Submissions for variant NM_014874.3(MFN2):c.58C>T (p.His20Tyr) (rs201715603)

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Total submissions: 5

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000196976	SCV000251732	benign	not specified	2015-08-31	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Illumina Clinical Services Laboratory,Illumina	RCV000556563	SCV000347962	uncertain significance	Charcot-Marie-Tooth disease, type 2	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV000342413	SCV000347963	uncertain significance	Hereditary motor and sensory neuropathy	2016-06-14	criteria provided, single submitter	clinical testing
Inherited Neuropathy Consortium	RCV000789062	SCV000928411	uncertain significance	Charcot-Marie-Tooth disease		no assertion criteria provided	literature only
Invitae	RCV000556563	SCV000657729	uncertain significance	Charcot-Marie-Tooth disease, type 2	2018-11-21	criteria provided, single submitter	clinical testing	This sequence change replaces histidine with tyrosine at codon 20 of the MFN2 protein (p.His20Tyr). The histidine residue is moderately conserved and there is a moderate physicochemical difference between histidine and tyrosine. This variant is present in population databases (rs201715603, ExAC 0.01%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in an individual affected with Charcot-Marie-Tooth disease (PMID: 24957169). ClinVar contains an entry for this variant (Variation ID: 214656). 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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