NM_014874.4(MFN2):c.748C>T (p.Arg250Trp) AND Charcot-Marie-Tooth disease, type 2

Clinical significance:Likely pathogenic (Last evaluated: Sep 19, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:

Allele description [Variation Report for NM_014874.4(MFN2):c.748C>T (p.Arg250Trp)]

NM_014874.4(MFN2):c.748C>T (p.Arg250Trp)

MFN2:mitofusin 2 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
NM_014874.4(MFN2):c.748C>T (p.Arg250Trp)
  • NC_000001.11:g.11999027C>T
  • NG_007945.1:g.23847C>T
  • NM_001127660.1:c.748C>T
  • NM_001127660.2:c.748C>T
  • NM_014874.3:c.748C>T
  • NM_014874.4:c.748C>TMANE SELECT
  • NP_001121132.1:p.Arg250Trp
  • NP_001121132.1:p.Arg250Trp
  • NP_055689.1:p.Arg250Trp
  • NP_055689.1:p.Arg250Trp
  • LRG_255t1:c.748C>T
  • LRG_255:g.23847C>T
  • LRG_255p1:p.Arg250Trp
  • NC_000001.10:g.12059084C>T
Protein change:
dbSNP: rs373107074
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_001127660.1:c.748C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001127660.2:c.748C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_014874.3:c.748C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_014874.4:c.748C>T - missense variant - [Sequence Ontology: SO:0001583]


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

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
SCV000775805Invitaecriteria provided, single submitter
Likely pathogenic
(Sep 19, 2019)
germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing



MFN2 mutation distribution and genotype/phenotype correlation in Charcot-Marie-Tooth type 2.

Verhoeven K, Claeys KG, Züchner S, Schröder JM, Weis J, Ceuterick C, Jordanova A, Nelis E, De Vriendt E, Van Hul M, Seeman P, Mazanec R, Saifi GM, Szigeti K, Mancias P, Butler IJ, Kochanski A, Ryniewicz B, De Bleecker J, Van den Bergh P, Verellen C, Van Coster R, et al.

Brain. 2006 Aug;129(Pt 8):2093-102. Epub 2006 May 19.

PubMed [citation]

Mutational mechanisms in MFN2-related neuropathy: compound heterozygosity for recessive and semidominant mutations.

Piscosquito G, Saveri P, Magri S, Ciano C, Di Bella D, Milani M, Taroni F, Pareyson D.

J Peripher Nerv Syst. 2015 Dec;20(4):380-6. doi: 10.1111/jns.12145.

PubMed [citation]
See all PubMed Citations (6)

Details of each submission

From Invitae, SCV000775805.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)


This sequence change replaces arginine with tryptophan at codon 250 of the MFN2 protein (p.Arg250Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs373107074, ExAC 0.004%). This variant has been observed in individual(s) with autosomal recessive MFN2-related neuropathy/Charcot-Marie-Tooth disease type 2 (PMID:16714318, 26306937, 28660751). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. This variant has also been reported as heterozygous in two siblings affected with hereditary sensory and motor neuropathy and an individual affected with CMT2A, however a second rare variant in MFN2 was not found in these individuals (PMID: 26686600, 27862672). ClinVar contains an entry for this variant (Variation ID: 543219). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Possibly Damaging; Align-GVGD: Class C0). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 30, 2021

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