ClinVar Miner

Submissions for variant NM_014336.5(AIPL1):c.971G>T (p.Arg324Leu) (rs150427474)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000723621 SCV000231735 uncertain significance not provided 2016-11-22 criteria provided, single submitter clinical testing
GeneDx RCV000723621 SCV000521101 uncertain significance not provided 2016-06-06 criteria provided, single submitter clinical testing The R324L variant in the AIPL1 gene has been reported previously in two individuals with a clinical diagnosis of Leber's congenital amaurosis; however, neither of these individuals had a second AIPL1 variant identified, and one individual was noted to have two reportedly pathogenic RPE65 variants also identified (Wiszniewski et al., 2011). The NHLBI ESP Exome Sequencing Project and the 1000 Genomes Project report R324L was observed in 56/8600 (0.65%) and 9/1006 (0.89%) alleles, respectively, from individuals of European background, indicating it may be a rare variant in this population. This variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties, and occurs at a position that is conserved across species. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret R324L as a variant of uncertain significance.
Fulgent Genetics,Fulgent Genetics RCV000765381 SCV000896654 uncertain significance Leber congenital amaurosis 4; Retinitis pigmentosa 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV001080307 SCV001020949 benign Leber congenital amaurosis 4 2020-11-10 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001124292 SCV001283226 likely benign Retinitis pigmentosa 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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Clinical Services Laboratory,Illumina RCV001080307 SCV001283227 likely benign 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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000723621 SCV001553947 uncertain significance not provided no assertion criteria provided clinical testing The AIPL1 p.Arg324Leu variant was identified in 2 of 120 proband chromosomes (frequency: 0.0167) from individuals with Leber congenital amaurosis (Wiszniewski_2011_PMID:21153841). The variant was identified in dbSNP (ID: rs150427474), ClinVar (classified as a VUS by EGL Genetics, Fulgent Genetics and GeneDx) and LOVD 3.0 (classified as a VUS and benign). The variant was also identified in control databases in 1055 of 279794 chromosomes (3 homozygous) at a frequency of 0.003771 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 795 of 127754 chromosomes (freq: 0.006223), Other in 26 of 7196 chromosomes (freq: 0.003613), Latino in 111 of 35420 chromosomes (freq: 0.003134), South Asian in 81 of 30602 chromosomes (freq: 0.002647), African in 25 of 24890 chromosomes (freq: 0.001004), European (Finnish) in 16 of 23664 chromosomes (freq: 0.000676) and Ashkenazi Jewish in 1 of 10350 chromosomes (freq: 0.000097), but was not observed in the East Asian population. The p.Arg324 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of 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. 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.

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