VCV000005565.65 - ClinVar

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

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(26)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 5565 Accession: VCV000005565.65

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17p13.2 17: 6425781 (GRCh38) [ NCBI UCSC ] 17: 6329101 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Oct 1, 2013	Nov 24, 2024	Jul 22, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_014336.5:c.834G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_055151.3:p.Trp278Ter	nonsense
NM_001033054.3:c.645G>A	NP_001028226.1:p.Trp215Ter	nonsense
NM_001033055.3:c.654G>A	NP_001028227.1:p.Trp218Ter	nonsense
NM_001285399.3:c.798G>A	NP_001272328.1:p.Trp266Ter	nonsense
NM_001285400.3:c.768G>A	NP_001272329.1:p.Trp256Ter	nonsense
NM_001285401.3:c.762G>A	NP_001272330.1:p.Trp254Ter	nonsense
NM_001285402.2:c.717G>A	NP_001272331.1:p.Trp239Ter	nonsense
NM_001285403.4:c.*805G>A		3 prime UTR
NC_000017.11:g.6425781C>T
NC_000017.10:g.6329101C>T
NG_008474.1:g.14419G>A

... more HGVS ... less HGVS

Protein change

W278*, W256*, W218*, W254*, W215*, W239*, W266*

Other names

Canonical SPDI

NC_000017.11:6425780:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00020 (T)

Allele frequency Help The frequency of the allele represented by this VCV record.

1000 Genomes Project 30x 0.00016

1000 Genomes Project 0.00020

The Genome Aggregation Database (gnomAD), exomes 0.00033

Exome Aggregation Consortium (ExAC) 0.00037

The Genome Aggregation Database (gnomAD) 0.00038

Trans-Omics for Precision Medicine (TOPMed) 0.00042

Links

ClinGen: CA227899 OMIM: 604392.0001 dbSNP: rs62637014 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
AIPL1		-	-	GRCh38 GRCh37	562	587

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Leber congenital amaurosis 4	Pathogenic (10)	criteria provided, multiple submitters, no conflicts	Jul 22, 2024	RCV000005906.27
not provided	Pathogenic (6)	criteria provided, multiple submitters, no conflicts	Oct 11, 2022	RCV000086235.35
AIPL1-related disorder	Pathogenic (2)	criteria provided, single submitter	Apr 27, 2017	RCV000365317.8
Leber congenital amaurosis	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	Apr 27, 2023	RCV000505017.6
Retinal dystrophy	Pathogenic (1)	criteria provided, single submitter	Jul 23, 2019	RCV001074840.4
Leber congenital amaurosis 4 Retinitis pigmentosa	Pathogenic (1)	criteria provided, single submitter	Mar 18, 2022	RCV002496274.3
AIPL1-related retinopathy	Pathogenic (1)	criteria provided, single submitter	Mar 31, 2022	RCV004786238.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Apr 08, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Leber congenital amaurosis 4 Affected status: no Allele origin: germline	Knight Diagnostic Laboratories, Oregon Health and Sciences University Study: CSER-NextGen Accession: SCV000494234.1 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016	Comment: 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 … (more) 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. (less)
Pathogenic (Apr 05, 2017)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000338213.4 First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018	Publications: PubMed (1) PubMed: 10615133 Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=AIPL1 Number of individuals with the variant: 3 Sex: mixed
Pathogenic (Jul 23, 2019)	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme) Method: clinical testing	Retinal dystrophy Affected status: yes Allele origin: germline	Blueprint Genetics Accession: SCV001240441.1 First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020 Comment: My Retina Tracker patient
Pathogenic (Jan 03, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Leber congenital amaurosis 4 Affected status: yes Allele origin: germline	3billion Accession: SCV002058854.1 First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022	Publications: PMID:10615133 PMID:10615133 Comment: 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) 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. (less) Clinical Features: Visual impairment (present) , Abnormal retinal morphology (present)
Pathogenic (Jul 03, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Leber congenital amaurosis 4 Affected status: yes Allele origin: germline	Genetics and Molecular Pathology, SA Pathology Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002761951.1 First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022
Pathogenic (Jul 11, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Leber congenital amaurosis 4 Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002024140.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Feb 01, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Leber congenital amaurosis (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV004847978.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024	Publications: PubMed (2) PubMed: 15347646‚ 10615133 Comment: 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 … (more) 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. (less)
Pathogenic (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019) Method: clinical testing	AIPL1-Related Disorders Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000405575.3 First in ClinVar: Dec 06, 2016 Last updated: May 24, 2019	Publications: PubMed (6) PubMed: 21474771‚ 25799540‚ 10873396‚ 10615133‚ 15249368‚ 15347646 Comment: 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 … (more) 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. (less)
Pathogenic (Apr 08, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Leber congenital amaurosis 4 Affected status: yes Allele origin: germline	Ocular Genomics Institute, Massachusetts Eye and Ear Accession: SCV001573248.1 First in ClinVar: May 10, 2021 Last updated: May 10, 2021	Publications: PubMed (4) PubMed: 10615133‚ 10873396‚ 15347646‚ 25799540 Comment: 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 … (more) 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. (less)
Pathogenic (Mar 18, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Retinitis pigmentosa Leber congenital amaurosis 4 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002813931.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (Oct 11, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000680497.5 First in ClinVar: Feb 13, 2018 Last updated: Mar 04, 2023	Comment: 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 … (more) 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) (less)
Pathogenic (Apr 27, 2023)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Leber congenital amaurosis Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV003928395.1 First in ClinVar: Jun 03, 2023 Last updated: Jun 03, 2023	Publications: PubMed (4) PubMed: 15347646‚ 25799540‚ 10873396‚ 10615133 Comment: 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 … (more) 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. (less)
Pathogenic (Jan 30, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Leber congenital amaurosis 4 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000833757.6 First in ClinVar: Oct 10, 2018 Last updated: Feb 20, 2024	Publications: PubMed (8) PubMed: 28492532‚ 10615133‚ 10873396‚ 15249368‚ 21474771‚ 22412862‚ 15347646‚ 25799540 Comment: 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, … (more) 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. (less)
Pathogenic (Jul 22, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Leber congenital amaurosis 4 (Autosomal recessive inheritance) Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV005368217.1 First in ClinVar: Oct 13, 2024 Last updated: Oct 13, 2024	Comment: Criteria applied: PVS1,PM3,PM2_SUP Clinical Features: Visual impairment (present) , Nystagmus (present) Sex: male
Pathogenic (Oct 01, 2017)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001246292.26 First in ClinVar: May 09, 2020 Last updated: Oct 20, 2024	Number of individuals with the variant: 2
Pathogenic (Mar 31, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	AIPL1-related retinopathy Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV005398878.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Publications: PubMed (1) PubMed: 33067476 Comment: 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 … (more) 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 (less)
Pathogenic (Jan 01, 2015)	no assertion criteria provided Method: research	Leber congenital amaurosis Affected status: yes Allele origin: unknown	NIHR Bioresource Rare Diseases, University of Cambridge Accession: SCV000599074.1 First in ClinVar: Sep 09, 2017 Last updated: Sep 09, 2017	Publications: PubMed (2) PubMed: 28041643‚ 10615133 Number of individuals with the variant: 1 Sex: male Ethnicity/Population group: European
Pathogenic (Apr 01, 2018)	no assertion criteria provided Method: research	Leber congenital amaurosis Affected status: yes Allele origin: unknown	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet Study: VeluxRD Accession: SCV000926500.2 First in ClinVar: Jul 21, 2019 Last updated: Sep 03, 2023	Publications: PubMed (1) PubMed: 30718709
Pathogenic (Apr 01, 2015)	no assertion criteria provided Method: literature only	LEBER CONGENITAL AMAUROSIS 4 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000026088.3 First in ClinVar: Apr 04, 2013 Last updated: May 19, 2020	Publications: PubMed (3) PubMed: 10615133‚ 10873396‚ 25596619 Comment on evidence: In the original Pakistani family identified as LCA4 (604393) and in a second Pakistani family, whose LCA had been mapped to 17p13.1, Sohocki et al. … (more) In the original Pakistani family identified as LCA4 (604393) and in a second Pakistani family, whose LCA had been mapped to 17p13.1, Sohocki et al. (2000) demonstrated homozygosity for a nonsense mutation (trp278 to ter; W278X), TGG-to-TGA, in the AIPL1 gene. The mutation segregated with disease in both families and was not found in 100 ethnically matched controls. The 2 families differed in haplotype (GCG and GAA, respectively) of the AIPL1 exon 3 polymorphisms, as well as for microsatellite markers tightly linked to AIPL1. These findings suggested that the W278X mutation causing LCA in these 2 families was not derived from a recent, common ancestor. In a European family (RFS127), Sohocki et al. (2000) found homozygosity for the W278X mutation. In this case haplotype analysis of tightly linked microsatellite markers and of the AIPL1 exon 3 polymorphisms suggested that the mutations in the RFS127 family and the second Pakistani family were likely to have descended from a common ancestor; however, there was no indication of Pakistani origin in this family. Noting that AIPL1 is not expressed in the cornea and that affected members of the second Pakistani family and the European family who were homozygous for W278X had LCA without keratoconus, the authors suggested that the keratoconus present in affected members of the original LCA4 family was possibly secondary to eye rubbing due to the LCA. In a more extensive study, Sohocki et al. (2000) found homozygosity for the W278X mutation in 3 of 13 families and compound heterozygosity in 3 additional families. The mutation was identified in affected individuals from multiple populations, including Pakistani, Spanish, French, and American. From a study of data on 42 patients from 18 countries with molecularly confirmed LCA4, Aboshiha et al. (2015) found that W278X was the most common mutation, being found on one or more alleles in 26 patients (62%) and on both alleles in 15 patients (36%). (less)
Pathogenic (-)	no assertion criteria provided Method: research	Leber congenital amaurosis 4 Affected status: yes Allele origin: inherited	Laboratory of Genetics in Ophthalmology, Institut Imagine Accession: SCV001335452.1 First in ClinVar: Jun 11, 2020 Last updated: Jun 11, 2020	Publications: PubMed (1) PubMed: 10873396 Number of individuals with the variant: 15
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001952602.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Pathogenic (Sep 19, 2024)	no assertion criteria provided Method: clinical testing	AIPL1-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005350214.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: 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 … (more) 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. (less)
Pathogenic (Jun 23, 2019)	no assertion criteria provided Method: research	Leber congenital amaurosis Affected status: yes Allele origin: inherited	Sharon lab, Hadassah-Hebrew University Medical Center Accession: SCV001160891.1 First in ClinVar: Feb 16, 2020 Last updated: Feb 16, 2020
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001919962.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
not provided (-)	no classification provided Method: not provided	not provided Affected status: not provided Allele origin: not provided	Retina International Accession: SCV000118381.1 First in ClinVar: Feb 20, 2014 Last updated: Feb 20, 2014 Comment: http://phencode.bx.psu.edu/cgi-bin/phencode/phencode?build=hg19&id=RISN_AIPL1:c.834G>A
not provided (-)	no classification provided Method: literature only	Leber congenital amaurosis 4 Affected status: not provided Allele origin: unknown	GeneReviews Accession: SCV000086966.2 First in ClinVar: Oct 01, 2013 Last updated: Oct 01, 2022	Publications: PubMed (1) PubMed: 20301475 BookShelf: NBK1298 BookShelf: NBK1298
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Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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)

Comment:

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.

Comment:

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.

Comment:

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

Comment:

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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Clinical and functional analyses of AIPL1 variants reveal mechanisms of pathogenicity linked to different forms of retinal degeneration.	Sacristan-Reviriego A	Scientific reports	2020	PMID: 33067476
Molecular genetic analysis using targeted NGS analysis of 677 individuals with retinal dystrophy.	Jespersgaard C	Scientific reports	2019	PMID: 30718709
Molecular and clinical analysis of 27 German patients with Leber congenital amaurosis.	Weisschuh N	PloS one	2018	PMID: 30576320
The Leber congenital amaurosis protein AIPL1 and EB proteins co-localize at the photoreceptor cilium.	Hidalgo-de-Quintana J	PloS one	2015	PMID: 25799540
Preserved outer retina in AIPL1 Leber's congenital amaurosis: implications for gene therapy.	Aboshiha J	Ophthalmology	2015	PMID: 25596619
Leber Congenital Amaurosis – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY.	Adam MP	-	2013	PMID: 20301475
Leber congenital amaurosis associated with AIPL1: challenges in ascribing disease causation, clinical findings, and implications for gene therapy.	Tan MH	PloS one	2012	PMID: 22412862
Evaluation of Italian patients with leber congenital amaurosis due to AIPL1 mutations highlights the potential applicability of gene therapy.	Testa F	Investigative ophthalmology & visual science	2011	PMID: 21474771
The Leber congenital amaurosis protein AIPL1 modulates the nuclear translocation of NUB1 and suppresses inclusion formation by NUB1 fragments.	van der Spuy J	The Journal of biological chemistry	2004	PMID: 15347646
The phenotype of Leber congenital amaurosis in patients with AIPL1 mutations.	Dharmaraj S	Archives of ophthalmology (Chicago, Ill. : 1960)	2004	PMID: 15249368
Prevalence of AIPL1 mutations in inherited retinal degenerative disease.	Sohocki MM	Molecular genetics and metabolism	2000	PMID: 10873396
Mutations in a new photoreceptor-pineal gene on 17p cause Leber congenital amaurosis.	Sohocki MM	Nature genetics	2000	PMID: 10615133
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=AIPL1	-	-	-	-
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Text-mined citations for rs62637014 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs62637014 ...