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

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001705126	SCV000251732	benign	not provided	2020-04-13	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 27884173, 31453851, 24957169)
Illumina Clinical Services Laboratory,Illumina	RCV000556563	SCV000347962	likely benign	Charcot-Marie-Tooth disease, type 2	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Illumina Clinical Services Laboratory,Illumina	RCV000342413	SCV000347963	likely benign	Hereditary motor and sensory neuropathy with optic atrophy	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
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.
Molecular Genetics Laboratory,London Health Sciences Centre	RCV000789062	SCV001335748	uncertain significance	Charcot-Marie-Tooth disease		criteria provided, single submitter	clinical testing
Inherited Neuropathy Consortium	RCV000789062	SCV000928411	uncertain significance	Charcot-Marie-Tooth disease		no assertion criteria provided	literature only