ClinVar Genomic variation as it relates to human health
NM_014874.4(MFN2):c.1090C>T (p.Arg364Trp)
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.1090C>T (p.Arg364Trp)
Variation ID: 2278 Accession: VCV000002278.41
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p36.22 1: 12002033 (GRCh38) [ NCBI UCSC ] 1: 12062090 (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 May 12, 2024 Aug 27, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_014874.4:c.1090C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_055689.1:p.Arg364Trp missense NM_001127660.2:c.1090C>T NP_001121132.1:p.Arg364Trp missense NC_000001.11:g.12002033C>T NC_000001.10:g.12062090C>T NG_007945.1:g.26853C>T LRG_255:g.26853C>T LRG_255t1:c.1090C>T LRG_255p1:p.Arg364Trp O95140:p.Arg364Trp - Protein change
- R364W
- Other names
- p.R364W:CGG>TGG
- chr1-12002033-C-T
- Canonical SPDI
- NC_000001.11:12002032: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
Help
The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
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
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
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 |
1239 | 1343 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
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
Help
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) |
criteria provided, single submitter
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Aug 22, 2018 | RCV000002367.7 | |
Pathogenic (8) |
criteria provided, multiple submitters, no conflicts
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Jul 8, 2022 | RCV000023711.15 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Apr 12, 2022 | RCV000198024.25 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Aug 27, 2023 | RCV000195560.13 | |
Uncertain significance (1) |
no assertion criteria provided
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Aug 14, 2019 | RCV000857103.2 | |
Uncertain significance (1) |
no assertion criteria provided
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Aug 14, 2019 | RCV000857104.2 |
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
Help
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
Help
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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Pathogenic
(Aug 22, 2018)
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criteria provided, single submitter
Method: clinical testing
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Neuropathy, hereditary motor and sensory, type 6A
Affected status: yes
Allele origin:
de novo
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Baylor Genetics
Accession: SCV001528900.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease causing [PMID 16437557, 21707411, … (more)
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease causing [PMID 16437557, 21707411, 27549087, 25448007, 28063088] (less)
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Pathogenic
(Jul 20, 2021)
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criteria provided, single submitter
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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Laboratório de Neurologia Aplicada e Experimental, Faculdade de Medicina de Ribeirao Preto – Universidade de Sao Paulo
Accession: SCV001938862.1
First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
Number of individuals with the variant: 4
Sex: mixed
Geographic origin: Brazil
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Pathogenic
(Apr 12, 2022)
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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: SCV000251715.17
First in ClinVar: Oct 11, 2015 Last updated: Mar 04, 2023 |
Comment:
Reported multiple times in association with hereditary motor and sensory neuropathy type VI and CMT2A in published literature (Zuchner et al., 2006; Chung et al., … (more)
Reported multiple times in association with hereditary motor and sensory neuropathy type VI and CMT2A in published literature (Zuchner et al., 2006; Chung et al., 2006; Gowrisankaran et al., 2011); Published functional studies demonstrate a damaging effect (Saporta et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24819634, 16835246, 21707411, 31832804, 21508331, 31211173, 16437557, 22206013, 27549087, 30996168, 30649465, 20587496, 25802885, 22492563, 31673878, 31315766, 33578441, 30569560, 33074106, 33742459, 30830587, 25448007, 28063088, 24863639) (less)
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Pathogenic
(Jul 01, 2023)
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criteria provided, single submitter
Method: research
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Charcot-Marie-Tooth disease type 2
Affected status: yes
Allele origin:
germline
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Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand
Accession: SCV004123108.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
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Pathogenic
(Aug 27, 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: SCV000253916.11
First in ClinVar: Oct 11, 2015 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 364 of the MFN2 protein … (more)
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 364 of the MFN2 protein (p.Arg364Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Charcot-Marie-Tooth disease type 2A and hereditary motor and sensory neuropathy type VI (PMID: 16437557, 16835246, 21508331, 21707411, 22206013, 22492563, 25448007, 25802885, 27549087, 28063088). ClinVar contains an entry for this variant (Variation ID: 2278). 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. This variant disrupts the p.Arg364 amino acid residue in MFN2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17444508, 18996695, 20008656, 21508331, 22492563). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Nov 18, 2014)
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criteria provided, single submitter
Method: clinical testing
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Charcot-Marie-Tooth disease, type 2A2
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Athena Diagnostics
Accession: SCV000255674.2
First in ClinVar: Oct 19, 2015 Last updated: Oct 19, 2015 |
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Pathogenic
(Dec 01, 2020)
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criteria provided, single submitter
Method: clinical testing
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Charcot-Marie-Tooth disease type 2A2
Affected status: yes
Allele origin:
germline
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CMT Laboratory, Bogazici University
Accession: SCV001548305.1
First in ClinVar: Apr 03, 2021 Last updated: Apr 03, 2021 |
Number of individuals with the variant: 2
Family history: yes
Secondary finding: no
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Pathogenic
(Jul 08, 2022)
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criteria provided, single submitter
Method: clinical testing
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Charcot-Marie-Tooth disease type 2A2
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002556395.2
First in ClinVar: Aug 08, 2022 Last updated: Dec 17, 2022 |
Comment:
The MFN2 c.1090C>T variant is classified as PATHOGENIC (PS2, PS4, PP3) The MFN2 c.1090C>T variant is a single nucleotide change in exon 11/19 of the … (more)
The MFN2 c.1090C>T variant is classified as PATHOGENIC (PS2, PS4, PP3) The MFN2 c.1090C>T variant is a single nucleotide change in exon 11/19 of the MFN2 gene, which is predicted to change the amino acid arginine at position 364 in the protein to tryptophan. This variant is de novo in this patient (PS2). This variant has been reported in multiple individuals with Charcot-Marie-Tooth disease type 2 (PMID:24819634, PMID:21508331, PMID:28063088) (PS4). this variant has not been reported in dbSNP and is absent from population databases. This variant has been reported in ClinVar as pathogenic for Charcot-Marie-Tooth disease (ClinVar Variation ID: 2278). Other variants affecting this amino acid residue have also been reported as pathogenic suggesting this residue is clinically significant. Computational predictions support a deleterious effect on the gene or gene product (PP3). (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Charcot-Marie-Tooth disease type 2A2
Affected status: yes
Allele origin:
unknown
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3billion
Accession: SCV004013597.1
First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023 |
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. Functional studies provide moderate evidence of the variant having a damaging effect on the gene … (more)
The variant is not observed in the gnomAD v2.1.1 dataset. Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 29898954). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.86; 3Cnet: 0.96). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000002278 / PMID: 16437557). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 22206013, 22762946, 25448007, 28063088). Different missense changes at the same codon (p.Arg364Gln, p.Arg364Leu, p.Arg364Pro) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000245944, VCV000572157, VCV000801445 / PMID: 17444508, 20008656 / 3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Difficulty walking (present) , Unsteady gait (present) , Frequent falls (present) , Lower limb hypertonia (present) , Steppage gait (present) , Slowly progressive (present) , … (more)
Difficulty walking (present) , Unsteady gait (present) , Frequent falls (present) , Lower limb hypertonia (present) , Steppage gait (present) , Slowly progressive (present) , Foot dorsiflexor weakness (present) , Foot dorsiflexor weakness (present) , Absent Achilles reflex (present) , Abnormality of peripheral nerve conduction (present) , Decreased motor nerve conduction velocity (present) (less)
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Pathogenic
(Jun 01, 2018)
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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: SCV001247289.21
First in ClinVar: May 12, 2020 Last updated: May 12, 2024 |
Number of individuals with the variant: 3
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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: SCV000188691.1
First in ClinVar: Sep 04, 2014 Last updated: Sep 04, 2014
Comment:
Family B
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Comment:
Converted during submission to Pathogenic.
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Pathogenic
(Aug 01, 2006)
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no assertion criteria provided
Method: literature only
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CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2A2A
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000298221.1
First in ClinVar: Sep 04, 2016 Last updated: Sep 04, 2016 |
Comment on evidence:
In a father and 2 sons with hereditary motor and sensory neuropathy type VIA (HMSN6A; 601152), Zuchner et al. (2006) identified a heterozygous 1090C-T transition … (more)
In a father and 2 sons with hereditary motor and sensory neuropathy type VIA (HMSN6A; 601152), Zuchner et al. (2006) identified a heterozygous 1090C-T transition in exon 11 of the MFN2 gene, resulting in an arg364-to-trp (R364W) substitution. All patients had a severe form of the disorder with neuropathy developing by age 1 year and optic atrophy by age 10 years. Chung et al. (2006) reported 4 unrelated Korean families with early-onset neuropathy before 10 years of age and a heterozygous R364W mutation. In 1 family, only 1 of 3 mutation carriers had optic atrophy. In another family, both mutation carriers had optic atrophy. Optic atrophy was not present in the remaining 2 families, more consistent with a diagnosis of Charcot-Marie-Tooth disease-2A2A (CMT2A2A; 609260). All except 1 patient had scoliosis and most had contractures. (less)
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Pathogenic
(Aug 01, 2006)
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no assertion criteria provided
Method: literature only
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NEUROPATHY, HEREDITARY MOTOR AND SENSORY, TYPE VIA
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000022525.4
First in ClinVar: Apr 04, 2013 Last updated: Sep 04, 2016 |
Comment on evidence:
In a father and 2 sons with hereditary motor and sensory neuropathy type VIA (HMSN6A; 601152), Zuchner et al. (2006) identified a heterozygous 1090C-T transition … (more)
In a father and 2 sons with hereditary motor and sensory neuropathy type VIA (HMSN6A; 601152), Zuchner et al. (2006) identified a heterozygous 1090C-T transition in exon 11 of the MFN2 gene, resulting in an arg364-to-trp (R364W) substitution. All patients had a severe form of the disorder with neuropathy developing by age 1 year and optic atrophy by age 10 years. Chung et al. (2006) reported 4 unrelated Korean families with early-onset neuropathy before 10 years of age and a heterozygous R364W mutation. In 1 family, only 1 of 3 mutation carriers had optic atrophy. In another family, both mutation carriers had optic atrophy. Optic atrophy was not present in the remaining 2 families, more consistent with a diagnosis of Charcot-Marie-Tooth disease-2A2A (CMT2A2A; 609260). All except 1 patient had scoliosis and most had contractures. (less)
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Pathogenic
(Feb 11, 2019)
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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:
unknown
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Department of Rehabilitation Medicine, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea
Accession: SCV000882757.1
First in ClinVar: Sep 04, 2016 Last updated: Sep 04, 2016 |
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Uncertain significance
(Aug 14, 2019)
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no assertion criteria provided
Method: research
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Charcot-Marie-Tooth disease
Affected status: yes
Allele origin:
germline
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Genesis Genome Database
Accession: SCV000999677.1
First in ClinVar: Dec 17, 2019 Last updated: Dec 17, 2019 |
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Uncertain significance
(Aug 14, 2019)
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no assertion criteria provided
Method: research
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Charcot-Marie-Tooth disease type 4
Affected status: yes
Allele origin:
germline
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Genesis Genome Database
Accession: SCV000999678.1
First in ClinVar: Dec 17, 2019 Last updated: Dec 17, 2019 |
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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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MFN2 Hereditary Motor and Sensory Neuropathy. | Adam MP | - | 2020 | PMID: 20301684 |
Mitofusin gain and loss of function drive pathogenesis in Drosophila models of CMT2A neuropathy. | El Fissi N | EMBO reports | 2018 | PMID: 29898954 |
Mosaicism for a pathogenic MFN2 mutation causes minimal clinical features of CMT2A in the parent of a severely affected child. | Schon K | Neurogenetics | 2017 | PMID: 28063088 |
Improving diagnosis of inherited peripheral neuropathies through gene panel analysis. | Laššuthová P | Orphanet journal of rare diseases | 2016 | PMID: 27549087 |
Homozygous mutations in MFN2 cause multiple symmetric lipomatosis associated with neuropathy. | Sawyer SL | Human molecular genetics | 2015 | PMID: 26085578 |
Improved inherited peripheral neuropathy genetic diagnosis by whole-exome sequencing. | Drew AP | Molecular genetics & genomic medicine | 2015 | PMID: 25802885 |
Axonal Charcot-Marie-Tooth disease patient-derived motor neurons demonstrate disease-specific phenotypes including abnormal electrophysiological properties. | Saporta MA | Experimental neurology | 2015 | PMID: 25448007 |
Mutation analysis of MFN2, GJB1, MPZ and PMP22 in Italian patients with axonal Charcot-Marie-Tooth disease. | Bergamin G | Neuromolecular medicine | 2014 | PMID: 24819634 |
Application of whole exome sequencing in undiagnosed inherited polyneuropathies. | Klein CJ | Journal of neurology, neurosurgery, and psychiatry | 2014 | PMID: 24604904 |
MFN2 mutations cause compensatory mitochondrial DNA proliferation. | Sitarz KS | Brain : a journal of neurology | 2012 | PMID: 22492563 |
The mutational spectrum in a cohort of Charcot-Marie-Tooth disease type 2 among the Han Chinese in Taiwan. | Lin KP | PloS one | 2011 | PMID: 22206013 |
Structural and functional measures of inner retinal integrity following visual acuity improvement in a patient with hereditary motor and sensory neuropathy type VI. | Gowrisankaran S | Ophthalmic genetics | 2011 | PMID: 21707411 |
MFN2 mutations cause severe phenotypes in most patients with CMT2A. | Feely SM | Neurology | 2011 | PMID: 21508331 |
Early-onset Charcot-Marie-Tooth patients with mitofusin 2 mutations and brain involvement. | Chung KW | Journal of neurology, neurosurgery, and psychiatry | 2010 | PMID: 20587496 |
MFN2 point mutations occur in 3.4% of Charcot-Marie-Tooth families. An investigation of 232 Norwegian CMT families. | Braathen GJ | BMC medical genetics | 2010 | PMID: 20350294 |
Genotype-phenotype correlations in Charcot-Marie-Tooth disease type 2 caused by mitofusin 2 mutations. | Calvo J | Archives of neurology | 2009 | PMID: 20008656 |
Two Spanish families with Charcot-Marie-Tooth type 2A: clinical, electrophysiological and molecular findings. | Banchs I | Neuromuscular disorders : NMD | 2008 | PMID: 18996695 |
Mitochondrial coupling defect in Charcot-Marie-Tooth type 2A disease. | Loiseau D | Annals of neurology | 2007 | PMID: 17444508 |
Early onset severe and late-onset mild Charcot-Marie-Tooth disease with mitofusin 2 (MFN2) mutations. | Chung KW | Brain : a journal of neurology | 2006 | PMID: 16835246 |
Charcot-Marie-Tooth neuropathy type 2A: novel mutations in the mitofusin 2 gene (MFN2). | Engelfried K | BMC medical genetics | 2006 | PMID: 16762064 |
Axonal neuropathy with optic atrophy is caused by mutations in mitofusin 2. | Züchner S | Annals of neurology | 2006 | PMID: 16437557 |
Mitochondrial GTPase mitofusin 2 mutation in Charcot-Marie-Tooth neuropathy type 2A. | Kijima K | Human genetics | 2005 | PMID: 15549395 |
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Text-mined citations for rs119103265 ...
HelpRecord last updated May 12, 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.