1-12002033-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_014874.4(MFN2):c.1090C>T(p.Arg364Trp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R364L) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Consequence

MFN2
NM_014874.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:15U:2

Conservation

PhyloP100: 5.12

Publications

49 publications found

Variant links:

Genes affected

MFN2 (HGNC:16877): (mitofusin 2) This gene encodes a mitochondrial membrane protein that participates in mitochondrial fusion and contributes to the maintenance and operation of the mitochondrial network. This protein is involved in the regulation of vascular smooth muscle cell proliferation, and it may play a role in the pathophysiology of obesity. Mutations in this gene cause Charcot-Marie-Tooth disease type 2A2, and hereditary motor and sensory neuropathy VI, which are both disorders of the peripheral nervous system. Defects in this gene have also been associated with early-onset stroke. Two transcript variants encoding the same protein have been identified. [provided by RefSeq, Jul 2008]

MFN2 Gene-Disease associations (from GenCC):

neuropathy, hereditary motor and sensory, type 6A
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2a2b;
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
axonal hereditary motor and sensory neuropathy
Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
Charcot-Marie-Tooth disease type 2A2
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
hereditary motor and sensory neuropathy type 6
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
multiple symmetric lipomatosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
severe early-onset axonal neuropathy due to MFN2 deficiency
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

MFN2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 19 ACMG points.

PM1

In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_014874.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-12002034-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 801445.

PP2

Missense variant in the MFN2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 123 curated pathogenic missense variants (we use a threshold of 10). The gene has 23 curated benign missense variants. Gene score misZ: 1.6575 (below the threshold of 3.09). Trascript score misZ: 3.2174 (above the threshold of 3.09). GenCC associations: The gene is linked to Charcot-Marie-Tooth disease type 2A2, Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2a2b;, severe early-onset axonal neuropathy due to MFN2 deficiency, hereditary motor and sensory neuropathy type 6, axonal hereditary motor and sensory neuropathy, multiple symmetric lipomatosis, neuropathy, hereditary motor and sensory, type 6A.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.984

PP5

Variant 1-12002033-C-T is Pathogenic according to our data. Variant chr1-12002033-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 2278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MFN2	NM_014874.4 link	c.1090C>T	p.Arg364Trp	missense_variant	Exon 11 of 19	ENST00000235329.10	NP_055689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MFN2	ENST00000235329.10 link	c.1090C>T	p.Arg364Trp	missense_variant	Exon 11 of 19	1	NM_014874.4	ENSP00000235329.5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00000427

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease type 2A2

Pathogenic:8

Feb 11, 2019

Department of Rehabilitation Medicine, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Northcott Neuroscience Laboratory, ANZAC Research Institute

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Aug 01, 2006

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Dec 01, 2020

CMT Laboratory, Bogazici University

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 20, 2021

Laboratório de Neurologia Aplicada e Experimental, Faculdade de Medicina de Ribeirao Preto – Universidade de Sao Paulo

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Dec 26, 2023

3billion

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Missense variant Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 29898954). In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.86 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.96 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000002278 /PMID: 16437557 /3billion dataset). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 22206013, 22762946, 25448007, 28063088). Different missense changes at the same codon (p.Arg364Gln, p.Arg364Leu, p.Arg364Pro) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000245944, VCV000572157, VCV000801445 /PMID: 17444508, 20008656 /3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Feb 10, 2025

Neurogenomics Lab, Neuroscience Institute, University Of Cape Town

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

Analysis of variants by whole exome sequencing in previously established disease genes identified a heterozygous variant in exon 11 of the MFN2 gene (p.Arg364Trp, ClinVar VCV000002278.36) which is an established pathogenic variant for autosomal dominant Charcot-Marie-Tooth disease type 2A2 (MONDO:0012231). Sequencing funded by the International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD): https://www.ucl.ac.uk/genomic-medicine-neuromuscular-diseases/. -

Jul 08, 2022

Genetics and Molecular Pathology, SA Pathology

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The MFN2 c.1090C>T variant is classified as PATHOGENIC (PS2, PS4, PP3) The MFN2 c.1090C>T variant is a single nucleotide change in exon 11/19 of the MFN2 gene, which is predicted to change the amino acid arginine at position 364 in the protein to tryptophan. This variant is de novo in this patient (PS2). This variant has been reported in multiple individuals with Charcot-Marie-Tooth disease type 2 (PMID:24819634, PMID:21508331, PMID:28063088) (PS4). this variant has not been reported in dbSNP and is absent from population databases. This variant has been reported in ClinVar as pathogenic for Charcot-Marie-Tooth disease (ClinVar Variation ID: 2278). Other variants affecting this amino acid residue have also been reported as pathogenic suggesting this residue is clinically significant. Computational predictions support a deleterious effect on the gene or gene product (PP3). -

not provided

Pathogenic:3

May 20, 2024

Athena Diagnostics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant has not been reported in large, multi-ethnic general populations. (http://gnomad.broadinstitute.org) This variant has been identified in multiple unrelated individuals with autosomal dominant Charcot-Marie-Tooth disease, including multiple de novo cases, and appears to segregate with disease in at least one family. Assessment of experimental evidence regarding the effect of this variant on protein function is inconclusive (PMID: 25448007, 29898954). At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. -

Jun 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 12, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported multiple times in association with hereditary motor and sensory neuropathy type VI and CMT2A in published literature (Zuchner et al., 2006; Chung et al., 2006; Gowrisankaran et al., 2011); Published functional studies demonstrate a damaging effect (Saporta et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24819634, 16835246, 21707411, 31832804, 21508331, 31211173, 16437557, 22206013, 27549087, 30996168, 30649465, 20587496, 25802885, 22492563, 31673878, 31315766, 33578441, 30569560, 33074106, 33742459, 30830587, 25448007, 28063088, 24863639) -

Charcot-Marie-Tooth disease type 2

Pathogenic:2

May 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 364 of the MFN2 protein (p.Arg364Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Charcot-Marie-Tooth disease type 2A and hereditary motor and sensory neuropathy type VI (PMID: 16437557, 16835246, 21508331, 21707411, 22206013, 22492563, 25448007, 25802885, 27549087, 28063088). ClinVar contains an entry for this variant (Variation ID: 2278). 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%. This variant disrupts the p.Arg364 amino acid residue in MFN2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17444508, 18996695, 20008656, 21508331, 22492563). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Jul 01, 2023

Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Hereditary motor and sensory neuropathy with optic atrophy

Pathogenic:2

Aug 01, 2006

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Aug 22, 2018

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease causing [PMID 16437557, 21707411, 27549087, 25448007, 28063088] -

Charcot-Marie-Tooth disease

Uncertain:1

Aug 14, 2019

Genesis Genome Database

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

- -

Charcot-Marie-Tooth disease type 4

Uncertain:1

Aug 14, 2019

Genesis Genome Database

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.46

BayesDel_addAF

Pathogenic

0.54

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.86

D;D

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Uncertain

0.89

LIST_S2

Pathogenic

0.99

D;.

M_CAP

Pathogenic

0.46

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.0

M;M

PhyloP100

5.1

PrimateAI

Pathogenic

0.85

PROVEAN

Pathogenic

-6.3

D;D

REVEL

Pathogenic

0.86

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

1.0

D;D

Vest4

0.97

MutPred

0.88

Loss of disorder (P = 0.0083);Loss of disorder (P = 0.0083);

MVP

0.97

MPC

1.8

ClinPred

0.99

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.85

gMVP

0.90

Mutation Taster

=4/96

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over