NM_014874.4(MFN2):c.281G>A (p.Arg94Gln) AND Charcot-Marie-Tooth disease type 2A2

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Aug 15, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000002356.13

Allele description [Variation Report for NM_014874.4(MFN2):c.281G>A (p.Arg94Gln)]

NM_014874.4(MFN2):c.281G>A (p.Arg94Gln)

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.281G>A (p.Arg94Gln)

Other names:

chr1-11992660-G-A

HGVS:

NC_000001.11:g.11992660G>A
NG_007945.1:g.17480G>A
NM_001127660.2:c.281G>A
NM_014874.4:c.281G>AMANE SELECT
NP_001121132.1:p.Arg94Gln
NP_001121132.1:p.Arg94Gln
NP_055689.1:p.Arg94Gln
NP_055689.1:p.Arg94Gln
LRG_255t1:c.281G>A
LRG_255:g.17480G>A
LRG_255p1:p.Arg94Gln
NC_000001.10:g.12052717G>A
NM_001127660.1:c.281G>A
NM_014874.3:c.281G>A
O95140:p.Arg94Gln

Protein change:

R94Q; ARG94GLN

Links:

UniProtKB: O95140#VAR_018609; OMIM: 608507.0001; dbSNP: rs28940291

NCBI 1000 Genomes Browser:

rs28940291

Molecular consequence:

NM_001127660.2:c.281G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_014874.4:c.281G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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
SCV000022514	OMIM	no assertion criteria provided	Pathogenic (Apr 1, 2010)	germline	literature only	PubMed (3) [See all records that cite these PMIDs] 9409358, 15064763, 19889647
SCV001938859	Laboratório de Neurologia Aplicada e Experimental, Faculdade de Medicina de Ribeirao Preto – Universidade de Sao Paulo	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 20, 2021)	germline	research	PubMed (18) [See all records that cite these PMIDs] 17437620, 20335458, 26230519, 17296794, 30882371, 29898954, 17215403, 16714318, 15549395, 19812251, 24604904, 20350294, 19889647, 15064763, 9409358, 25025039, 20418531, 25741868
SCV003927862	Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)	no assertion criteria provided	Pathogenic (Apr 1, 2023)	germline	clinical testing
SCV004040908	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 15, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004048344	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	7	3	not provided	not provided	not provided	clinical testing, research
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mitofusin 2 gene mutation (R94Q) causing severe early-onset axonal polyneuropathy (CMT2A).

Neusch C, Senderek J, Eggermann T, Elolff E, Bähr M, Schneider-Gold C.

Eur J Neurol. 2007 May;14(5):575-7.

PubMed [citation]

PMID:: 17437620

Mitofusin 2 is necessary for transport of axonal mitochondria and interacts with the Miro/Milton complex.

Misko A, Jiang S, Wegorzewska I, Milbrandt J, Baloh RH.

J Neurosci. 2010 Mar 24;30(12):4232-40. doi: 10.1523/JNEUROSCI.6248-09.2010.

PubMed [citation]

PMID:: 20335458
PMCID:: PMC2852190

See all PubMed Citations (18)

Details of each submission

From OMIM, SCV000022514.2

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

Description

In affected members of a Japanese kindred (family 693) with autosomal dominant Charcot-Marie-Tooth disease-2A2A (CMT2A2A; 609260) originally reported by Saito et al. (1997) as well as in a Russian kindred with CMT2A2A, Zuchner et al. (2004) identified a heterozygous 281G-A transition in the MFN2 gene, resulting in an arg94-to-gln (R94Q) substitution in the predicted beginning of the GTPase domain of the protein. Age at disease onset in the 2 kindreds ranged from 3 to 17 years. A different mutation affecting the same codon (R94W; 608507.0009) was identified in another patient.

Casasnovas et al. (2010) identified a heterozygous R94Q mutation in affected members of a Spanish family with early-onset severe CMT2A2A and optic atrophy.

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

From Laboratório de Neurologia Aplicada e Experimental, Faculdade de Medicina de Ribeirao Preto – Universidade de Sao Paulo, SCV001938859.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	7	not provided	not provided	research	PubMed (18)

#	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		7	not provided	3	not provided

From Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS), SCV003927862.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	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		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV004040908.1

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

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

From Neuberg Centre For Genomic Medicine, NCGM, SCV004048344.1

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

Description

The amino acid Arg at position 94 is changed to a Gln changing protein sequence and it might alter its composition and physico-chemical properties. This sequence change replaces arginine with glutamine at codon 94 of the mitofusin 2 protein (p.Arg94Gln). This variant has been reported in multiple unrelated individuals affected with autosomal dominant Charcot-Marie-Tooth disease type 2 (CMT2) (Casasnovas C et al, Neusch C et al) and in several families where it was observed to co-segregate with disease (Klein CJ et al). This variant has also been shown to arise de novo in an individual affected with CMT2 (Braathen GJ et al). The p.Arg94Gln variant is reported with the allele frequency of 0.0003976% and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Arg94Gln in MFN2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. 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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 8, 2024

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