ClinVar Miner

Submissions for variant NM_022489.4(INF2):c.3535A>G (p.Thr1179Ala) (rs778879482)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000490158 SCV000577331 uncertain significance not provided 2017-04-04 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the INF2 gene. The T1179A variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The T1179A variant is observed in 1/62,090 alleles from individuals of European background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The T1179A 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 RCV000649970 SCV000771807 uncertain significance Focal segmental glomerulosclerosis 5; Charcot-Marie-Tooth disease, dominant intermediate E 2018-05-21 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 1179 of the INF2 protein (p.Thr1179Ala). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and alanine. This variant is present in population databases (rs778879482, ExAC 0.002%). This variant has not been reported in the literature in individuals with INF2-related disease. ClinVar contains an entry for this variant (Variation ID: 426793). 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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