ClinVar Miner

Submissions for variant NM_014336.5(AIPL1):c.784G>A (p.Gly262Ser) (rs142326926)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000086234 SCV000321388 likely pathogenic not provided 2016-03-30 criteria provided, single submitter clinical testing The G262S variant in the AIPL1 gene has been reported previously in association with Leber congenital amaurosis, in affected individuals who were heterozygous for the G262S variant and another variant (Sohocki et al., 2000; Jacobson et al., 2011; Tan et al., 2012). In vitro splice assays show the G262S variant alters AIPL1 splicing, supporting this variant as a loss-of-function variant (Bellingham et al., 2015). The G262S variant was not observed at any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G262S 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. This substitution occurs at a position that is conserved across species. The G262S variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
Invitae RCV000055941 SCV001219632 pathogenic Leber congenital amaurosis 4 2019-12-05 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 262 of the AIPL1 protein (p.Gly262Ser). The glycine residue is moderately conserved and there is a small physicochemical difference between glycine and serine. This variant also falls at the last nucleotide of exon 5 of the AIPL1 coding sequence, which is part of the consensus splice site for this exon. This variant is present in population databases (rs142326926, ExAC 0.01%). This variant has been observed in individual(s) with Leber congenital amaurosis (PMID: 10873396, 15249368, 20702822). ClinVar contains an entry for this variant (Variation ID: 65711). This variant has been reported to have conflicting or insufficient data to determine the effect on AIPL1 protein function (PMID: 15347646, 22347407, 28973376, 25799540, 27268253). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 26650897). For these reasons, this variant has been classified as Pathogenic.
GeneReviews RCV000055941 SCV000086965 pathologic Leber congenital amaurosis 4 2013-05-02 no assertion criteria provided curation Converted during submission to Pathogenic.
Retina International RCV000086234 SCV000118380 not provided not provided no assertion provided not provided

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