NM_014874.4(MFN2):c.1085C>T (p.Thr362Met) AND Charcot-Marie-Tooth disease type 2

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Oct 20, 2024
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001388766.8

Allele description [Variation Report for NM_014874.4(MFN2):c.1085C>T (p.Thr362Met)]

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

Gene:

MFN2:mitofusin 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1p36.22

Genomic location:

Preferred name:

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

Other names:

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

HGVS:

NC_000001.11:g.12002028C>T
NG_007945.1:g.26848C>T
NM_001127660.2:c.1085C>T
NM_014874.4:c.1085C>TMANE SELECT
NP_001121132.1:p.Thr362Met
NP_001121132.1:p.Thr362Met
NP_055689.1:p.Thr362Met
NP_055689.1:p.Thr362Met
LRG_255t1:c.1085C>T
LRG_255:g.26848C>T
LRG_255p1:p.Thr362Met
NC_000001.10:g.12062085C>T
NM_001127660.1:c.1085C>T
NM_014874.3:c.1085C>T
O95140:p.Thr362Met

Protein change:

T362M; THR362MET

Links:

UniProtKB: O95140#VAR_076897; OMIM: 608507.0019; dbSNP: rs387906991

NCBI 1000 Genomes Browser:

rs387906991

Molecular consequence:

NM_001127660.2:c.1085C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_014874.4:c.1085C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Charcot-Marie-Tooth disease type 2
Synonyms:: Charcot-Marie-Tooth, Type 2
Identifiers:: MONDO: MONDO:0018993; MedGen: C0270914

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001589889	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 20, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 16835246, 18458227, 21715711, 26114802, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001589889

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 20, 2024)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Early onset severe and late-onset mild Charcot-Marie-Tooth disease with mitofusin 2 (MFN2) mutations.

Chung KW, Kim SB, Park KD, Choi KG, Lee JH, Eun HW, Suh JS, Hwang JH, Kim WK, Seo BC, Kim SH, Son IH, Kim SM, Sunwoo IN, Choi BO.

Brain. 2006 Aug;129(Pt 8):2103-18. Epub 2006 Jul 10.

PubMed [citation]

PMID:: 16835246

Severe early-onset axonal neuropathy with homozygous and compound heterozygous MFN2 mutations.

Nicholson GA, Magdelaine C, Zhu D, Grew S, Ryan MM, Sturtz F, Vallat JM, Ouvrier RA.

Neurology. 2008 May 6;70(19):1678-81. doi: 10.1212/01.wnl.0000311275.89032.22.

PubMed [citation]

PMID:: 18458227

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001589889.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Mar 16, 2025

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