NM_014874.4(MFN2):c.2129T>C (p.Leu710Pro) AND Charcot-Marie-Tooth disease type 2

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Sep 8, 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:: RCV000697850.6

Allele description [Variation Report for NM_014874.4(MFN2):c.2129T>C (p.Leu710Pro)]

NM_014874.4(MFN2):c.2129T>C (p.Leu710Pro)

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.2129T>C (p.Leu710Pro)

HGVS:

NC_000001.11:g.12009651T>C
NG_007945.1:g.34471T>C
NM_001127660.2:c.2129T>C
NM_014874.4:c.2129T>CMANE SELECT
NP_001121132.1:p.Leu710Pro
NP_055689.1:p.Leu710Pro
NP_055689.1:p.Leu710Pro
LRG_255t1:c.2129T>C
LRG_255:g.34471T>C
LRG_255p1:p.Leu710Pro
NC_000001.10:g.12069708T>C
NM_014874.3:c.2129T>C

Protein change:

L710P

Links:

dbSNP: rs1557537223

NCBI 1000 Genomes Browser:

rs1557537223

Molecular consequence:

NM_001127660.2:c.2129T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_014874.4:c.2129T>C - 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
SCV000826482	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 8, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 16714318, 28660751, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000826482

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Sep 8, 2023)

germline

clinical testing

PubMed (3)
[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

MFN2 mutation distribution and genotype/phenotype correlation in Charcot-Marie-Tooth type 2.

Verhoeven K, Claeys KG, Züchner S, Schröder JM, Weis J, Ceuterick C, Jordanova A, Nelis E, De Vriendt E, Van Hul M, Seeman P, Mazanec R, Saifi GM, Szigeti K, Mancias P, Butler IJ, Kochanski A, Ryniewicz B, De Bleecker J, Van den Bergh P, Verellen C, Van Coster R, et al.

Brain. 2006 Aug;129(Pt 8):2093-102. Epub 2006 May 19.

PubMed [citation]

PMID:: 16714318

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

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV000826482.4

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

Description

This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 710 of the MFN2 protein (p.Leu710Pro). This missense change has been observed in individuals with autosomal dominant Charcot-Marie-Tooth disease (PMID: 16714318, 28660751; Invitae). ClinVar contains an entry for this variant (Variation ID: 575589). 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. 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: Jun 23, 2024

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