NM_014874.4(MFN2):c.2119C>T (p.Arg707Trp) AND Inborn genetic diseases

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Nov 4, 2022
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:: RCV000624830.11

Allele description [Variation Report for NM_014874.4(MFN2):c.2119C>T (p.Arg707Trp)]

NM_014874.4(MFN2):c.2119C>T (p.Arg707Trp)

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.2119C>T (p.Arg707Trp)

Other names:

p.R707W:CGG>TGG; NM_001127660.1(MFN2):c.2119C>T(p.Arg707Trp); NM_014874.3(MFN2):c.2119C>T(p.Arg707Trp)

HGVS:

NC_000001.11:g.12009641C>T
NG_007945.1:g.34461C>T
NM_001127660.1:c.2119C>T
NM_001127660.2:c.2119C>T
NM_014874.4:c.2119C>TMANE SELECT
NP_001121132.1:p.Arg707Trp
NP_055689.1:p.Arg707Trp
NP_055689.1:p.Arg707Trp
LRG_255t1:c.2119C>T
LRG_255:g.34461C>T
LRG_255p1:p.Arg707Trp
NC_000001.10:g.12069698C>T
NM_014874.3:c.2119C>T
NM_014874.4:c.2119C>T
p.Arg707Trp

Protein change:

R707W; ARG707TRP

Links:

OMIM: 608507.0013; dbSNP: rs119103267

NCBI 1000 Genomes Browser:

rs119103267

Molecular consequence:

NM_001127660.2:c.2119C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_014874.4:c.2119C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Inborn genetic diseases
Identifiers:: MeSH: D030342; MedGen: C0950123

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000741959	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Nov 4, 2022)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 18458227, 20008656, 20482598, 24126688, 26085578, 26114802, 28251916, 28414270, 30158064, 33415332, 33502018 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000741959

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Nov 4, 2022)

germline

clinical testing

PubMed (11)
[See all records that cite these PMIDs]

Citation Link

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

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

Genotype-phenotype correlations in Charcot-Marie-Tooth disease type 2 caused by mitofusin 2 mutations.

Calvo J, Funalot B, Ouvrier RA, Lazaro L, Toutain A, De Mas P, Bouche P, Gilbert-Dussardier B, Arne-Bes MC, Carrière JP, Journel H, Minot-Myhie MC, Guillou C, Ghorab K, Magy L, Sturtz F, Vallat JM, Magdelaine C.

Arch Neurol. 2009 Dec;66(12):1511-6. doi: 10.1001/archneurol.2009.284.

PubMed [citation]

PMID:: 20008656

See all PubMed Citations (11)

Details of each submission

From Ambry Genetics, SCV000741959.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (11)

Description

The c.2119C>T (p.R707W) alteration is located in exon 18 (coding exon 16) of the MFN2 gene. This alteration results from a C to T substitution at nucleotide position 2119, causing the arginine (R) at amino acid position 707 to be replaced by a tryptophan (W)._x000D_ _x000D_ Based on the available evidence, the MFN2 c.2119C>T (p.R707W) alteration is classified as pathogenic for autosomal recessive MFN2-related neuropathy; however, it is unlikely to be causative of autosomal dominant MFN2-related neuropathy. Based on data from gnomAD, the T allele has an overall frequency of 0.025% (71/282876) total alleles studied. The highest observed frequency was 0.051% (66/129186) of European (non-Finnish) alleles. This alteration was reported in the homozygous state or in trans with another MFN2 variant in multiple individuals with axonal neuropathy and lipodystrophy (Nicholson, 2008; Calvo, 2009; Carr, 2015; Sawyer, 2015; Rocha, 2017; Capel, 2018). Heterozygous parents with affected children have been reported to be asymptomatic (Nicholson, 2008; Carr, 2015; Rocha, 2017). This amino acid position is well conserved in available vertebrate species. Functional analysis in patient fibroblasts demonstrated that the p.R707W alteration impairs mitofusin 2 homodimer formation leading to mitochondrial aggregation (Sawyer, 2015). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is 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: Nov 3, 2024

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