NM_014874.4(MFN2):c.2177C>G (p.Ser726Ter) AND Charcot-Marie-Tooth disease type 2

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jul 13, 2019
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:: RCV001202315.8

Allele description [Variation Report for NM_014874.4(MFN2):c.2177C>G (p.Ser726Ter)]

NM_014874.4(MFN2):c.2177C>G (p.Ser726Ter)

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.2177C>G (p.Ser726Ter)

HGVS:

NC_000001.11:g.12009699C>G
NG_007945.1:g.34519C>G
NM_001127660.2:c.2177C>G
NM_014874.4:c.2177C>GMANE SELECT
NP_001121132.1:p.Ser726Ter
NP_055689.1:p.Ser726Ter
LRG_255t1:c.2177C>G
LRG_255:g.34519C>G
NC_000001.10:g.12069756C>G
NM_014874.3:c.2177C>G

Protein change:

S726*

Links:

dbSNP: rs1317009723

NCBI 1000 Genomes Browser:

rs1317009723

Molecular consequence:

NM_001127660.2:c.2177C>G - nonsense - [Sequence Ontology: SO:0001587]
NM_014874.4:c.2177C>G - nonsense - [Sequence Ontology: SO:0001587]

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
SCV001373423	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jul 13, 2019)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 16714318, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001373423

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jul 13, 2019)

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

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

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, SCV001373423.5

#	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. This variant disrupts the C-terminus of the MFN2 protein. Other variant(s) that disrupt this region (p.Gln751* ) have been determined to be pathogenic (PMID: 16714318). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. This variant has not been reported in the literature in individuals with MFN2-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the MFN2 gene (p.Ser726*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 32 amino acids of the MFN2 protein.

#	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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