ClinVar Miner

Submissions for variant NM_014874.3(MFN2):c.2146G>A (p.Ala716Thr) (rs144860227)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000731890 SCV000251723 uncertain significance not provided 2018-03-08 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the MFN2 gene. The A716T variant has been published as a pathogenic variant in a family with intermediate Charcot-Marie-Tooth disease (Braathen et al., 2010). The proband in this family is described as having recurrent ankle sprains, weakness and reduced balance, while an affected cousin is reported to have paresthesia in foot (Braathen et al., 2010). A716T was also reported in a patient with early-onset CMT2 who had a severe neuropathy (Feely et al., 2011). The A716T variant is observed in 15/24030 (0.06%) alleles from individuals of African background (Lek et al., 2016). This 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, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter 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.
Illumina Clinical Services Laboratory,Illumina RCV000334497 SCV000348006 likely benign Hereditary motor and sensory neuropathy with optic atrophy 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Clinical Services Laboratory,Illumina RCV000554698 SCV000348007 likely benign Charcot-Marie-Tooth disease, type 2 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Invitae RCV000554698 SCV000657720 uncertain significance Charcot-Marie-Tooth disease, type 2 2019-10-17 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 716 of the MFN2 protein (p.Ala716Thr). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs144860227, ExAC 0.04%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported to segregate with dominant intermediate Charcot Marie Tooth disease in a single family (PMID: 20350294) and has been reported in 2 additional individuals affected with Charcot Marie Tooth disease type 2 (PMID: 21508331, 22492563). ClinVar contains an entry for this variant (Variation ID: 214649). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The threonine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, this variant has uncertain impact on MFN2 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000731890 SCV000859758 uncertain significance not provided 2018-02-20 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000731890 SCV001147159 uncertain significance not provided 2019-12-01 criteria provided, single submitter clinical testing
Molecular Genetics Laboratory,London Health Sciences Centre RCV000790008 SCV001336793 likely pathogenic Charcot-Marie-Tooth disease criteria provided, single submitter clinical testing
Inherited Neuropathy Consortium RCV000790008 SCV000929398 uncertain significance Charcot-Marie-Tooth disease no assertion criteria provided literature only

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