NM_014874.4(MFN2):c.292A>G (p.Lys98Glu) AND Charcot-Marie-Tooth disease type 2

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Dec 18, 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:: RCV001360038.7

Allele description [Variation Report for NM_014874.4(MFN2):c.292A>G (p.Lys98Glu)]

NM_014874.4(MFN2):c.292A>G (p.Lys98Glu)

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.292A>G (p.Lys98Glu)

HGVS:

NC_000001.11:g.11992671A>G
NG_007945.1:g.17491A>G
NM_001127660.2:c.292A>G
NM_014874.4:c.292A>GMANE SELECT
NP_001121132.1:p.Lys98Glu
NP_055689.1:p.Lys98Glu
NP_055689.1:p.Lys98Glu
LRG_255t1:c.292A>G
LRG_255:g.17491A>G
LRG_255p1:p.Lys98Glu
NC_000001.10:g.12052728A>G
NM_014874.3:c.292A>G

Protein change:

K98E

Links:

dbSNP: rs1553141706

NCBI 1000 Genomes Browser:

rs1553141706

Molecular consequence:

NM_001127660.2:c.292A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_014874.4:c.292A>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
SCV001555933	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Dec 18, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 18957892, 32376792, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001555933

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Dec 18, 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

Histopathological findings in hereditary motor and sensory neuropathy of axonal type with onset in early childhood associated with mitofusin 2 mutations.

Vallat JM, Ouvrier RA, Pollard JD, Magdelaine C, Zhu D, Nicholson GA, Grew S, Ryan MM, Funalot B.

J Neuropathol Exp Neurol. 2008 Nov;67(11):1097-102. doi: 10.1097/NEN.0b013e31818b6cbc.

PubMed [citation]

PMID:: 18957892

Comprehensive genetic sequence and copy number analysis for Charcot-Marie-Tooth disease in a Canadian cohort of 2517 patients.

Volodarsky M, Kerkhof J, Stuart A, Levy M, Brady LI, Tarnopolsky M, Lin H, Ainsworth P, Sadikovic B.

J Med Genet. 2021 Apr;58(4):284-288. doi: 10.1136/jmedgenet-2019-106641. Epub 2020 May 6.

PubMed [citation]

PMID:: 32376792

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001555933.4

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

Description

This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 98 of the MFN2 protein (p.Lys98Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of autosomal dominant MFN2-related conditions (PMID: 18957892, 32376792; Invitae). ClinVar contains an entry for this variant (Variation ID: 447723). 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 with a positive predictive value of 95%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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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