rs142326926

Variant names:

• chr17-6426615-C-T
• rs142326926
• ENST00000575265.5:c.784G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PP3 PP5_Very_Strong

The ENST00000575265.5(AIPL1):​c.784G>A​(p.Gly262Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000719 in 1,613,738 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. G262G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000075 (0 hom.)
• Consequence: AIPL1 ENST00000575265.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:4 O:3
• Conservation: PhyloP100: 5.75
• Publications: 8 publications found

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]

AIPL1 Gene-Disease associations (from GenCC):

• AIPL1-related retinopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Leber congenital amaurosis 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• Leber congenital amaurosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 17-6426615-C-T is Pathogenic according to our data. Variant chr17-6426615-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 65711.Status of the report is reviewed_by_expert_panel, 3 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000575265.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AIPL1	NM_014336.5	MANE Select	c.784G>A	p.Gly262Ser	missense splice_region	Exon 5 of 6	NP_055151.3
	AIPL1	NM_001285403.4		c.760G>A	p.Gly254Ser	missense	Exon 5 of 5	NP_001272332.1
	AIPL1	NM_001285399.3		c.748G>A	p.Gly250Ser	missense splice_region	Exon 5 of 6	NP_001272328.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AIPL1	ENST00000575265.5	TSL:1	c.784G>A	p.Gly262Ser	missense	Exon 5 of 5	ENSP00000459673.1
	AIPL1	ENST00000571740.5	TSL:1	c.760G>A	p.Gly254Ser	missense	Exon 5 of 5	ENSP00000460134.1
	AIPL1	ENST00000381129.8	TSL:1 MANE Select	c.784G>A	p.Gly262Ser	missense splice_region	Exon 5 of 6	ENSP00000370521.3

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152270 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000882

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000319 AC: 8 AN: 250650 AF XY: 0.0000443

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000617

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000746 AC: 109 AN: 1461468 Hom.: 0 Cov.: 34 AF XY: 0.0000646 AC XY: 47 AN XY: 727056

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53118

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000935 AC: 104 AN: 1111932

Other (OTH) AF: 0.0000662 AC: 4 AN: 60388

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152270 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74394

African (AFR) AF: 0.0000241 AC: 1 AN: 41472

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68048

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000441 Hom.: 0

Bravo AF: 0.0000264

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Other:3

Revision: reviewed by expert panel

Submissions by phenotype

Leber congenital amaurosis 4 Pathogenic:1 Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 262 of the AIPL1 protein (p.Gly262Ser). RNA analysis indicates that this missense change induces altered splicing and likely disrupts the C-terminus of the protein. This variant is present in population databases (rs142326926, gnomAD 0.006%). This missense change has been observed in individuals with Leber congenital amaurosis (PMID: 10873396, 15249368, 20702822). ClinVar contains an entry for this variant (Variation ID: 65711). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on AIPL1 protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on AIPL1 function (PMID: 15347646, 22347407, 25799540, 27268253, 28973376). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change results in partial skipping of exon 5 and introduces a new termination codon (PMID: 26650897). However the mRNA is not expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.

not provided Pathogenic:1 Other:1

Jun 11, 2025

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate abnormal gene splicing (PMID: 26650897); In silico analysis supports that this missense variant has a deleterious effect on splicing; In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 15469903, 15180275, 22412862, 15347646, 22347407, 20301475, 15081406, 24596939, 25799540, 12374762, 16052170, 20702822, 10873396, 26650897, 35456422, 31964843, 38219857)

Retina International

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

AIPL1-related disorder Pathogenic:1

Aug 29, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The AIPL1 c.784G>A variant is predicted to result in the amino acid substitution p.Gly262Ser. This variant has been reported in the compound heterozygous state in individuals with autosomal recessive Leber congenital amaurosis (Sohocki et al. 2000. PubMed ID: 10873396; Table S1, Zhu et al. 2022. PubMed ID: 35456422; Table S1, Lin et al. 2024. PubMed ID: 38219857). This variant affects the last nucleotide of exon 5 and a functional study using a minigene assay has shown that this variant alters splicing (Bellingham et al. 2015. PubMed ID: 26650897). This variant is reported in 0.0062% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.

AIPL1-related retinopathy Pathogenic:1

Sep 29, 2025

ClinGen Leber Congenital Amaurosis/early Onset Retinal Dystrophy Variant Curation Expert Panel, ClinGen

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

NM_014336.5(AIPL1):c.784G>A (p.Gly262Ser) is an apparent missense variant predicted to result in replacement of glycine with serine at codon 262 but which is also located in the final nucleotide of exon 5 of 6. The splicing impact predictor SpliceAI gives a score of 0.72 for donor gain, which is above the ClinGen LCA/eoRD VCEP recommended threshold of ≥0.2 and predicts a damaging impact on splicing. A minigene assay indicates that the variant abolishes the production of normal length splice products and instead results in cryptic splice usage and either complete skipping of exon 5 or skipping of the last 40 bp of exon 5. These computational and experimental data have not been used to meet PP3 and PS3_Supporting but rather combined to indicate a null impact on AIPL1 (PVS1(RNA)). A number of publications studying this variant as an exogenously expressed missense change p.Gly262Ser have shown functional activity comparable to the wild-type control (PMID: 15347646 , PMID: 18408180, PMID: 27268253), however BS3_Supporting has not been applied as the variant appears to impact AIPL1 functionally through a splicing defect rather than a missense mechanism. This variant is present in gnomAD v.4.1.0 at a total allele frequency of 0.00007188, with 116 alleles / 1,613,738 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 (PM2_Supporting). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the NM_014336.5(AIPL1):c.834G>A (p.Trp278Ter) variant suspected but not confirmed in trans (0.5 points, PMID: 10873396), which was previously classified pathogenic by the ClinGen LCA/eoRD VCEP (PM3_Supporting). At least one proband harboring this variant exhibits a phenotype including a diagnosis of Leber congenital amaurosis (0.5 pts) with visual acuity limited to hand movements (1 pt), mild maculopathy (0.5 pts), mild optic nerve pallor (0.5 pts), moderate-to-severe pigmentary retinopathy (1 pt), and photoattraction (1 pt), which together are specific for AIPL1-related retinopathy (total 4.5 points, PMID: 15249368, PP4). 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(RNA), PM2_Supporting, PM3_Supporting, and PP4. (VCEP specifications version 1.0.0; date of approval 09/24/2025),

Leber congenital amaurosis 4;C2751763:Juvenile retinitis pigmentosa, AIPL1-related;C2751764:CONE-ROD DYSTROPHY, AIPL1-RELATED;CN239169:AIPL1-related disorder Other:1

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant classified as Likely pathogenic and reported on 05-02-2016 by GeneDx. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Uncertain	0.022	T
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	35
DANN	Uncertain	0.99
DEOGEN2	Benign	0.067	T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.81	T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.36	T
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		5.8
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.46
Sift	Benign	0.13	T
Sift4G	Benign	0.27	T
Polyphen		0.86	P
Vest4		0.47
MVP		0.88
MPC		0.30
ClinPred		0.49	T
GERP RS		5.1
Varity_R		0.28
gMVP		0.34
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.72		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.72		Position offset: 40

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

Other links and lift over

dbSNP: rs142326926; hg19: chr17-6329935;