rs62637014

Positions:

• chr17-6425781-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Strong PP5_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:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00035 (1 hom.)
• Consequence: AIPL1 NM_014336.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:26 O:2
• Conservation: PhyloP100: 7.47

Genes affected

AIPL1 (HGNC:359): (aryl hydrocarbon receptor interacting protein like 1) Leber congenital amaurosis (LCA) is the most severe inherited retinopathy with the earliest age of onset and accounts for at least 5% of all inherited retinal diseases. Affected individuals are diagnosed at birth or in the first few months of life with nystagmus, severely impaired vision or blindness and an abnormal or flat electroretinogram. The photoreceptor/pineal-expressed gene, AIPL1, encoding aryl-hydrocarbon interacting protein-like 1, is located within the LCA4 candidate region. The encoded protein contains three tetratricopeptide motifs, consistent with chaperone or nuclear transport activity. Mutations in this gene may cause approximately 20% of recessive LCA. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 14 pathogenic variants in the truncated region.
• PP5: Variant 17-6425781-C-T is Pathogenic according to our data. Variant chr17-6425781-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 5565.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-6425781-C-T is described in Lovd as [Pathogenic]. Variant chr17-6425781-C-T is described in Lovd as [Likely_pathogenic]. Variant chr17-6425781-C-T is described in Lovd as [Likely_pathogenic]. Variant chr17-6425781-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AIPL1	NM_014336.5	c.834G>A	p.Trp278*	stop_gained	6/6	ENST00000381129.8	NP_055151.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AIPL1	ENST00000381129.8	c.834G>A	p.Trp278*	stop_gained	6/6	1	NM_014336.5	ENSP00000370521.3

Frequencies

GnomAD3 genomes AF: 0.000368 AC: 56 AN: 152194 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000691

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000329 AC: 80 AN: 243060 Hom.: 0 AF XY: 0.000348 AC XY: 46 AN XY: 132192

Gnomad AFR exome AF: 0.000248

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000604

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000353 AC: 513 AN: 1454210 Hom.: 1 Cov.: 31 AF XY: 0.000351 AC XY: 254 AN XY: 723758

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000197

Gnomad4 FIN exome AF: 0.0000436

Gnomad4 NFE exome AF: 0.000426

Gnomad4 OTH exome AF: 0.000215

GnomAD4 genome AF: 0.000368 AC: 56 AN: 152312 Hom.: 0 Cov.: 32 AF XY: 0.000322 AC XY: 24 AN XY: 74466

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000691

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000471 Hom.: 1

Bravo AF: 0.000416

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.000362 AC: 44

EpiCase AF: 0.000818

EpiControl AF: 0.000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:26 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Leber congenital amaurosis 4 Pathogenic:9 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 11, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Jul 03, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Apr 08, 2016	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. -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2015	- -
Pathogenic, no assertion criteria provided	research	Laboratory of Genetics in Ophthalmology, Institut Imagine	-	- -
Pathogenic, criteria provided, single submitter	research	Ocular Genomics Institute, Massachusetts Eye and Ear	Apr 08, 2021	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jul 22, 2024	Criteria applied: PVS1,PM3,PM2_SUP -

not provided Pathogenic:5 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 05, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 11, 2022	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) -
not provided, no classification provided	literature only	Retina International	-	- -

Leber congenital amaurosis Pathogenic:5

Pathogenic, no assertion criteria provided	research	NIHR Bioresource Rare Diseases, University of Cambridge	Jan 01, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 01, 2016	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. -
Pathogenic, no assertion criteria provided	research	Sharon lab, Hadassah-Hebrew University Medical Center	Jun 23, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 27, 2023	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. -
Pathogenic, no assertion criteria provided	research	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	Apr 01, 2018	- -

Retinal dystrophy Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Jul 23, 2019	- -
Pathogenic, criteria provided, single submitter	research	Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel	May 27, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	Jan 01, 2022	- -

AIPL1-related disorder Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Sep 19, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -

AIPL1-related retinopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Mar 31, 2022

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 -

Retinitis pigmentosa;C1858386:Leber congenital amaurosis 4 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 18, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	45
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
Vest4		0.79
GERP RS		5.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs62637014; hg19: chr17-6329101;