NM_014874.4(MFN2):c.310C>T (p.Arg104Trp) AND Charcot-Marie-Tooth disease type 2

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Nov 25, 2023
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:: RCV000556047.9

Allele description [Variation Report for NM_014874.4(MFN2):c.310C>T (p.Arg104Trp)]

NM_014874.4(MFN2):c.310C>T (p.Arg104Trp)

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.310C>T (p.Arg104Trp)

Other names:

p.R104W:CGG>TGG; chr1-11992689-C-T; p.Arg104Trp

HGVS:

NC_000001.11:g.11992689C>T
NG_007945.1:g.17509C>T
NM_001127660.2:c.310C>T
NM_014874.4:c.310C>TMANE SELECT
NP_001121132.1:p.Arg104Trp
NP_001121132.1:p.Arg104Trp
NP_055689.1:p.Arg104Trp
NP_055689.1:p.Arg104Trp
LRG_255t1:c.310C>T
LRG_255:g.17509C>T
LRG_255p1:p.Arg104Trp
NC_000001.10:g.12052746C>T
NM_001127660.1:c.310C>T
NM_014874.3:c.310C>T

Protein change:

R104W; ARG104TRP

Links:

OMIM: 608507.0014; dbSNP: rs119103268

NCBI 1000 Genomes Browser:

rs119103268

Molecular consequence:

NM_001127660.2:c.310C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_014874.4:c.310C>T - 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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000657723	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 25, 2023)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 18425620, 18946002, 18957892, 20008656, 21531138, 21840889, 25025039, 22492563, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000657723

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 25, 2023)

germline

clinical testing

PubMed (9)
[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

Cerebral involvement in axonal Charcot-Marie-Tooth neuropathy caused by mitofusin2 mutations.

Brockmann K, Dreha-Kulaczewski S, Dechent P, Bönnemann C, Helms G, Kyllerman M, Brück W, Frahm J, Huehne K, Gärtner J, Rautenstrauss B.

J Neurol. 2008 Jul;255(7):1049-58. doi: 10.1007/s00415-008-0847-1. Epub 2008 Apr 21.

PubMed [citation]

PMID:: 18425620

Mutated mitofusin 2 presents with intrafamilial variability and brain mitochondrial dysfunction.

Del Bo R, Moggio M, Rango M, Bonato S, D'Angelo MG, Ghezzi S, Airoldi G, Bassi MT, Guglieri M, Napoli L, Lamperti C, Corti S, Federico A, Bresolin N, Comi GP.

Neurology. 2008 Dec 9;71(24):1959-66. doi: 10.1212/01.wnl.0000327095.32005.a4. Epub 2008 Oct 22.

PubMed [citation]

PMID:: 18946002

See all PubMed Citations (9)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000657723.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 104 of the MFN2 protein (p.Arg104Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 18425620, 18946002, 18957892, 20008656, 21531138, 21840889, 25025039). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2281). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.Arg104 amino acid residue in MFN2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22492563). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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