17-6425781-C-T
Variant summary
Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_StrongPP5_Very_Strong
The NM_014336.5(AIPL1):c.834G>A(p.Trp278*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000354 in 1,606,522 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★).
Frequency
Consequence
NM_014336.5 stop_gained
Scores
Clinical Significance
Conservation
Publications
- AIPL1-related retinopathyInheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
- Leber congenital amaurosis 4Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
- Leber congenital amaurosisInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Pathogenic. The variant received 12 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| AIPL1 | NM_014336.5 | c.834G>A | p.Trp278* | stop_gained | Exon 6 of 6 | ENST00000381129.8 | NP_055151.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| AIPL1 | ENST00000381129.8 | c.834G>A | p.Trp278* | stop_gained | Exon 6 of 6 | 1 | NM_014336.5 | ENSP00000370521.3 |
Frequencies
GnomAD3 genomes 0.000368 AC: 56AN: 152194Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.000329 AC: 80AN: 243060 AF XY: 0.000348 show subpopulations
GnomAD4 exome AF: 0.000353 AC: 513AN: 1454210Hom.: 1 Cov.: 31 AF XY: 0.000351 AC XY: 254AN XY: 723758 show subpopulations
Age Distribution
GnomAD4 genome 0.000368 AC: 56AN: 152312Hom.: 0 Cov.: 32 AF XY: 0.000322 AC XY: 24AN XY: 74466 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Leber congenital amaurosis 4 Pathogenic:9Other:1
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 gene product 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.
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.
The variant is observed at an extremely low frequency in the gnomAD v4.1.0 dataset (total allele frequency: 0.035%). Predicted Consequence/Location: 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%. The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 20702822, 21474771). The variant has been reported to co-segregate with the disease in at least one similarly affected relative/individual in the same family or similarly affected unrelated families (PMID: 20702822, 21474771). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000005565 /PMID: 10615133 /3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
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.
Criteria applied: PVS1,PM3,PM2_SUP
not provided Pathogenic:6Other:1
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)
Leber congenital amaurosis Pathogenic:6
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.
The p.Trp278X variant in AIPL1 has been reported in at least 4 individuals (3 homozygotes and 1 compound heterozygote) with Leber congenital amaurosis and segregated with the disease in their families (Sohocki 2000) and in vitro functional studies provide evidence that the p.Trp278X variant impacts protein function (van der Spuy 2004). This variant has been identified in 0.057% (37/65408) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs62637014). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This nonsense variant leads to a premature termination codon at position 278. This alteration occurs within the last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. In summary, this variant meets our criteria to be classified as pathogenic for Leber congenital amaurosis in an autosomal recessive manner based upon case studies, segregation analyses, low frequency in controls and functional evidence.
ACMG/AMP guidelines: PM2, PP4_PP, PVS1_PS2, PS3, PP1_PS, PM3_2
Retinal dystrophy Pathogenic:3
AIPL1-related disorder Pathogenic:2
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.
The AIPL1 c.834G>A variant is predicted to result in premature protein termination (p.Trp278*). This variant is a common pathogenic variant in the AIPL1 gene and has previously been reported to be causative for autosomal recessive Leber congenital amaurosis (Sohocki et al. 2000. PubMed ID: 10615133; Aboshiha et al. 2015. PubMed ID: 25596619). This variant is reported in 0.061% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Nonsense variants in AIPL1 are expected to be pathogenic. This variant is interpreted as pathogenic.
AIPL1-related retinopathy Pathogenic:2
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with AIPL1 retinopathy (MONDO#0100438 ) (I) 0108 - This gene is associated with both recessive and dominant disease. Biallelic variants are generally associated with the more severe, early-onset leber congenital amaurosis 4 (MIM#604393) while monoallelic variants are associated with the milder juvenile retinitis pigmentosa (MIM#604393). (I) 0205 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with less than 1/3 of the protein sequence affected. (SP) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD <0.01 (v2: 92 heterozygotes, 0 homozygotes). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in at least ten homozygous or compound heterozygous individuals with leber congenital amaurosis 4 and retinitis pigmentosa, and is consistently classified as pathogenic by diagnostic laboratories in ClinVar (PMID: 33067476). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
NM_014336.5(AIPL1):c.834G>A (p.Trp278Ter) is a nonsense variant that introduces a premature stop codon into exon 6 of 6, and is predicted to lead to C-terminal truncation of a region that is critical to AIPL1 function (PVS1). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through at least 3 probands plus 11 similarly affected relatives, with the variant present in the homozygous state (PP1_Strong; PMID: 10615133). At least one proband harboring this variant exhibits a phenotype including a diagnosis of Leber congenital amaurosis (0.5 pts) with blindness (1 pt) from birth (1 pt), absence of electroretinogram responses from both rods (0.5 pts) and cones (1 pt), and a fundus exam indicating pigmentary retinopathy with attenuated blood vessels (0.5 pts) and macular degeneration, which together are specific for AIPL1-related retinopathy (4.5 pts, PMID: 10615133). This variant is present in gnomAD v.4.1.0 at an allele frequency of 0.0003542, with 569/1606522 alleles which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0004 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for AIPL1-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PVS1, PP1_Strong, PP4, and PM2_Supporting. (VCEP specifications version 1.0.0; date of approval 9/24/2025).
Retinitis pigmentosa;C1858386:Leber congenital amaurosis 4 Pathogenic:1
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at