rs62637012

Variant names:

• chr17-6426684-A-G
• rs62637012
• NM_014336.5:c.715T>C

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_014336.5(AIPL1):​c.715T>C​(p.Cys239Arg) 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. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. C239C) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: AIPL1 NM_014336.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1 O:2
• Conservation: PhyloP100: 8.82
• Publications: 10 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 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 17-6426684-A-G is Pathogenic according to our data. Variant chr17-6426684-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 5567.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.715T>C	p.Cys239Arg	missense_variant	Exon 5 of 6	ENST00000381129.8	NP_055151.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AIPL1	ENST00000381129.8	c.715T>C	p.Cys239Arg	missense_variant	Exon 5 of 6	1	NM_014336.5	ENSP00000370521.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1 Other:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Leber congenital amaurosis 4 Pathogenic:2 Uncertain:1 Other:1

Jan 01, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

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Laboratory of Genetics in Ophthalmology, Institut Imagine

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Mar 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 239 of the AIPL1 protein (p.Cys239Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Leber congenital amaurosis (PMID: 10615133; Invitae). ClinVar contains an entry for this variant (Variation ID: 5567). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt AIPL1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects AIPL1 function (PMID: 15347646, 22347407, 25799540, 27268253, 28973376). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Leber congenital amaurosis Pathogenic:1

Apr 21, 2024

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.715T>C (p.Cys239Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251430 control chromosomes. c.715T>C has been reported in the literature as a homozygous genotype in multiple individuals affected with Leber Congenital Amaurosis (example, Sohocki_2000, Dharmaraj_2004). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function demonstrating severely reduced interactions with NUB1, leading to defective inhibition of FAT10-DHFR degradation (Bett_2012). The following publications have been ascertained in the context of this evaluation (PMID: 22347407, 15249368, 10615133, 17964524). ClinVar contains an entry for this variant (Variation ID: 5567). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Other:1

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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	1.0
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D;.;D;.;.;.;.;D
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D;D;D;D;T;T;D;D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.31	D
MutationAssessor	Pathogenic	3.1	M;.;.;.;.;.;.;.
PhyloP100		8.8
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-12	D;D;.;.;.;.;.;.
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0010	D;D;.;.;.;.;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;.;D;.;.;D;.
Vest4		0.97
MutPred		0.94		Loss of catalytic residue at L240 (P = 0.0101);.;.;Loss of catalytic residue at L240 (P = 0.0101);.;.;.;.;
MVP		0.94
MPC		0.97
ClinPred		1.0	D
GERP RS		4.1
Varity_R		0.98
gMVP		0.84
Mutation Taster		=3/97	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs62637012; hg19: chr17-6330004;