Submissions for variant NM_014336.5(AIPL1):c.1006G>A (p.Ala336Thr)

gnomAD frequency: 0.00200  dbSNP: rs143092701

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000723947	SCV000202151	uncertain significance	not provided	2017-11-16	criteria provided, single submitter	clinical testing
GeneDx	RCV000152763	SCV000516754	likely benign	not specified	2015-04-30	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae	RCV001085552	SCV001021493	benign	Leber congenital amaurosis 4	2024-01-29	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001085552	SCV001283225	uncertain significance	Leber congenital amaurosis 4	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
CeGaT Center for Human Genetics Tuebingen	RCV000723947	SCV004141710	likely benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	AIPL1: BP4, BS2
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000723947	SCV001552492	likely benign	not provided		no assertion criteria provided	clinical testing	The AIPL1 p.Ala324Thr variant was not identified in the literature but was identified in dbSNP (ID: rs143092701), ClinVar (classified as benign by Invitae; as likely benign by GeneDx; as uncertain significance by EGL Genetics), and LOVD 3.0. The variant was identified in control databases in 486 of 281528 chromosomes (2 homozygous) at a frequency of 0.001726 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 388 of 128476 chromosomes (freq: 0.00302), Ashkenazi Jewish in 27 of 10350 chromosomes (freq: 0.002609), Latino in 47 of 35428 chromosomes (freq: 0.001327), Other in 4 of 7200 chromosomes (freq: 0.000556), African in 12 of 24912 chromosomes (freq: 0.000482), European (Finnish) in 7 of 24610 chromosomes (freq: 0.000284) and South Asian in 1 of 30612 chromosomes (freq: 0.000033), but was not observed in the East Asian population. The p.Ala324 residue is conserved in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.