Submissions for variant NM_014336.5(AIPL1):c.112C>T (p.Arg38Cys)

gnomAD frequency: 0.00003  dbSNP: rs200899521

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000431163	SCV000511489	uncertain significance	not provided	2016-09-22	criteria provided, single submitter	clinical testing	Converted during submission to Uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001861487	SCV002171023	uncertain significance	Leber congenital amaurosis 4	2022-02-09	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 38 of the AIPL1 protein (p.Arg38Cys). This variant is present in population databases (rs200899521, gnomAD 0.01%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with clinical features of Leber congenital amaurosis (PMID: 17964524). ClinVar contains an entry for this variant (Variation ID: 377207). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change does not substantially affect AIPL1 function (PMID: 23737531, 27268253). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003330664	SCV004038986	uncertain significance	not specified	2023-08-10	criteria provided, single submitter	clinical testing	Variant summary: AIPL1 c.112C>T (p.Arg38Cys) results in a non-conservative amino acid change located in the FKBP-type peptidyl-prolyl cis-trans isomerase domain (IPR001179) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 250994 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in AIPL1 causing Leber Congenital Amaurosis (4e-05 vs 0.0011), allowing no conclusion about variant significance. c.112C>T has been reported in the literature in individuals affected with Leber Congenital Amaurosis or nonsyndromic blindness without strong evidence of causality (Stone_2007, Dineiro_2020). These reports do not provide unequivocal conclusions about association of the variant with Leber Congenital Amaurosis. Publications reports experimental evidence evaluating an impact on protein function, finding no effect of the variant on the ability for AIPL1 to interact with FAT10 or to chaperone PDE6C (Boehm_2020, Gopalakrishna_2016). The following publications have been ascertained in the context of this evaluation (PMID: 17964524, 32483926, 32817338, 27268253). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Both submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000431163	SCV001549658	uncertain significance	not provided		no assertion criteria provided	clinical testing	The AIPL1 p.Arg38Cys variant was identified in the literature in 1 of 1284 proband chromosomes (frequency: 0.0008) from individuals with Leber congenital amaurosis (Stone_2007_PMID:17964524). The variant was identified in dbSNP (ID: rs200899521) and ClinVar (classified as uncertain significance by the Center for Pediatric Genomic Medicine Children's Mercy Hospital and Clinics). The variant was identified in control databases in 11 of 282324 chromosomes (1 homozygous) at a frequency of 0.00003896 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Latino in 4 of 35398 chromosomes (freq: 0.000113), South Asian in 3 of 30550 chromosomes (freq: 0.000098), African in 1 of 24916 chromosomes (freq: 0.00004) and European (non-Finnish) in 3 of 128980 chromosomes (freq: 0.000023), but was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), or Other populations. The p.Arg38 residue is conserved in mammals but not in more distantly related organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. Data from two functional studies demonstrated that the chaperone ability of the AIPL1 protein containing the p.R38C variant did not differ significantly from the wild type (Gopalakrishna_2016_PMID:27268253), and the p.R38C variant did not significantly affect the binding of farnesyl-Cys-AMCA to AIPL1 (Majumder_2013_PMID:23737531). In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.