rs587777875
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_014874.4(MFN2):c.775C>T(p.Arg259Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R259H) has been classified as Likely pathogenic.
Frequency
Consequence
NM_014874.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 19 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MFN2 | NM_014874.4 | c.775C>T | p.Arg259Cys | missense_variant | 8/19 | ENST00000235329.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MFN2 | ENST00000235329.10 | c.775C>T | p.Arg259Cys | missense_variant | 8/19 | 1 | NM_014874.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461886Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727246
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Feb 16, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2023 | MFN2: PM1, PM2, PM5, PS2:Moderate, PP2, PP3, PP4 - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 28, 2017 | A variant that is likely pathogenic has been identified in the MFN2 gene. The R259C variant has been previously reported in multiple individuals with CMT2A (Sitarz et al., 2012; Drew et al., 2015; Leonardi et al., 2015). TheR259C variant is not observed in large population cohorts (Lek et al., 2016). The R259C variant is anon-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Additionally, missense variants in a nearby residue (S263P) and at the sameresidue (R259L/H) have been reported in the Human Gene Mutation Database in association with MFN2-related neuropathy (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. - |
Charcot-Marie-Tooth disease type 2A2 Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | Northcott Neuroscience Laboratory, ANZAC Research Institute | - | - - |
Pathogenic, criteria provided, single submitter | research | Neurogenomics Lab, Neuroscience Institute, University Of Cape Town | May 22, 2024 | PM2_supporting: The highest population allele frequency in gnomAD v4.0. is 0.00003311(0.003%; 2/60396 alleles in Remaining populations). PM1 met: variant occurs in the dynamin-like GTPase domain together with other pathogenic variants. PS4 met: variant identified in =10 unrelated probands with consistent phenotype for disorder. PP3_strong: Revel score is 0.95. PM5 met: MFN2 p.Arg259Leu classified as LP. PP1 not met: variant segregates with 2 informative meioses in 1 family (PMID 25802885). - |
Charcot-Marie-Tooth disease Pathogenic:1Uncertain:1
Uncertain significance, no assertion criteria provided | literature only | Inherited Neuropathy Consortium | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Molecular Genetics Laboratory, London Health Sciences Centre | - | - - |
Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 12, 2022 | The p.R259C variant (also known as c.775C>T), located in coding exon 6 of the MFN2 gene, results from a C to T substitution at nucleotide position 775. The arginine at codon 259 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been detected in the heterozygous state in multiple patients with Charcot-Marie-Tooth Type 2A (CMT2A) disease (Sitarz KS et al. Brain, 2012 Aug;135:e219, 1-3; author reply e220, 1-3; Bombelli F et al. JAMA Neurol, 2014 Aug;71:1036-42; Drew AP et al. Mol Genet Genomic Med, 2015 Mar;3:143-54; Volodarsky M et al. J Med Genet, 2021 04;58:284-288; Ma Y et al. Front Neurol, 2021 Oct;12:757518; Wu R et al. Front Neurosci, 2021 Jul;15:705277). This variant was detected de novo in the heterozygous state in a patient with CMT2A (Felice KJ et al. Muscle Nerve, 2021 10;64:454-461). This amino acid position is highly 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 expected to be causative of autosomal dominant CMT2A; however, its clinical significance for autosomal recessive Charcot-Marie-Tooth disease, axonal, type 2A2B is unclear. - |
Charcot-Marie-Tooth disease type 2 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 13, 2023 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg259 amino acid residue in MFN2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19350291, 24627108, 24863639). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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) performed at Invitae indicates that this missense variant is expected to disrupt MFN2 protein function. ClinVar contains an entry for this variant (Variation ID: 155730). This missense change has been observed in individuals with autosomal dominant Charcot-Marie-Tooth disease (PMID: 22492563, 24957169, 25802885, 25957633). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 259 of the MFN2 protein (p.Arg259Cys). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at