecular Pathology, SA Pathology	RCV000005906	SCV002761951	pathogenic	Leber congenital amaurosis 4	2020-07-03	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002496274	SCV002813931	pathogenic	Leber congenital amaurosis 4; Retinitis pigmentosa	2022-03-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000505017	SCV003928395	pathogenic	Leber congenital amaurosis	2023-04-27	criteria provided, single submitter	clinical testing	Variant summary: AIPL1 c.834G>A (p.Trp278X) results in a premature termination codon, predicted to cause a truncation of the encoded protein, which is a commonly known mechanism for disease. While this variant is not expected to result in nonsense mediated decay, it is predicted to disrupt the last 107 amino acids of the protein. The variant allele was found at a frequency of 0.00033 in 243060 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in AIPL1 causing Leber Congenital Amaurosis (0.00033 vs 0.0011), allowing no conclusion about variant significance. c.834G>A has been reported in the literature in numerous homozygous and compound heterozygous individuals affected with Leber Congenital Amaurosis and has been shown to segregate with disease in multiple families (e.g., Sohocki_2000, Sohocki_2000b). These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function, finding that the variant completely abolished the ability to enhance Hsp70-mediated suppression of GFP-NUB1-N inclusions and led to the formation of SDS-insoluble cytoplasmic inclusions (e.g., van der Spuy_2004, Hidalgo-de-Quintana_2008). The following publications have been ascertained in the context of this evaluation (PMID: 25799540, 10873396, 10615133, 15347646). Multiple ClinVar submitters (evaluation after 2014) have cited the variant, and all submitters classified the variant as pathogenic (n = 16). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000005906	SCV000026088	pathogenic	Leber congenital amaurosis 4	2015-04-01	no assertion criteria provided	literature only
GeneReviews	RCV000005906	SCV000086966	not provided	Leber congenital amaurosis 4		no assertion provided	literature only
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
Department of Clinical Genetics, Copenhagen University Hospital, 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
Clinical Genetics, Academic Medical Center	RCV000086235	SCV001919962	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000086235	SCV001952602	pathogenic	not provided		no assertion criteria provided	clinical testing