ClinVar Genomic variation as it relates to human health

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 250 of the MFN2 protein (p.Arg250Gln). This variant is present in population databases (rs140234726, gnomAD 0.04%). This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 21258814, 22492563, 25850958, 26930221, 32376792). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant shows reduced penetrance with mild disease symptoms, later onset and some individuals may be asymptomatic (PMID: 26930221, 25850958). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 214653). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MFN2 protein function. This variant disrupts the p.Arg250 amino acid residue in MFN2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16714318, 26306937, 28660751, 35922214). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, this variant is reported to cause disease. However, as this variant is associated with a lower penetrance than other pathogenic alleles in the MFN2 gene, it has been classified as Pathogenic (low penetrance).

Reported previously in unrelated individuals with Charcot-Marie-Tooth neuropathy type 2A (CMT2A) who were heterozygous for p.(R250Q), although familial segregation was not evaluated for either individual (PMID: 16714318, 21258814, 25850958); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22492563, 30442897, 21258814, 26968897, 25850958, 31827005, 26752306, 32376792, 35399520, 24863639, 23800155, 26930221, 16714318)

The MFN2 c.749G>A variant is predicted to result in the amino acid substitution p.Arg250Gln. This variant was previously reported in the heterozygous state in individuals who presented with Charcot-Marie-Tooth type 2 or 1 disease (Verhoeven et al. 2006. PubMed ID: 16714318; McCorquodale et al. 2011. PubMed ID: 21258814; Sitarz et al. 2012. PubMed ID: 22492563; Antoniadi et al. 2015. PubMed ID: 26392352, see supplementary table 3, rs140234726). This variant was also detected in an individual with non-ataxic spastic paraplegia and peripheral neuropathy, although the variant did not segregate with disease within the family (Gregianin et al. 2013. PubMed ID: 23800155). Additionally, the c.749G>A variant was reported in the compound heterozygous state in two brothers with early-onset sensory motor neuropathy; the unaffected father harbored this variant in the heterozygous state (Tomaselli et al. 2016. PubMed ID: 26930221). The p.Arg250Gln variant was also described in an affected individual who harbored a likely pathogenic variant in LRSAM1 (Lupo et al. 2016. PubMed ID: 26752306). Taken together, the clinical significance of this variant is classified as uncertain at this time due to the absence of conclusive functional and genetic evidence. We suspect this variant may be benign for autosomal dominant disease, although we cannot rule out the possibility that this variant may be relevant to autosomal recessive inheritance of this disorder.

The p.Arg250Gln variant in MFN2 has been reported in the heterozygous state in 7 individuals with clinical features of Charcot-Marie-Tooth (CMT) disease (Verhoeven 2006 PMID: 16714318, McCorquodale 2011 PMID: 21258814, Sitarz 2012 PMID: 22492563, Antoniadi 2015 PMID: 26392352, Tomaselli 2016 PMID: 26930221, Rudnik-Schoneborn 2016 PMID: 25850958, Volodarsky 2021 PMID: 32376792). This variant was also reported in the compound heterozygous state with another MFN2 variant in 2 siblings with features of CMT disease with earlier disease onset. The variant was determined to be paternally inherited, and the father had not symptoms of neuropathy (Lupo 2016 PMID: 26752306). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 214653) and has been identified in 0.03% (5/15252) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS4, PM2_Supporting.

The p.R250Q variant (also known as c.749G>A), located in coding exon 6 of the MFN2 gene, results from a G to A substitution at nucleotide position 749. The arginine at codon 250 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in a compound heterozygous state in two siblings with early-onset sensory motor neuropathy (Tomaselli PJ et al. J Peripher Nerv Syst, 2016 Mar;21:52-4), as well as in a heterozygous state in multiple unrelated individuals with Charcot-Marie-Tooth disease (CMT) (Verhoeven K et al. Brain, 2006 Aug;129:2093-102; McCorquodale DS et al. J. Neurol., 2011 Jul;258:1234-9; Sitarz KS et al. Brain, 2012 Aug;135:e219, 1-3; author reply e220, 1-3; Rudnik-Schöneborn S et al. Clin Genet, 2016 Jan;89:34-43). Another alteration at the same codon, p.R250W (c.748C>T), has been described in multiple individuals with phenotypes consistent with CMT disease (Di Meglio C et al. Brain Dev, 2016 May;38:498-506; Piscosquito G et al. J Peripher Nerv Syst, 2015 Dec;20:380-6; Sun B et al. J Peripher Nerv Syst, 2017 03;22:13-18; Verhoeven K et al. Brain, 2006 Aug;129:2093-102). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is unlikely to be causative of autosomal dominant MFN2-related neuropathy; however, its contribution to the development of autosomal recessive MFN2-related neuropathy is uncertain.