ClinVar Miner

Submissions for variant NM_014336.5(AIPL1):c.715T>C (p.Cys239Arg)

dbSNP: rs62637012
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004585988 SCV005077111 pathogenic Leber congenital amaurosis 2024-04-21 criteria provided, single submitter 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV000005908 SCV005839147 uncertain significance Leber congenital amaurosis 4 2024-03-24 criteria provided, single submitter 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.
OMIM RCV000005908 SCV000026090 pathogenic Leber congenital amaurosis 4 2000-01-01 no assertion criteria provided literature only
GeneReviews RCV000005908 SCV000086964 not provided Leber congenital amaurosis 4 no assertion provided literature only
Retina International RCV000086231 SCV000118377 not provided not provided no assertion provided not provided
Laboratory of Genetics in Ophthalmology, Institut Imagine RCV000005908 SCV001335450 pathogenic Leber congenital amaurosis 4 no assertion criteria provided research

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