VCV000030738.21 - ClinVar

NM_014874.4(MFN2):c.1085C>T (p.Thr362Met)

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Pathogenic/Likely pathogenic
Pathogenic (4); Likely pathogenic (5)

9 out of 13 submissions contributed to this classification

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.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_014874.4(MFN2):c.1085C>T (p.Thr362Met)

Variation ID: 30738 Accession: VCV000030738.21

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p36.22 1: 12002028 (GRCh38) [ NCBI UCSC ] 1: 12062085 (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	Sep 4, 2016	Mar 7, 2026	Dec 20, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_014874.4:c.1085C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_055689.1:p.Thr362Met	missense
NM_001127660.2:c.1085C>T	NP_001121132.1:p.Thr362Met	missense
NC_000001.11:g.12002028C>T
NC_000001.10:g.12062085C>T
NG_007945.1:g.26848C>T
LRG_255:g.26848C>T
LRG_255t1:c.1085C>T	LRG_255p1:p.Thr362Met
	O95140:p.Thr362Met

... more HGVS ... less HGVS

Protein change

T362M

Other names

NM_001127660.1:c.1085C>T(p.Thr362Met)
NM_014874.3:c.1085C>T(p.Thr362Met)

Canonical SPDI

NC_000001.11:12002027:C:T

Global minor allele frequency (GMAF) Help The 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.

The Genome Aggregation Database (gnomAD), exomes 0.00005

Exome Aggregation Consortium (ExAC) 0.00002

Trans-Omics for Precision Medicine (TOPMed) 0.00004

The Genome Aggregation Database (gnomAD) 0.00003

The Genome Aggregation Database (gnomAD), exomes 0.00003

Links

ClinGen: CA129423 UniProtKB: O95140#VAR_076897 OMIM: 608507.0019 dbSNP: rs387906991 VarSome

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
Gene	OMIM	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	1405	1518

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.
Charcot-Marie-Tooth disease type 2A2	Pathogenic (2)	criteria provided, single submitter	Dec 1, 2020	RCV000023716.6
Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2a2b;	Likely pathogenic (3)	criteria provided, single submitter	Apr 16, 2018	RCV000240513.3
Charcot-Marie-Tooth disease	Likely pathogenic (2)	criteria provided, single submitter	-	RCV000857102.2
Hereditary motor and sensory neuropathy with optic atrophy	Likely pathogenic (1)	criteria provided, single submitter	Jun 20, 2019	RCV001198485.2
Charcot-Marie-Tooth disease type 2	Pathogenic (1)	criteria provided, single submitter	Dec 20, 2025	RCV001388766.9
not provided	Pathogenic (1)	criteria provided, single submitter	Jul 6, 2022	RCV002472935.2
Inborn genetic diseases	Likely pathogenic (1)	criteria provided, single submitter	Oct 19, 2020	RCV002415428.2
MFN2-related disorder	Likely pathogenic (1)	criteria provided, single submitter	Nov 28, 2024	RCV005867795.1
Charcot-Marie-Tooth disease type 2A2 Neuropathy, hereditary motor and sensory, type 6A	Pathogenic (1)	criteria provided, single submitter	May 28, 2024	RCV005409608.1

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.	Expand all rows Collapse all rows 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.
Likely pathogenic (-) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Charcot-Marie-Tooth disease	Molecular Genetics Laboratory, London Health Sciences Centre Accession: SCV001336794.1 First in ClinVar: Jun 15, 2020 Last updated: Jun 15, 2020	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Pathogenic (May 28, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Charcot-Marie-Tooth disease type 2A2 Neuropathy, hereditary motor and sensory, type 6A Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. (Autosomal recessive inheritance)	Kariminejad - Najmabadi Pathology & Genetics Center Accession: SCV006075049.1 First in ClinVar: May 15, 2025 Last updated: May 15, 2025	Comment: show (PM1,PM2,PM5,PP3,PP5_Moderate) (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Likely pathogenic (Jun 20, 2019) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Neuropathy, hereditary motor and sensory, type 6A	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV001369432.2 First in ClinVar: Jul 06, 2020 Last updated: Jul 06, 2020	Comment: show This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM1,PM2,PP3. (less) Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: yes Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: yes

Likely pathogenic (Apr 16, 2018) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2a2b;	SIB Swiss Institute of Bioinformatics Accession: SCV000787447.1 First in ClinVar: Jul 21, 2018 Last updated: Jul 21, 2018	Publications: PubMed (3) PubMed: 16835246‚ 18458227‚ 21715711 Comment: show This variant is interpreted as a Likely Pathogenic, for Charcot-Marie-Tooth disease, axonal, type 2A2B, Autosomal Recessive inheritance. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PP1 => Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PMID:21715711). PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate => PS4 downgraded in strength to Moderate (PMID:16835246, 21715711, 18458227). (less) Observation: 1 Collection method: curation Allele origin: germline Affected status: unknown Observation 1 Collection method: curation Allele origin: germline Affected status: unknown

Pathogenic (Dec 01, 2020) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Charcot-Marie-Tooth disease type 2A2	CMT Laboratory, Bogazici University Accession: SCV001548312.1 First in ClinVar: Apr 03, 2021 Last updated: Apr 03, 2021	Publications: PubMed (1) PubMed: 31673878 Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Number of individuals with the variant: 1 Family history: yes Secondary finding: no Platform type: Next-gen sequencing

Pathogenic (Jul 06, 2022) C Contributing to aggregate classification	criteria provided, single submitter (Athena Diagnostics Criteria)	not provided	Athena Diagnostics Accession: SCV002771026.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022	Publications: PubMed (12) PubMed: 16835246‚ 18458227‚ 18957892‚ 21715711‚ 24819634‚ 24863639‚ 26114802‚ 29625556‚ 29858556‚ 31701603‚ 33415332‚ 33475540 Comment: show The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant is primarily reported in severe, early onset, autosomal recessive form of Charcot-Marie-Tooth type 2A (CMT2A; PMID: 9736777 15786415, 17932099, 18337730, 21387378, 24037712, 28662944). Heterozygous members of these families are reported as asymptomatic. However, this variant has also been reported in autosomal dominant CMT2A (PMID: 16835246, 33475540). Computational tools predict that this variant is damaging. (less) Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Likely pathogenic (Oct 19, 2020) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Inborn genetic diseases	Ambry Genetics Accession: SCV002724932.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (3) PubMed: 21715711‚ 26114802‚ 29858556 Comment: show The p.T362M variant (also known as c.1085C>T), located in coding exon 9 of the MFN2 gene, results from a C to T substitution at nucleotide position 1085. The threonine at codon 362 is replaced by methionine, an amino acid with similar properties. This alteration has been reported homozygous in an individual with Charcot-Marie-Tooth disease (CMT) type 2 (CMT2)(Karakaya M et al. Hum Mutat, 2018 09;39:1284-1298) and has been detected in trans with another MFN2 pathogenic mutation in multiple unrelated individuals with CMT2 (Carr AS et al. J Peripher Nerv Syst, 2015 Jun;20:67-71). This alteration has also been reported to segregate with disease in a family with CMT2 (Polke JM et al. Neurology, 2011 Jul;77:168-73). In addition to the clinical data presented in the literature, this amino acid position is highly conserved in available vertebrate species and is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is expected to be causative of Charcot-Marie-Tooth disease (CMT) type 2A2B when present along with a second pathogenic variant on the other allele; however, its clinical significance for Charcot-Marie-Tooth disease (CMT) type 2A2A and hereditary motor and sensory neuropathy VIA is unclear. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Likely pathogenic (Nov 28, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	MFN2-related disorder	3billion Accession: SCV006583188.1 First in ClinVar: Oct 25, 2025 Last updated: Oct 25, 2025	Publications: PubMed (2) PubMed: 16835246‚ 26392352 Comment: show The variant is observed at an extremely low frequency in the gnomAD v4.1.0 dataset (total allele frequency: 0.005%). Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.83 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.95 (>=0.6, sensitivity 0.72 and precision 0.9)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000030738 /PMID: 16835246). Different missense changes at the same codon (p.Thr362Arg, p.Thr362Pro) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000246245, VCV000408317 /PMID: 26392352). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Method: exome sequencing

Pathogenic (Dec 20, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Charcot-Marie-Tooth disease type 2	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001589889.6 First in ClinVar: May 10, 2021 Last updated: Mar 07, 2026	Publications: PubMed (4) PubMed: 16835246‚ 18458227‚ 21715711‚ 26114802 Comment: show This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 362 of the MFN2 protein (p.Thr362Met). This variant is present in population databases (rs387906991, gnomAD 0.02%). This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 16835246, 18458227, 21715711, 26114802). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 30738). Invitae Evidence 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 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. For these reasons, this variant has been classified as Pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Apr 25, 2018) N Not contributing to aggregate classification	no assertion criteria provided	Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2a2b;	Institute of Human Genetics, Cologne University Accession: SCV000787795.1 First in ClinVar: Jul 21, 2018 Last updated: Jul 21, 2018	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Uncertain significance (Aug 14, 2019) N Not contributing to aggregate classification	no assertion criteria provided	Charcot-Marie-Tooth disease	Genesis Genome Database Accession: SCV000999676.1 First in ClinVar: Dec 17, 2019 Last updated: Dec 17, 2019	Observation: 1 Collection method: research Allele origin: germline Affected status: yes Observation 1 Collection method: research Allele origin: germline Affected status: yes

Pathogenic (Jul 12, 2011) N Not contributing to aggregate classification	no assertion criteria provided	CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2A2A	OMIM Accession: SCV000045007.4 First in ClinVar: Apr 04, 2013 Last updated: Jun 10, 2023	Publications: PubMed (3) PubMed: 16835246‚ 18458227‚ 21715711 Observation: 1 Collection method: literature only Allele origin: germline Affected status: not provided more Observation 1 Collection method: literature only Allele origin: germline Affected status: not provided Comment on evidence: In a Korean mother and daughter with Charcot-Marie-Tooth disease-2A2A (CMT2A2A; 609260), Chung et al. (2006) identified a heterozygous 1085C-T transition in the MFN2 gene, resulting … (more) In a Korean mother and daughter with Charcot-Marie-Tooth disease-2A2A (CMT2A2A; 609260), Chung et al. (2006) identified a heterozygous 1085C-T transition in the MFN2 gene, resulting in a thr362-to-met (T362M) substitution. The patients had late onset and a mild phenotype. In 2 adult Italian sibs with autosomal recessive inheritance of severe early-onset CMT2A2B (617087), Polke et al. (2011) identified compound heterozygosity for 2 mutations in the MFN2 gene: a T362M substitution on the maternal allele, and a 3-bp in-frame deletion (113delAGA; 608507.0020) resulting in a deletion of lys38 (lys38del), presumably from the paternal allele, although no DNA was available from the deceased father. The patients had onset of foot drop and upper and lower limb weakness at age 3 years. They also had decreased pinprick and vibration senses, more severe in the lower limbs, kyphosis, pale optic discs, visual loss, severe facial weakness, and respiratory muscle weakness. One had hearing loss and vocal cord palsy. Both were wheelchair-bound. Nerve conduction studies showed absence of nerve conduction in 1 patient tested. Neither parent was affected. Polke et al. (2011) noted that the T362M mutation had also been reported in families with dominant transmission, suggesting that it has a dominant-negative effect; the pathogenic effect of the lys38 deletion mutation was unknown, although it was not found in 550 control chromosomes. In a 32-year-old woman (CMT742) with autosomal recessive CMT2A2B, Nicholson et al. (2008) identified compound heterozygosity for 2 missense mutations in the MFN2 gene: T362M and A164V (608507.0021). (less)

Pathogenic (Jul 12, 2011) N Not contributing to aggregate classification	no assertion criteria provided	CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2A2B, AUTOSOMAL RECESSIVE	OMIM Accession: SCV000298224.2 First in ClinVar: Sep 04, 2016 Last updated: Jun 10, 2023	Publications: PubMed (3) PubMed: 16835246‚ 18458227‚ 21715711 Observation: 1 Collection method: literature only Allele origin: germline Affected status: not provided more Observation 1 Collection method: literature only Allele origin: germline Affected status: not provided Comment on evidence: In a Korean mother and daughter with Charcot-Marie-Tooth disease-2A2A (CMT2A2A; 609260), Chung et al. (2006) identified a heterozygous 1085C-T transition in the MFN2 gene, resulting … (more) In a Korean mother and daughter with Charcot-Marie-Tooth disease-2A2A (CMT2A2A; 609260), Chung et al. (2006) identified a heterozygous 1085C-T transition in the MFN2 gene, resulting in a thr362-to-met (T362M) substitution. The patients had late onset and a mild phenotype. In 2 adult Italian sibs with autosomal recessive inheritance of severe early-onset CMT2A2B (617087), Polke et al. (2011) identified compound heterozygosity for 2 mutations in the MFN2 gene: a T362M substitution on the maternal allele, and a 3-bp in-frame deletion (113delAGA; 608507.0020) resulting in a deletion of lys38 (lys38del), presumably from the paternal allele, although no DNA was available from the deceased father. The patients had onset of foot drop and upper and lower limb weakness at age 3 years. They also had decreased pinprick and vibration senses, more severe in the lower limbs, kyphosis, pale optic discs, visual loss, severe facial weakness, and respiratory muscle weakness. One had hearing loss and vocal cord palsy. Both were wheelchair-bound. Nerve conduction studies showed absence of nerve conduction in 1 patient tested. Neither parent was affected. Polke et al. (2011) noted that the T362M mutation had also been reported in families with dominant transmission, suggesting that it has a dominant-negative effect; the pathogenic effect of the lys38 deletion mutation was unknown, although it was not found in 550 control chromosomes. In a 32-year-old woman (CMT742) with autosomal recessive CMT2A2B, Nicholson et al. (2008) identified compound heterozygosity for 2 missense mutations in the MFN2 gene: T362M and A164V (608507.0021). (less)

Comment:

This variant is interpreted as a Likely Pathogenic, for Charcot-Marie-Tooth disease, axonal, type 2A2B, Autosomal Recessive inheritance. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PP1 => Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PMID:21715711). PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate => PS4 downgraded in strength to Moderate (PMID:16835246, 21715711, 18458227).

Comment:

The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant is primarily reported in severe, early onset, autosomal recessive form of Charcot-Marie-Tooth type 2A (CMT2A; PMID: 9736777 15786415, 17932099, 18337730, 21387378, 24037712, 28662944). Heterozygous members of these families are reported as asymptomatic. However, this variant has also been reported in autosomal dominant CMT2A (PMID: 16835246, 33475540). Computational tools predict that this variant is damaging.

Comment:

The p.T362M variant (also known as c.1085C>T), located in coding exon 9 of the MFN2 gene, results from a C to T substitution at nucleotide position 1085. The threonine at codon 362 is replaced by methionine, an amino acid with similar properties. This alteration has been reported homozygous in an individual with Charcot-Marie-Tooth disease (CMT) type 2 (CMT2)(Karakaya M et al. Hum Mutat, 2018 09;39:1284-1298) and has been detected in trans with another MFN2 pathogenic mutation in multiple unrelated individuals with CMT2 (Carr AS et al. J Peripher Nerv Syst, 2015 Jun;20:67-71). This alteration has also been reported to segregate with disease in a family with CMT2 (Polke JM et al. Neurology, 2011 Jul;77:168-73). In addition to the clinical data presented in the literature, this amino acid position is highly conserved in available vertebrate species and is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is expected to be causative of Charcot-Marie-Tooth disease (CMT) type 2A2B when present along with a second pathogenic variant on the other allele; however, its clinical significance for Charcot-Marie-Tooth disease (CMT) type 2A2A and hereditary motor and sensory neuropathy VIA is unclear.

Comment:

The variant is observed at an extremely low frequency in the gnomAD v4.1.0 dataset (total allele frequency: 0.005%). Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.83 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.95 (>=0.6, sensitivity 0.72 and precision 0.9)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000030738 /PMID: 16835246). Different missense changes at the same codon (p.Thr362Arg, p.Thr362Pro) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000246245, VCV000408317 /PMID: 26392352). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 362 of the MFN2 protein (p.Thr362Met). This variant is present in population databases (rs387906991, gnomAD 0.02%). This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 16835246, 18458227, 21715711, 26114802). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 30738). Invitae Evidence 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 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. For these reasons, this variant has been classified as Pathogenic.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Analysis of the conformational changes caused by the mutations in mitofusin2 gene by Insilico approach.	Rasheed MA	JPMA. The Journal of the Pakistan Medical Association	2020	PMID: 33475540
Natural history of Charcot-Marie-Tooth disease type 2A: a large international multicentre study.	Pipis M	Brain : a journal of neurology	2020	PMID: 33415332
Yield of next-generation neuropathy gene panels in axonal neuropathies.	Lee DC	Journal of the peripheral nervous system : JPNS	2019	PMID: 31701603
Targeted sequencing with expanded gene profile enables high diagnostic yield in non-5q-spinal muscular atrophies.	Karakaya M	Human mutation	2018	PMID: 29858556
Targeted next generation sequencing with an extended gene panel does not impact variant detection in mitochondrial diseases.	Plutino M	BMC medical genetics	2018	PMID: 29625556
Application of targeted multi-gene panel testing for the diagnosis of inherited peripheral neuropathy provides a high diagnostic yield with unexpected phenotype-genotype variability.	Antoniadi T	BMC medical genetics	2015	PMID: 26392352
MFN2 deletion of exons 7 and 8: founder mutation in the UK population.	Carr AS	Journal of the peripheral nervous system : JPNS	2015	PMID: 26114802
A cohort study of MFN2 mutations and phenotypic spectrums in Charcot-Marie-Tooth disease 2A patients.	Choi BO	Clinical genetics	2015	PMID: 24863639
Mutation analysis of MFN2, GJB1, MPZ and PMP22 in Italian patients with axonal Charcot-Marie-Tooth disease.	Bergamin G	Neuromolecular medicine	2014	PMID: 24819634
Recessive axonal Charcot-Marie-Tooth disease due to compound heterozygous mitofusin 2 mutations.	Polke JM	Neurology	2011	PMID: 21715711
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
Severe early-onset axonal neuropathy with homozygous and compound heterozygous MFN2 mutations.	Nicholson GA	Neurology	2008	PMID: 18458227
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
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Text-mined citations for rs387906991 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Jul 06, 2026