17-6426934-C-G

Variant names:

• chr17-6426934-C-G
• rs62637010
• NM_014336.5:c.589G>C

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_014336.5(AIPL1):​c.589G>C​(p.Ala197Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: AIPL1 NM_014336.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:3 O:2
• Conservation: PhyloP100: 7.52
• Publications: 7 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: Pathogenic. The variant received 16 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_014336.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 17-6426934-C-G is Pathogenic according to our data. Variant chr17-6426934-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 65709.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AIPL1	NM_014336.5	c.589G>C	p.Ala197Pro	missense_variant	Exon 4 of 6	ENST00000381129.8	NP_055151.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AIPL1	ENST00000381129.8	c.589G>C	p.Ala197Pro	missense_variant	Exon 4 of 6	1	NM_014336.5	ENSP00000370521.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Other:2

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

Laboratory of Genetics in Ophthalmology, Institut Imagine

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

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.589G>C (p.Ala197Pro) is a missense variant replacing the alanine at position p.197 with proline. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.969, which is above the ClinGen LCA / eoRD VCEP threshold of ≥0.93 and predicts a damaging effect on AIPL1 function (PP3_Strong). This variant has been reported in 2 probands with early-onset severe retinal dystrophy who were homozygous for the variant (PMIDs 10873396, 15024725). (1 point, PM3). At least one proband harboring this variant exhibits a phenotype including a diagnosis of LCA (0.5 pts) with severe visual impairment from birth or during early infancy (1 pt) accompanied by nystagmus (1 pt), absent or very sluggish pupillary responses (0.5 pts), and absent or markedly reduced electroretinogram responses from both rods (0.5 pts) and cones (1 pt), which together are specific for AIPL1-related retinopathy (total 4.5 points, PMID: 10873396, PP4). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus at least 3 similarly affected relatives, with the variant present in the homozygous state (PP1_Strong; PMID: 10873396). 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: PM2_Supporting, PP3_Strong, PM3, PP4, and PP1_Strong. (VCEP specifications version 1.0.0; date of approval 09/24/2025).

Leber congenital amaurosis Pathogenic:1

Jun 18, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: AIPL1 c.589G>C (p.Ala197Pro) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant was absent in 251468 control chromosomes. c.589G>C has been observed the homozygous state in multiple individuals affected with Leber Congenital Amaurosis from one family where it segregated with disease (Sohocki_2000). These data indicate that the variant is very likely to be associated with disease. At least two publications reports experimental evidence that this variant has an impact on protein function (Hidalgo-de_Quintana_2015, van der Spuy_2004). The following publications have been ascertained in the context of this evaluation (PMID: 25799540, 10873396, 15347646). ClinVar contains an entry for this variant (Variation ID: 65709). Based on the evidence outlined above, the variant was classified as pathogenic.

not provided Other:1

Retina International

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.67	D;.;T;.;.;.;.;T;T
Eigen	Pathogenic	0.76
Eigen_PC	Uncertain	0.61
LIST_S2	Uncertain	0.92	D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.56	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.0	H;.;.;.;.;H;.;.;.
PhyloP100		7.5
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-4.9	D;D;.;.;.;.;.;.;.
Sift	Pathogenic	0.0	D;D;.;.;.;.;.;.;.
Sift4G	Uncertain	0.0050	D;D;D;D;D;D;D;D;.
Vest4		0.98
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.98
gMVP		0.93
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs62637010; hg19: chr17-6330254;