ClinVar Miner

Submissions for variant NM_001134831.2(AHI1):c.3503A>G (p.Glu1168Gly) (rs199578341)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Fulgent Genetics,Fulgent Genetics RCV000764640 SCV000895748 uncertain significance Joubert syndrome 3 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000445026 SCV000531336 uncertain significance not specified 2017-10-13 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the AHI1 gene. The E1168G variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The NHLBI Exome Sequencing Project reports E1168G was observed in 25/8242 (0.3%) alleles from individuals of European background, and the 1000 Genomes Project reports E1168G was observed in 1/198 (0.5%) alleles from individuals of Western European ancestry living in Utah. The E1168G 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. However, this substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000701724 SCV000830537 uncertain significance Joubert syndrome 2018-01-17 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with glycine at codon 1168 of the AHI1 protein (p.Glu1168Gly). The glutamic acid residue is weakly conserved and there is a moderate physicochemical difference between glutamic acid and glycine. This variant is present in population databases (rs199578341, ExAC 0.1%). This variant has not been reported in the literature in individuals with AHI1-related disease. ClinVar contains an entry for this variant (Variation ID: 388935). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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