Submissions for variant NM_014336.5(AIPL1):c.140C>G (p.Thr47Arg)

gnomAD frequency: 0.00357  dbSNP: rs150656720

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV000488128	SCV000575084	uncertain significance	not provided	2016-11-30	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001081379	SCV001091613	benign	Leber congenital amaurosis 4	2025-02-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001700132	SCV002500481	likely benign	not specified	2022-03-18	criteria provided, single submitter	clinical testing	Variant summary: AIPL1 c.140C>G (p.Thr47Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00092 in 251278 control chromosomes, predominantly at a frequency of 0.01 within the African or African-American subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 8.9 fold of the estimated maximal expected allele frequency for a pathogenic variant in AIPL1 causing Leber Congenital Amaurosis phenotype (0.0011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.140C>G has been reported in the literature as a VUS identified in settings of clinical exome sequencing for Inherited Retinal Dystrophies (IRD) (example, Florin Iancu_2021). These report(s) do not provide unequivocal conclusions about a penetrant association of the variant with Leber Congenital Amaurosis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as benign and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Clinical Genetics, Academic Medical Center	RCV001700132	SCV001920273	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000488128	SCV001975892	likely benign	not provided		no assertion criteria provided	clinical testing