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NM_014874.4(MFN2):c.2146G>A (p.Ala716Thr)

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Interpretation:
Conflicting interpretations of pathogenicity​

Likely benign(3);Likely pathogenic(1);Uncertain significance(3)

Review status:
criteria provided, conflicting interpretations
Submissions:
8 (Most recent: Jul 14, 2021)
Last evaluated:
Sep 24, 2020
Accession:
VCV000214649.17
Variation ID:
214649
Description:
single nucleotide variant
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NM_014874.4(MFN2):c.2146G>A (p.Ala716Thr)

Allele ID
210603
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
1p36.22
Genomic location
1: 12009668 (GRCh38) GRCh38 UCSC
1: 12069725 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
LRG_255:g.34488G>A
LRG_255t1:c.2146G>A LRG_255p1:p.Ala716Thr
NC_000001.10:g.12069725G>A
... more HGVS
Protein change
A716T
Other names
p.A716T:GCC>ACC
Canonical SPDI
NC_000001.11:12009667:G:A
Functional consequence
-
Global minor allele frequency (GMAF)
0.00120 (A)

Allele frequency
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00038
Trans-Omics for Precision Medicine (TOPMed) 0.00040
1000 Genomes Project 0.00120
The Genome Aggregation Database (gnomAD) 0.00032
The Genome Aggregation Database (gnomAD), exomes 0.00011
Links
ClinGen: CA321153
dbSNP: rs144860227
VarSome
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Likely benign 1 criteria provided, single submitter Apr 27, 2017 RCV000334497.2
Likely pathogenic 2 criteria provided, single submitter - RCV000790008.2
Conflicting interpretations of pathogenicity 2 criteria provided, conflicting interpretations Sep 24, 2020 RCV000554698.7
Conflicting interpretations of pathogenicity 3 criteria provided, conflicting interpretations Mar 24, 2020 RCV000731890.6
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Gene OMIM ClinGen Gene Dosage Sensitivity Curation Variation viewer Related variants
HI score Help TS score Help Within gene All
MFN2 No evidence available No evidence available GRCh38
GRCh37
775 822

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
Likely benign
(Apr 27, 2017)
criteria provided, single submitter
Method: clinical testing
Hereditary motor and sensory neuropathy with optic atrophy
Allele origin: germline
Illumina Clinical Services Laboratory,Illumina
Accession: SCV000348006.3
Submitted: (Feb 20, 2020)
Evidence details
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
Likely benign
(Apr 27, 2017)
criteria provided, single submitter
Method: clinical testing
Charcot-Marie-Tooth disease, type 2
Allele origin: germline
Illumina Clinical Services Laboratory,Illumina
Accession: SCV000348007.3
Submitted: (Feb 20, 2020)
Evidence details
Publications
PubMed (4)
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
Likely benign
(Mar 24, 2020)
criteria provided, single submitter
Method: clinical testing
Not Provided
Allele origin: germline
GeneDx
Accession: SCV000251723.12
Submitted: (Jul 14, 2021)
Evidence details
Comment:
This variant is associated with the following publications: (PMID: 29361379, 29341354, 20350294, 23106488, 21508331, 22492563, 20482598)
Uncertain significance
(Feb 20, 2018)
criteria provided, single submitter
Method: clinical testing
not provided
Allele origin: germline
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics
Accession: SCV000859758.1
Submitted: (Sep 19, 2018)
Evidence details
Other databases
http://www.egl-eurofins.com/emvc…
Likely pathogenic
(-)
criteria provided, single submitter
Method: clinical testing
Charcot-Marie-Tooth disease
Allele origin: germline
Molecular Genetics Laboratory,London Health Sciences Centre
Accession: SCV001336793.1
Submitted: (Apr 07, 2020)
Evidence details
Uncertain significance
(Sep 24, 2020)
criteria provided, single submitter
Method: clinical testing
Charcot-Marie-Tooth disease, type 2
Allele origin: germline
Invitae
Accession: SCV000657720.5
Submitted: (Jan 07, 2021)
Evidence details
Publications
PubMed (5)
Comment:
This sequence change replaces alanine with threonine at codon 716 of the MFN2 protein (p.Ala716Thr). The alanine residue is weakly conserved and there is a … (more)
Uncertain significance
(Dec 01, 2019)
criteria provided, single submitter
Method: clinical testing
not provided
Allele origin: germline
CeGaT Praxis fuer Humangenetik Tuebingen
Accession: SCV001147159.7
Submitted: (Jul 04, 2021)
Evidence details
Uncertain significance
(-)
no assertion criteria provided
Method: literature only
Charcot-Marie-Tooth disease
Allele origin: germline
Inherited Neuropathy Consortium
Accession: SCV000929398.1
Submitted: (Jul 10, 2019)
Evidence details
Publications
PubMed (1)

Functional evidence

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There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Citations for this variant

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Title Author Journal Year Link
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. Nykamp K Genetics in medicine : official journal of the American College of Medical Genetics 2017 PMID: 28492532
Pathogenic variant burden in the ExAC database: an empirical approach to evaluating population data for clinical variant interpretation. Kobayashi Y Genome medicine 2017 PMID: 28166811
MFN2 mutations cause compensatory mitochondrial DNA proliferation. Sitarz KS Brain : a journal of neurology 2012 PMID: 22492563
MFN2 mutations cause severe phenotypes in most patients with CMT2A. Feely SM Neurology 2011 PMID: 21508331
Genetic epidemiology of Charcot-Marie-Tooth in the general population. Braathen GJ European journal of neurology 2011 PMID: 20482598
MFN2 point mutations occur in 3.4% of Charcot-Marie-Tooth families. An investigation of 232 Norwegian CMT families. Braathen GJ BMC medical genetics 2010 PMID: 20350294
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=MFN2 - - - -

Text-mined citations for rs144860227...

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These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 30, 2021