NM_014874.4(MFN2):c.1078C>G (p.Gln360Glu) AND Charcot-Marie-Tooth disease type 2

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Apr 24, 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:: RCV001856863.6

Allele description [Variation Report for NM_014874.4(MFN2):c.1078C>G (p.Gln360Glu)]

NM_014874.4(MFN2):c.1078C>G (p.Gln360Glu)

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.1078C>G (p.Gln360Glu)

HGVS:

NC_000001.11:g.12002021C>G
NG_007945.1:g.26841C>G
NM_001127660.2:c.1078C>G
NM_014874.4:c.1078C>GMANE SELECT
NP_001121132.1:p.Gln360Glu
NP_001121132.1:p.Gln360Glu
NP_055689.1:p.Gln360Glu
NP_055689.1:p.Gln360Glu
LRG_255t1:c.1078C>G
LRG_255:g.26841C>G
LRG_255p1:p.Gln360Glu
NC_000001.10:g.12062078C>G
NM_001127660.1:c.1078C>G
NM_014874.3:c.1078C>G

Protein change:

Q360E

Links:

dbSNP: rs1064795818

NCBI 1000 Genomes Browser:

rs1064795818

Molecular consequence:

NM_001127660.2:c.1078C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_014874.4:c.1078C>G - 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
SCV002176115	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Apr 24, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 28660751, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002176115

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Apr 24, 2023)

germline

clinical testing

PubMed (2)
[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

Clinical and genetic diversities of Charcot-Marie-Tooth disease with MFN2 mutations in a large case study.

Ando M, Hashiguchi A, Okamoto Y, Yoshimura A, Hiramatsu Y, Yuan J, Higuchi Y, Mitsui J, Ishiura H, Umemura A, Maruyama K, Matsushige T, Morishita S, Nakagawa M, Tsuji S, Takashima H.

J Peripher Nerv Syst. 2017 Sep;22(3):191-199. doi: 10.1111/jns.12228. Epub 2017 Jul 30. Erratum in: J Peripher Nerv Syst. 2018 Jun;23(2):149-150. doi: 10.1111/jns.12263.

PubMed [citation]

PMID:: 28660751
PMCID:: PMC5697682

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002176115.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 422500). This missense change has been observed in individual(s) with clinical features of Charcot-Marie-Tooth (PMID: 28660751; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 360 of the MFN2 protein (p.Gln360Glu).

#	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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