NM_014874.4(MFN2):c.746C>G (p.Ser249Cys) AND Charcot-Marie-Tooth disease type 2A2

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jul 20, 2021
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:: RCV002221162.2

Allele description [Variation Report for NM_014874.4(MFN2):c.746C>G (p.Ser249Cys)]

NM_014874.4(MFN2):c.746C>G (p.Ser249Cys)

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.746C>G (p.Ser249Cys)

Other names:

chr1-11999025-C-G; p.Ser249Cys

HGVS:

NC_000001.11:g.11999025C>G
NG_007945.1:g.23845C>G
NM_001127660.2:c.746C>G
NM_014874.4:c.746C>GMANE SELECT
NP_001121132.1:p.Ser249Cys
NP_055689.1:p.Ser249Cys
LRG_255t1:c.746C>G
LRG_255:g.23845C>G
NC_000001.10:g.12059082C>G
NM_014874.3:c.746C>G

Protein change:

S249C

Links:

dbSNP: rs794729198

NCBI 1000 Genomes Browser:

rs794729198

Molecular consequence:

NM_001127660.2:c.746C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_014874.4:c.746C>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Charcot-Marie-Tooth disease type 2A2
Synonyms:: CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2A2; CHARCOT-MARIE-TOOTH DISEASE, NEURONAL, TYPE 2A2; HEREDITARY MOTOR AND SENSORY NEUROPATHY IIA2; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0012231; MedGen: C4721887; Orphanet: 99947; OMIM: 609260

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001976644	Laboratório de Neurologia Aplicada e Experimental, Faculdade de Medicina de Ribeirao Preto – Universidade de Sao Paulo	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jul 20, 2021)	germline	research	PubMed (7) [See all records that cite these PMIDs] 15297672, 22189565, 15064763, 21326314, 26378787, 26801520, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001976644

Laboratório de Neurologia Aplicada e Experimental, Faculdade de Medicina de Ribeirao Preto – Universidade de Sao Paulo

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jul 20, 2021)

germline

research

PubMed (7)
[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	yes	1	1	not provided	not provided	yes	research

Citations

PubMed

Structural basis of mitochondrial tethering by mitofusin complexes.

Koshiba T, Detmer SA, Kaiser JT, Chen H, McCaffery JM, Chan DC.

Science. 2004 Aug 6;305(5685):858-62.

PubMed [citation]

PMID:: 15297672

The MFN2 gene is responsible for mitochondrial DNA instability and optic atrophy 'plus' phenotype.

Rouzier C, Bannwarth S, Chaussenot A, Chevrollier A, Verschueren A, Bonello-Palot N, Fragaki K, Cano A, Pouget J, Pellissier JF, Procaccio V, Chabrol B, Paquis-Flucklinger V.

Brain. 2012 Jan;135(Pt 1):23-34. doi: 10.1093/brain/awr323. Epub 2011 Dec 20.

PubMed [citation]

PMID:: 22189565

See all PubMed Citations (7)

Details of each submission

From Laboratório de Neurologia Aplicada e Experimental, Faculdade de Medicina de Ribeirao Preto – Universidade de Sao Paulo, SCV001976644.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	yes	research	PubMed (7)

Description

The c.746C>G (p.Ser249Cys) variant in the MFN2 gene has not been described in the literature to our knowledge. This variant is not present in the population database (GnomAD and ABraOM), suggesting it is not a common benign variant in these populations. This variant replaces Serine with Cysteine at codon 249 of the MFN2 protein, a hot spot region that is highly conserved across different species. This substitution occurs in the critical GTPase domain of the protein, which is essential for the function of mitofusins (PMID: 15297672; PMID: 22189565; PMID: 15064763). Additionally, a missense variant in the same amino acid (p.Ser249Phe) has been reported as pathogenic/likely pathogenic in ClinVar, 2 stars (Variation ID: 202171) and some families with Charcot-Marie-Tooth Disease Type 2A (PMID: 21326314; PMID: 26378787; PMID: 26801520). Our lab found it once, in heterozygosity, in a 5-year-old female with a moderate CMT2 phenotype. Segregation analysis suggests it is a de novo mutation. In summary, p.Ser249Cys meets our criteria to be classified as likely pathogenic.

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

Last Updated: Sep 29, 2024

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