ClinVar Miner

Submissions for variant NM_001134831.2(AHI1):c.400C>T (p.Pro134Ser) (rs368077581)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000427341 SCV000534623 uncertain significance not provided 2016-12-15 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the AHI1 gene. The P134S variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The P134S 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, and in silico analysis predicts this variant likely does not alter the protein structure/function. Based on the currently available information, it is unclear whether the P134S variant is a pathogenic variant or a rare benign variant.
Invitae RCV000527501 SCV000634572 uncertain significance Joubert syndrome 2017-02-07 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 134 of the AHI1 protein (p.Pro134Ser). The proline residue is weakly conserved and there is a moderate physicochemical difference between proline and serine. This variant is present in population databases (rs368077581, ExAC 0.01%) but has not been reported in the literature in individuals with an AHI1-related disease. 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. In summary, this variant is a rare missense change that is not predicted to affect protein function, and is found in the population at an appreciable frequency. This variant is not anticipated to cause disease; however, the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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