NM_014874.4(MFN2):c.669T>A (p.Phe223Leu) AND Charcot-Marie-Tooth disease type 2

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jan 9, 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:: RCV003581716.1

Allele description [Variation Report for NM_014874.4(MFN2):c.669T>A (p.Phe223Leu)]

NM_014874.4(MFN2):c.669T>A (p.Phe223Leu)

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.669T>A (p.Phe223Leu)

HGVS:

NC_000001.11:g.11998839T>A
NG_007945.1:g.23659T>A
NM_001127660.2:c.669T>A
NM_014874.4:c.669T>AMANE SELECT
NP_001121132.1:p.Phe223Leu
NP_055689.1:p.Phe223Leu
NP_055689.1:p.Phe223Leu
LRG_255t1:c.669T>A
LRG_255:g.23659T>A
LRG_255p1:p.Phe223Leu
NC_000001.10:g.12058896T>A
NM_014874.3:c.669T>A

Protein change:

F223L

Links:

dbSNP: rs1440006845

NCBI 1000 Genomes Browser:

rs1440006845

Molecular consequence:

NM_001127660.2:c.669T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_014874.4:c.669T>A - 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

Recent activity

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Rattus norvegicus coiled-coil domain containing 69 (Ccdc69), mRNA
Rattus norvegicus coiled-coil domain containing 69 (Ccdc69), mRNA
gi|157817331|ref|NM_001109031.1|

Nucleotide
JGI_XZT19123.rev NIH_XGC_tropTad5 Xenopus tropicalis cDNA clone IMAGE:7595912 3'...
JGI_XZT19123.rev NIH_XGC_tropTad5 Xenopus tropicalis cDNA clone IMAGE:7595912 3', mRNA sequence
gi|57072882|gnl|dbEST|26958274|gb|C 10.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004291591	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jan 9, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 15549395, 23733358, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004291591

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jan 9, 2024)

germline

clinical testing

PubMed (3)
[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

Mitochondrial GTPase mitofusin 2 mutation in Charcot-Marie-Tooth neuropathy type 2A.

Kijima K, Numakura C, Izumino H, Umetsu K, Nezu A, Shiiki T, Ogawa M, Ishizaki Y, Kitamura T, Shozawa Y, Hayasaka K.

Hum Genet. 2005 Jan;116(1-2):23-7. Epub 2004 Nov 11.

PubMed [citation]

PMID:: 15549395

Ethambutol toxicity exacerbating the phenotype of CMT2A2.

Fonkem E, Skordilis MA, Binkley EM, Raymer DS, Epstein A, Arnold WD, Kissel JT, Lawson VH.

Muscle Nerve. 2013 Jul;48(1):140-4. doi: 10.1002/mus.23766. Epub 2013 Jun 4.

PubMed [citation]

PMID:: 23733358

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV004291591.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 223 of the MFN2 protein (p.Phe223Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant Charcot-Marie-Tooth disease (PMID: 15549395, 23733358). ClinVar contains an entry for this variant (Variation ID: 637299). 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 with a positive predictive value of 95%. 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.

#	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: Feb 20, 2024

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