ClinVar Genomic variation as it relates to human health
NM_014874.4(MFN2):c.775C>T (p.Arg259Cys)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_014874.4(MFN2):c.775C>T (p.Arg259Cys)
Variation ID: 155730 Accession: VCV000155730.30
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p36.22 1: 11999054 (GRCh38) [ NCBI UCSC ] 1: 12059111 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Sep 4, 2014 Apr 15, 2024 May 13, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_014874.4:c.775C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_055689.1:p.Arg259Cys missense NM_001127660.2:c.775C>T NP_001121132.1:p.Arg259Cys missense NC_000001.11:g.11999054C>T NC_000001.10:g.12059111C>T NG_007945.1:g.23874C>T LRG_255:g.23874C>T LRG_255t1:c.775C>T LRG_255p1:p.Arg259Cys - Protein change
- R259C
- Other names
- p.R259C:CGC>TGC
- Canonical SPDI
- NC_000001.11:11999053:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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MFN2 | No evidence available | No evidence available |
GRCh38 GRCh37 |
1236 | 1340 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (2) |
no assertion criteria provided
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Jun 4, 2023 | RCV000143799.3 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Apr 1, 2023 | RCV000197364.9 | |
Pathogenic (1) |
criteria provided, single submitter
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May 13, 2023 | RCV000653884.12 | |
Likely pathogenic (2) |
criteria provided, single submitter
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- | RCV000789066.4 | |
Likely pathogenic (1) |
criteria provided, single submitter
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May 12, 2022 | RCV002408639.3 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Likely pathogenic
(Feb 16, 2017)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Athena Diagnostics Inc
Accession: SCV000614094.1
First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
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Likely pathogenic
(Nov 28, 2017)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000251712.12
First in ClinVar: Oct 11, 2015 Last updated: Apr 17, 2019 |
Comment:
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 … (more)
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. (less)
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Likely pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Charcot-Marie-Tooth disease
Affected status: yes
Allele origin:
germline
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Molecular Genetics Laboratory, London Health Sciences Centre
Accession: SCV001336795.1
First in ClinVar: Jun 14, 2020 Last updated: Jun 14, 2020 |
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Likely pathogenic
(May 12, 2022)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002674884.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
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 … (more)
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. (less)
Number of individuals with the variant: 1
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Pathogenic
(May 13, 2023)
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criteria provided, single submitter
Method: clinical testing
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Charcot-Marie-Tooth disease type 2
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000775774.8
First in ClinVar: May 28, 2018 Last updated: Feb 14, 2024 |
Comment:
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 … (more)
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). (less)
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Pathogenic
(Apr 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV004009734.6
First in ClinVar: Jul 16, 2023 Last updated: Apr 15, 2024 |
Comment:
MFN2: PM1, PM2, PM5, PS2:Moderate, PP2, PP3, PP4
Number of individuals with the variant: 1
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pathogenic
(-)
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no assertion criteria provided
Method: not provided
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Charcot-Marie-Tooth disease, type 2A2
Affected status: not provided
Allele origin:
germline
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Northcott Neuroscience Laboratory, ANZAC Research Institute
Accession: SCV000188692.1
First in ClinVar: Sep 04, 2014 Last updated: Sep 04, 2014
Comment:
Family A
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Comment:
Converted during submission to Pathogenic.
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Uncertain significance
(-)
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no assertion criteria provided
Method: literature only
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Charcot-Marie-Tooth disease
Affected status: yes
Allele origin:
germline
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Inherited Neuropathy Consortium
Accession: SCV000928415.1
First in ClinVar: Jul 27, 2019 Last updated: Jul 27, 2019 |
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Pathogenic
(Jun 04, 2023)
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no assertion criteria provided
Method: research
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Charcot-Marie-Tooth disease type 2A2
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Neurogenomics Lab, Neuroscience Institute, University Of Cape Town
Accession: SCV003930377.1
First in ClinVar: Aug 19, 2023 Last updated: Aug 19, 2023 |
Comment:
PM2_supporting: this variant is absent from gnomAD v2.1.1 and v3.1.2 (adequate coverage >20X confirmed) and an internal database of 1074 control alleles. PM1 met: variant … (more)
PM2_supporting: this variant is absent from gnomAD v2.1.1 and v3.1.2 (adequate coverage >20X confirmed) and an internal database of 1074 control alleles. 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). (less)
Sex: male
Geographic origin: South Africa
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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The Genotype and Phenotype Features in a Large Chinese MFN2 Mutation Cohort. | Ma Y | Frontiers in neurology | 2021 | PMID: 34721278 |
The Pathological Features of Common Hereditary Mitochondrial Dynamics Neuropathy. | Wu R | Frontiers in neuroscience | 2021 | PMID: 34366782 |
Diagnostic yield of advanced genetic testing in patients with hereditary neuropathies: A retrospective single-site study. | Felice KJ | Muscle & nerve | 2021 | PMID: 34232518 |
Comprehensive genetic sequence and copy number analysis for Charcot-Marie-Tooth disease in a Canadian cohort of 2517 patients. | Volodarsky M | Journal of medical genetics | 2021 | PMID: 32376792 |
Acute optic neuropathy associated with a novel MFN2 mutation. | Leonardi L | Journal of neurology | 2015 | PMID: 25957633 |
Improved inherited peripheral neuropathy genetic diagnosis by whole-exome sequencing. | Drew AP | Molecular genetics & genomic medicine | 2015 | PMID: 25802885 |
A cohort study of MFN2 mutations and phenotypic spectrums in Charcot-Marie-Tooth disease 2A patients. | Choi BO | Clinical genetics | 2015 | PMID: 24863639 |
Charcot-Marie-Tooth disease type 2A: from typical to rare phenotypic and genotypic features. | Bombelli F | JAMA neurology | 2014 | PMID: 24957169 |
Whole-exome sequencing in patients with inherited neuropathies: outcome and challenges. | Schabhüttl M | Journal of neurology | 2014 | PMID: 24627108 |
[MFN2 gene analysis in patients with hereditary motor and sensory neuropathy from Bashkortostan Republic]. | Khidiyatova IM | Genetika | 2013 | PMID: 24450158 |
MFN2 mutations cause compensatory mitochondrial DNA proliferation. | Sitarz KS | Brain : a journal of neurology | 2012 | PMID: 22492563 |
A novel de novo MFN2 mutation causing CMT2A with upper motor neuron signs. | Ajroud-Driss S | Neurogenetics | 2009 | PMID: 19350291 |
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Text-mined citations for rs587777875 ...
HelpRecord last updated Apr 15, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.