Submissions for variant NM_022489.4(INF2):c.1957G>A (p.Glu653Lys) (rs368576387)

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Total submissions: 1

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000649964	SCV000771801	uncertain significance	Focal segmental glomerulosclerosis 5; Charcot-Marie-Tooth disease, dominant intermediate E	2017-11-13	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid with lysine at codon 653 of the INF2 protein (p.Glu653Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs368576387, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with INF2-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 disruptive, 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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