Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18425620, 26307494, 25025039, 30442897, 21840889, 21531138, 18946002, 30340945, 33851411, 34169998, 24863639)
ClinVar Genomic variation as it relates to human health
NM_014874.4(MFN2):c.310C>T (p.Arg104Trp)
Germline
Classification
Help
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.
(17)
Help
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.
Pathogenic
17
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_014874.4(MFN2):c.310C>T (p.Arg104Trp)
Variation ID: 2281 Accession: VCV000002281.29
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 1p36.22 1: 11992689 (GRCh38) [ NCBI UCSC ] 1: 12052746 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Nov 9, 2014 May 1, 2024 Nov 25, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_014874.4:c.310C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_055689.1:p.Arg104Trp missense NM_001127660.2:c.310C>T NP_001121132.1:p.Arg104Trp missense NC_000001.11:g.11992689C>T NC_000001.10:g.12052746C>T NG_007945.1:g.17509C>T LRG_255:g.17509C>T LRG_255t1:c.310C>T LRG_255p1:p.Arg104Trp - Protein change
- R104W
- Other names
-
p.R104W:CGG>TGG
chr1-11992689-C-T
p.Arg104Trp
- Canonical SPDI
- NC_000001.11:11992688:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
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 | ||
|---|---|---|---|---|---|---|
| HI score
Help
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. |
|||
| MFN2 | No evidence available | No evidence available |
GRCh38 GRCh37 |
1248 | 1354 | |
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
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
|
Mar 13, 2023 | RCV000002371.13 | |
| Pathogenic (2) |
criteria provided, single submitter
|
Sep 4, 2019 | RCV000002370.7 | |
| Pathogenic (2) |
criteria provided, single submitter
|
- | RCV000144872.4 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Nov 25, 2023 | RCV000556047.9 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Apr 14, 2022 | RCV000197230.10 | |
| Pathogenic (1) |
criteria provided, single submitter
|
May 18, 2017 | RCV000515385.2 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Apr 6, 2021 | RCV001267430.3 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Mar 13, 2023 | RCV003332995.1 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Mar 13, 2023 | RCV003332994.1 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(May 18, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Neuropathy, hereditary motor and sensory, type 6A
Charcot-Marie-Tooth disease type 2A2 Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2a2b;
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000611283.1
First in ClinVar: Nov 11, 2017 Last updated: Nov 11, 2017 |
|
|
|
Pathogenic
(Apr 14, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000251709.15
First in ClinVar: Oct 11, 2015 Last updated: Mar 04, 2023 |
Comment:
Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is … (more)
Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18425620, 26307494, 25025039, 30442897, 21840889, 21531138, 18946002, 30340945, 33851411, 34169998, 24863639) (less)
|
|
|
Pathogenic
(Mar 01, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000706491.2
First in ClinVar: Dec 15, 2018 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Charcot-Marie-Tooth disease
Affected status: yes
Allele origin:
germline
|
Molecular Genetics Laboratory, London Health Sciences Centre
Accession: SCV001336788.1
First in ClinVar: Jun 15, 2020 Last updated: Jun 15, 2020 |
|
|
|
Pathogenic
(Sep 04, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Neuropathy, hereditary motor and sensory, type 6A
Affected status: yes
Allele origin:
unknown
|
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001367007.2
First in ClinVar: Jul 06, 2020 Last updated: Dec 12, 2020 |
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM1,PM2,PM5,PP3.
|
|
|
Pathogenic
(Dec 01, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Charcot-Marie-Tooth disease type 2A2
Affected status: yes
Allele origin:
germline
|
CMT Laboratory, Bogazici University
Accession: SCV001548319.1
First in ClinVar: Apr 03, 2021 Last updated: Apr 03, 2021 |
Number of individuals with the variant: 1
Family history: yes
Secondary finding: no
|
|
|
Pathogenic
(Jul 20, 2021)
|
criteria provided, single submitter
Method: research
|
Charcot-Marie-Tooth disease type 2A2
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Laboratório de Neurologia Aplicada e Experimental, Faculdade de Medicina de Ribeirao Preto – Universidade de Sao Paulo
Accession: SCV001938863.1
First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
Number of individuals with the variant: 2
Sex: male
Geographic origin: Brazil
|
|
|
Pathogenic
(Feb 23, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Charcot-Marie-Tooth disease type 2A2
Affected status: yes
Allele origin:
unknown
|
3billion
Accession: SCV003841982.1
First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023 |
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of … (more)
The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.93; 3Cnet: 1.00). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000002281). Different missense changes at the same codon (p.Arg104Gln, p.Arg104Leu) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000214651, VCV000637289). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Foot dorsiflexor weakness (present) , Pes planus (present) , Decreased Achilles reflex (present) , Broad-based gait (present) , Frequent falls (present) , Muscular atrophy (present) … (more)
Foot dorsiflexor weakness (present) , Pes planus (present) , Decreased Achilles reflex (present) , Broad-based gait (present) , Frequent falls (present) , Muscular atrophy (present) , Abnormality of peripheral nervous system electrophysiology (present) , Distal lower limb muscle weakness (present) (less)
|
|
|
Pathogenic
(Mar 13, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Neuropathy, hereditary motor and sensory, type 6A
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004040658.1
First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023 |
|
|
|
Pathogenic
(Mar 13, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2a2b;
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004040770.1
First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023 |
|
|
|
Pathogenic
(Mar 13, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Charcot-Marie-Tooth disease type 2A2
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Study: Adult_WES
Accession: SCV000245506.2 First in ClinVar: Sep 29, 2015 Last updated: Oct 06, 2023 |
|
|
|
Pathogenic
(Nov 25, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Charcot-Marie-Tooth disease type 2
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000657723.8
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 104 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 104 of the MFN2 protein (p.Arg104Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 18425620, 18946002, 18957892, 20008656, 21531138, 21840889, 25025039). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2281). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.Arg104 amino acid residue in MFN2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 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)
|
|
|
Pathogenic
(Apr 06, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV001445611.3
First in ClinVar: Nov 21, 2020 Last updated: May 01, 2024 |
Comment:
The p.R104W pathogenic mutation (also known as c.310C>T), located in coding exon 2 of the MFN2 gene, results from a C to T substitution at … (more)
The p.R104W pathogenic mutation (also known as c.310C>T), located in coding exon 2 of the MFN2 gene, results from a C to T substitution at nucleotide position 310. The arginine at codon 104 is replaced by tryptophan, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. The p.R104W alteration has been reported in multiple patients with Charcot-Marie-Tooth disease (Brockmann K et al. J Neurol, 2008 Jul;255(7):1049-58; Baets J et al. Brain, 2011 Sep;134:2664-76; Genari AB et al. Neuromuscul Disord, 2011 Jun;21:428-32; Høyer H et al. Biomed Res Int, 2014 Jun;2014:210401). Another alteration at the same codon, p.R104Q (c.311G>A), has been described in a patient with Charcot-Marie-Tooth (Bombelli F et al. JAMA Neurol, 2014 Aug;71:1036-42). The p.R104W amino acid is located in the GTPase domain which is required for mitochondrial membrane fusion reaction, and multiple alterations in this region have been reported (Amiott EA et al. Exp Neurol, 2008 May;211:115-27; Ando M et al. J Peripher Nerv Syst, 2017 09;22:191-199). Based on the supporting evidence, this variant is expected to be causative of autosomal dominant Charcot-Marie-Tooth disease (CMT) type 2A2A and hereditary motor and sensory neuropathy VIA; however, its clinical significance for autosomal recessive Charcot-Marie-Tooth disease (CMT) type 2A2B is unclear. (less)
|
|
|
Pathogenic
(Dec 09, 2008)
|
no assertion criteria provided
Method: literature only
|
NEUROPATHY, HEREDITARY MOTOR AND SENSORY, TYPE VIA
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000022528.4
First in ClinVar: Apr 04, 2013 Last updated: Sep 04, 2016 |
Comment on evidence:
In an Italian father and 2 sons with peripheral neuropathy, Del Bo et al. (2008) identified a heterozygous c.310C-T transition in exon 4 of the … (more)
In an Italian father and 2 sons with peripheral neuropathy, Del Bo et al. (2008) identified a heterozygous c.310C-T transition in exon 4 of the MFN2 gene, resulting in an arg104-to-trp (R104W) substitution at a highly conserved residue in the GTPase domain. The phenotype was highly variable within the family. The father had a symmetric axonal, predominantly motor polyneuropathy, spastic gait, and pes cavus, consistent with Charcot-Marie-Tooth disease-2A2A (CMT2A2A; 609260), as well as impaired nocturnal vision and sensorineural hearing loss, consistent with hereditary motor and sensory neuropathy type VIA (HMSN6A; 601152). He also showed cognitive decline first noted in his forties. Both sons had delayed motor and language development, decreased IQ, steppage gait, distal muscle weakness and atrophy, and axonal sensorimotor neuropathy at ages 10 and 7 years, respectively. One son also had optic nerve dysfunction. MR spectroscopy (MRS) in the father suggested a defect in mitochondrial energy metabolism in the occipital cortex. Del Bo et al. (2008) suggested that central nervous system involvement and cognitive impairment may be other phenotypic features of MFN2 mutations. (less)
|
|
|
Pathogenic
(Nov 01, 2013)
|
no assertion criteria provided
Method: research
|
Charcot-Marie-Tooth disease
Affected status: yes
Allele origin:
de novo
|
Dept. of Medical Genetics, Telemark Hospital Trust, Telemark Hospital Trust
Study: Charcot-Marie-Tooth disease study
Accession: SCV000172144.1 First in ClinVar: Nov 09, 2014 Last updated: Nov 09, 2014
Comment:
Populational based study of Charcot-Marie-Tooth disease in Norway
|
Clinical Features:
demyelinating type (present)
|
|
|
Pathogenic
(Dec 09, 2008)
|
no assertion criteria provided
Method: literature only
|
CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2A2A
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000298223.1
First in ClinVar: Sep 04, 2016 Last updated: Sep 04, 2016 |
Comment on evidence:
In an Italian father and 2 sons with peripheral neuropathy, Del Bo et al. (2008) identified a heterozygous c.310C-T transition in exon 4 of the … (more)
In an Italian father and 2 sons with peripheral neuropathy, Del Bo et al. (2008) identified a heterozygous c.310C-T transition in exon 4 of the MFN2 gene, resulting in an arg104-to-trp (R104W) substitution at a highly conserved residue in the GTPase domain. The phenotype was highly variable within the family. The father had a symmetric axonal, predominantly motor polyneuropathy, spastic gait, and pes cavus, consistent with Charcot-Marie-Tooth disease-2A2A (CMT2A2A; 609260), as well as impaired nocturnal vision and sensorineural hearing loss, consistent with hereditary motor and sensory neuropathy type VIA (HMSN6A; 601152). He also showed cognitive decline first noted in his forties. Both sons had delayed motor and language development, decreased IQ, steppage gait, distal muscle weakness and atrophy, and axonal sensorimotor neuropathy at ages 10 and 7 years, respectively. One son also had optic nerve dysfunction. MR spectroscopy (MRS) in the father suggested a defect in mitochondrial energy metabolism in the occipital cortex. Del Bo et al. (2008) suggested that central nervous system involvement and cognitive impairment may be other phenotypic features of MFN2 mutations. (less)
|
|
|
Pathogenic
(Apr 25, 2018)
|
no assertion criteria provided
Method: clinical testing
|
Charcot-Marie-Tooth disease type 2A2
Affected status: yes
Allele origin:
de novo
|
Institute of Human Genetics, Cologne University
Accession: SCV000787801.1
First in ClinVar: Sep 04, 2016 Last updated: Sep 04, 2016 |
|
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Comment:
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM1,PM2,PM5,PP3.
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.93; 3Cnet: 1.00). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000002281). Different missense changes at the same codon (p.Arg104Gln, p.Arg104Leu) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000214651, VCV000637289). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 104 of the MFN2 protein (p.Arg104Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 18425620, 18946002, 18957892, 20008656, 21531138, 21840889, 25025039). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2281). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.Arg104 amino acid residue in MFN2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 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.
Comment:
The p.R104W pathogenic mutation (also known as c.310C>T), located in coding exon 2 of the MFN2 gene, results from a C to T substitution at nucleotide position 310. The arginine at codon 104 is replaced by tryptophan, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. The p.R104W alteration has been reported in multiple patients with Charcot-Marie-Tooth disease (Brockmann K et al. J Neurol, 2008 Jul;255(7):1049-58; Baets J et al. Brain, 2011 Sep;134:2664-76; Genari AB et al. Neuromuscul Disord, 2011 Jun;21:428-32; Høyer H et al. Biomed Res Int, 2014 Jun;2014:210401). Another alteration at the same codon, p.R104Q (c.311G>A), has been described in a patient with Charcot-Marie-Tooth (Bombelli F et al. JAMA Neurol, 2014 Aug;71:1036-42). The p.R104W amino acid is located in the GTPase domain which is required for mitochondrial membrane fusion reaction, and multiple alterations in this region have been reported (Amiott EA et al. Exp Neurol, 2008 May;211:115-27; Ando M et al. J Peripher Nerv Syst, 2017 09;22:191-199). Based on the supporting evidence, this variant is expected to be causative of autosomal dominant Charcot-Marie-Tooth disease (CMT) type 2A2A and hereditary motor and sensory neuropathy VIA; however, its clinical significance for autosomal recessive Charcot-Marie-Tooth disease (CMT) type 2A2B is unclear.
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. |
Comment:
Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18425620, 26307494, 25025039, 30442897, 21840889, 21531138, 18946002, 30340945, 33851411, 34169998, 24863639)
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM1,PM2,PM5,PP3.
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.93; 3Cnet: 1.00). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000002281). Different missense changes at the same codon (p.Arg104Gln, p.Arg104Leu) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000214651, VCV000637289). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 104 of the MFN2 protein (p.Arg104Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 18425620, 18946002, 18957892, 20008656, 21531138, 21840889, 25025039). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2281). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.Arg104 amino acid residue in MFN2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 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.
Comment:
The p.R104W pathogenic mutation (also known as c.310C>T), located in coding exon 2 of the MFN2 gene, results from a C to T substitution at nucleotide position 310. The arginine at codon 104 is replaced by tryptophan, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. The p.R104W alteration has been reported in multiple patients with Charcot-Marie-Tooth disease (Brockmann K et al. J Neurol, 2008 Jul;255(7):1049-58; Baets J et al. Brain, 2011 Sep;134:2664-76; Genari AB et al. Neuromuscul Disord, 2011 Jun;21:428-32; Høyer H et al. Biomed Res Int, 2014 Jun;2014:210401). Another alteration at the same codon, p.R104Q (c.311G>A), has been described in a patient with Charcot-Marie-Tooth (Bombelli F et al. JAMA Neurol, 2014 Aug;71:1036-42). The p.R104W amino acid is located in the GTPase domain which is required for mitochondrial membrane fusion reaction, and multiple alterations in this region have been reported (Amiott EA et al. Exp Neurol, 2008 May;211:115-27; Ando M et al. J Peripher Nerv Syst, 2017 09;22:191-199). Based on the supporting evidence, this variant is expected to be causative of autosomal dominant Charcot-Marie-Tooth disease (CMT) type 2A2A and hereditary motor and sensory neuropathy VIA; however, its clinical significance for autosomal recessive Charcot-Marie-Tooth disease (CMT) type 2A2B is unclear.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Clinical and genetic diversities of Charcot-Marie-Tooth disease with MFN2 mutations in a large case study. | Ando M | Journal of the peripheral nervous system : JPNS | 2017 | PMID: 28660751 |
| Molecular diagnostic experience of whole-exome sequencing in adult patients. | Posey JE | Genetics in medicine : official journal of the American College of Medical Genetics | 2016 | PMID: 26633545 |
| Clinical application of whole-exome sequencing across clinical indications. | Retterer K | Genetics in medicine : official journal of the American College of Medical Genetics | 2016 | PMID: 26633542 |
| A cohort study of Han Chinese MFN2-related Charcot-Marie-Tooth 2A. | Lv H | Journal of the neurological sciences | 2015 | PMID: 26382835 |
| Early onset Charcot-Marie-Tooth neuropathy type 2A and severe developmental delay: expanding the clinical phenotype of MFN2-related neuropathy. | Tufano M | Journal of the peripheral nervous system : JPNS | 2015 | PMID: 26307494 |
| Genetic diagnosis of Charcot-Marie-Tooth disease in a population by next-generation sequencing. | Høyer H | BioMed research international | 2014 | PMID: 25025039 |
| Charcot-Marie-Tooth disease type 2A: from typical to rare phenotypic and genotypic features. | Bombelli F | JAMA neurology | 2014 | PMID: 24957169 |
| Clinical whole-exome sequencing for the diagnosis of mendelian disorders. | Yang Y | The New England journal of medicine | 2013 | PMID: 24088041 |
| MFN2 mutations cause compensatory mitochondrial DNA proliferation. | Sitarz KS | Brain : a journal of neurology | 2012 | PMID: 22492563 |
| Genetic spectrum of hereditary neuropathies with onset in the first year of life. | Baets J | Brain : a journal of neurology | 2011 | PMID: 21840889 |
| Characterizing the phenotypic manifestations of MFN2 R104W mutation in Charcot-Marie-Tooth type 2. | Genari AB | Neuromuscular disorders : NMD | 2011 | PMID: 21531138 |
| Molecular diagnosis and clinical onset of Charcot-Marie-Tooth disease in Japan. | Abe A | Journal of human genetics | 2011 | PMID: 21326314 |
| Genotype-phenotype correlations in Charcot-Marie-Tooth disease type 2 caused by mitofusin 2 mutations. | Calvo J | Archives of neurology | 2009 | PMID: 20008656 |
| Histopathological findings in hereditary motor and sensory neuropathy of axonal type with onset in early childhood associated with mitofusin 2 mutations. | Vallat JM | Journal of neuropathology and experimental neurology | 2008 | PMID: 18957892 |
| Mutated mitofusin 2 presents with intrafamilial variability and brain mitochondrial dysfunction. | Del Bo R | Neurology | 2008 | PMID: 18946002 |
| Cerebral involvement in axonal Charcot-Marie-Tooth neuropathy caused by mitofusin2 mutations. | Brockmann K | Journal of neurology | 2008 | PMID: 18425620 |
| Mitochondrial fusion and function in Charcot-Marie-Tooth type 2A patient fibroblasts with mitofusin 2 mutations. | Amiott EA | Experimental neurology | 2008 | PMID: 18316077 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=MFN2 | - | - | - | - |
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Text-mined citations for rs119103268 ...
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Record last updated Sep 29, 2024
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