Submissions for variant NM_014874.4(MFN2):c.58C>T (p.His20Tyr)

gnomAD frequency: 0.00004  dbSNP: rs201715603

Total submissions: 10

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 Laboratory Services, 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 Laboratory Services, 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000556563	SCV000657729	uncertain significance	Charcot-Marie-Tooth disease type 2	2024-12-07	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 20 of the MFN2 protein (p.His20Tyr). This variant is present in population databases (rs201715603, gnomAD 0.01%). This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 24957169, 31453851). ClinVar contains an entry for this variant (Variation ID: 214656). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt MFN2 protein function with a negative predictive value of 80%. 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
CeGaT Center for Human Genetics Tuebingen	RCV001705126	SCV002543868	uncertain significance	not provided	2022-04-01	criteria provided, single submitter	clinical testing	MFN2: PP3
Ambry Genetics	RCV002354554	SCV002652563	uncertain significance	Inborn genetic diseases	2020-08-14	criteria provided, single submitter	clinical testing	The p.H20Y variant (also known as c.58C>T), located in coding exon 1 of the MFN2 gene, results from a C to T substitution at nucleotide position 58. The histidine at codon 20 is replaced by tyrosine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. This alteration has been reported in a compound heterozygous state together with MFN c.2218T>A (p.Trp740Arg) in an individual with CMT2A (Al-Harbi TM et al. J Clin Neuromuscul Dis, 2019 Sep;21:25-29), as well as in a heterozygous state in an individual with CMT (Bombelli F et al. JAMA Neurol, 2014 Aug;71:1036-42). In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV004816328	SCV005069299	uncertain significance	Optic atrophy	2022-01-01	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV001705126	SCV005622075	uncertain significance	not provided	2024-04-30	criteria provided, single submitter	clinical testing	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity. (http://gnomad.broadinstitute.org) This variant has been identified in at least one individual with clinical features associated with CMT. Polyphen and MutationTaster yielded discordant predictions regarding whether this amino acid change is damaging to the protein.
Inherited Neuropathy Consortium	RCV000789062	SCV000928411	uncertain significance	Charcot-Marie-Tooth disease		no assertion criteria provided	literature only