Submissions for variant NM_014336.5(AIPL1):c.1053_1064del (p.Ala352_Pro355del)

dbSNP: rs281865195

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001517242	SCV001725712	benign	Leber congenital amaurosis 4	2024-01-25	criteria provided, single submitter	clinical testing
GeneDx	RCV000086210	SCV001782366	likely benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002222344	SCV002500342	uncertain significance	not specified	2022-03-12	criteria provided, single submitter	clinical testing	Variant summary: AIPL1 c.1053_1064del12 (p.Ala352_Pro355del) results in an in-frame deletion that is predicted to remove four amino acids from the encoded protein. The variant allele was found at a frequency of 0.00087 in 250120 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in AIPL1 causing Leber Congenital Amaurosis (0.00087 vs 0.0011), allowing no conclusion about variant significance. Although reported in the literature, as unlikely to be associated with autosomal dominant Inherited Retinal Degeneration (example, Hanany_2019), to our knowledge, no penetrant association of c.1053_1064del12 in individuals affected with Autosomal Recessive Leber Congenital Amaurosis and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign/benign, n=2; VUS, n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
OMIM	RCV000005909	SCV000026091	pathogenic	Juvenile retinitis pigmentosa, AIPL1-related	2000-06-01	no assertion criteria provided	literature only
OMIM	RCV000005910	SCV000026092	pathogenic	CONE-ROD DYSTROPHY, AIPL1-RELATED	2000-06-01	no assertion criteria provided	literature only
Retina International	RCV000086210	SCV000118354	not provided	not provided		no assertion provided	not provided
Reproductive Health Research and Development, BGI Genomics	RCV000005910	SCV001142467	uncertain significance	CONE-ROD DYSTROPHY, AIPL1-RELATED	2020-01-06	no assertion criteria provided	curation	NM_014336.3:c.1053_1064delTGCAGAGCCACC in the AIPL1 gene has an allele frequency of 0.01 in Ashkenazi Jewish subpopulation in the gnomAD database. It has been detected in two individuals with cone-rod dystrophy (PMID: 10873396). This in-frame deletion happens in a repetitive region without known function. We interpret it as variant of uncertain significance (VUS). ACMG/AMP criteria applied: BP3, PP4.
PreventionGenetics, part of Exact Sciences	RCV004732531	SCV005367619	uncertain significance	AIPL1-related disorder	2024-09-06	no assertion criteria provided	clinical testing	The AIPL1 c.1053_1064del12 variant is predicted to result in an in-frame deletion (p.Ala352_Pro355del). This variant has been reported in the heterozygous state in individuals with autosomal dominant cone-rod dystrophy or juvenile retinitis pigmentosa (Sohocki et al. 2000. PubMed ID: 10873396; Sacristan-Reviriego et al. 2020. PubMed ID: 33067476). This deletion is located in the highly conserved "hinge region" of AIPL1, which is only present in primates (Sohocki et al. 2000. PubMed ID: 10873396). A transgenic mouse model has demonstrated a dominant negative effect on photoreceptors, leading to cone degeneration (Ku et al. 2015. PubMed ID: 25274777). In vitro functional studies revealed that this variant does not affect its cytoplasmic distribution, interaction with HSP90 or cGMP modulation; however these studies are not known to be informative for modeling of gain-of-function disease mechanisms (Sacristan-Reviriego et al 2020. PubMed ID: 33067476). Additionally, this variant is reported in 1.0% of alleles in individuals of Ashkenazi Jewish descent in gnomAD, which is likely too frequent to be a primary cause of disease. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.