rs28940292

Positions:

chr1-12011510-G-C

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_Very_Strong

The NM_014874.4(MFN2):c.2219G>C(p.Trp740Ser) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W740C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

MFN2
NM_014874.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12U:1

Conservation

PhyloP100: 7.74

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 links:

MFN2 (HGNC:):

MFN2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 17 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 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 chr1-12011511-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 408331.Status of the report is criteria_provided_single_submitter, 1 stars.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MFN2. . Gene score misZ 1.6575 (greater than the threshold 3.09). Trascript score misZ 3.2174 (greater than threshold 3.09). GenCC has associacion of gene with Charcot-Marie-Tooth disease type 2A2, axonal hereditary motor and sensory neuropathy, hereditary motor and sensory neuropathy type 6, Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2a2b;, multiple symmetric lipomatosis, severe early-onset axonal neuropathy due to MFN2 deficiency.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.887

PP5

Variant 1-12011510-G-C is Pathogenic according to our data. Variant chr1-12011510-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2269.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-12011510-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MFN2	NM_014874.4 linkuse as main transcript	c.2219G>C	p.Trp740Ser	missense_variant	19/19	ENST00000235329.10	NP_055689.1	O95140-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MFN2	ENST00000235329.10 linkuse as main transcript	c.2219G>C	p.Trp740Ser	missense_variant	19/19	1	NM_014874.4	ENSP00000235329.5		O95140-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 16, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 19, 2023	This variant has been identified in multiple unrelated individuals with clinical features associated with Charcot-Marie-Tooth disease. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Assessment of experimental evidence suggests this variant results in abnormal protein function. PMID: 17215403, 20335458. -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 29, 2021	PS3, PS4, PM2, PP1, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 18, 2024	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26143526, 21508331, 31156446, 24088041, 31827005, 17296794, 16714318, 17215403, 18568013, 24819634, 15064763, 24126688, 26257172, 8406488, 29790872, 30649465, 29341354, 29361379, 23806086, 32399692, 25614874, 20335458, 37536398, Barsa2024[functionalstudy]) -

Charcot-Marie-Tooth disease type 2A2

Pathogenic:3

Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Apr 13, 2017	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2004	- -
Pathogenic, criteria provided, single submitter	research	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	Aug 18, 2015	This variant has been previously reported as disease-causing and was found in a 31 yo patient with axonal neuropathy -

not specified

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Aug 17, 2018

The MFN2 c.2219G>C; p.Trp740Ser variant (rs28940292), is reported in the literature in multiple individuals affected with Charcot-Marie-Tooth disease type 2 (Brozkova 2013, DiVincenzo 2014, Feely 2011, Gonzaga-Jauregui 2015, Verhoeven 2006, Zuchner 2004). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 2269), and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. Functional analyses of the variant protein in heterologous cell types shows no impact on mitochondrial fusion or oxidative activity (Baloh 2007, Detmer 2007). However, microtubule-assisted mitochondrial transport is severely impaired in neurons expressing the variant protein (Baloh 2007, Misko 2010). The tryptophan at codon 740 is highly conserved, but computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, the variant is predicted to extend the coiled-coil domain at the C-terminal (Zuchner 2004). Based on available information, the p.Trp740Ser variant is considered to be pathogenic. References: Baloh R et al. Altered axonal mitochondrial transport in the pathogenesis of Charcot-Marie-Tooth disease from mitofusin 2 mutations. J Neurosci. 2007; 27(2):422-30. Brozkova D et al. Spectrum and frequencies of mutations in the MFN2 gene and its phenotypical expression in Czech hereditary motor and sensory neuropathy type II patients. Mol Med Rep. 2013; 8(6):1779-84. Detmer S et al. Complementation between mouse Mfn1 and Mfn2 protects mitochondrial fusion defects caused by CMT2A disease mutations. J Cell Biol. 2007; 176(4):405-14. DiVincenzo C et al. The allelic spectrum of Charcot-Marie-Tooth disease in over 17,000 individuals with neuropathy. Mol Genet Genomic Med. 2014 Nov;2(6):522-9. Feely S et al. MFN2 mutations cause severe phenotypes in most patients with CMT2A. Neurology. 2011; 76(20):1690-6. Gonzaga-Jauregui C et al. Exome Sequence Analysis Suggests that Genetic Burden Contributes to Phenotypic Variability and Complex Neuropathy. Cell Rep. 2015; 12(7):1169-83. Misko A et al. Mitofusin 2 is necessary for transport of axonal mitochondria and interacts with the Miro/Milton complex. J Neurosci. 2010; 30(12):4232-40. Verhoeven K et al. MFN2 mutation distribution and genotype/phenotype correlation in Charcot-Marie-Tooth type 2. Brain. 2006; 129(Pt 8):2093-102. Zuchner S et al. Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A. Nat Genet. 2004; 36(5):449-51. -

MFN2-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Variantyx, Inc.

Nov 07, 2022

This is a nonsynonymous variant in the MFN2 gene (OMIM 608507). Pathogenic variants in this gene have been associated with autosomal dominant and autosomal recessive MFN2-related disorders. This variant has been reported in several affected unrelated individuals (PMID: 15064763, 16714318, 21508331, 24126688, 25614874, 29341354, 33415332) (PS4_Moderate). Functional studies have shown that this variant alters MFN2 protein function (PMID: 17215403, 17296794, 20335458) (PS3). This variant lies within a known hotspot for pathogenic variants or a well-established critical functional domain of the MFN2 protein (PMID: 29068134) (PM1). This variant is absent from control populations (https://gnomad.broadinstitute.org/) (PM2_Supporting). Multiple computational algorithms predict a deleterious effect for this substitution (PP3). Based on current evidence, this variant is classified as pathogenic for MFN2- related disorders. -

Hereditary motor and sensory neuropathy with optic atrophy;C4310725:Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2a2b;;C4721887:Charcot-Marie-Tooth disease type 2A2

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 09, 2021

The c.2219G>C (p.W740S) alteration is located in exon 19 (coding exon 17) of the MFN2 gene. This alteration results from a G to C substitution at nucleotide position 2219, causing the tryptophan (W) at amino acid position 740 to be replaced by a serine (S)._x000D_ _x000D_ Based on the available evidence, the MFN2 c.2219G>C (p.W740S) alteration is classified as pathogenic for autosomal dominant MFN2-related neuropathy; however, its clinical significance for autosomal recessive MFN2-related neuropathy is unclear. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been detected in heterozygous state in multiple individuals with neuropathy (Züchner, 2004; Broková, 2013; Gonzaga-Jauregui, 2015). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Charcot-Marie-Tooth disease type 2

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 16, 2024

This sequence change replaces tryptophan, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 740 of the MFN2 protein (p.Trp740Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Charcot-Marie-Tooth disease (PMID: 15064763, 16714318, 21508331, 24126688, 25614874). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2269). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MFN2 protein function. Experimental studies have shown that this missense change affects MFN2 function (PMID: 17215403, 17296794, 20335458). For these reasons, this variant has been classified as Pathogenic. -

Charcot-Marie-Tooth disease

Uncertain:1

Uncertain significance, no assertion criteria provided

research

Genesis Genome Database

Aug 14, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.48

BayesDel_noAF

Pathogenic

0.45

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.81

D;D

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.80

T;.

M_CAP

Uncertain

0.20

MetaRNN

Pathogenic

0.89

D;D

MetaSVM

Uncertain

0.58

MutationAssessor

Benign

1.9

L;L

PrimateAI

Pathogenic

0.80

PROVEAN

Pathogenic

-4.5

D;D

REVEL

Pathogenic

0.84

Sift

Benign

0.11

T;T

Sift4G

Benign

0.24

T;T

Polyphen

0.35

B;B

Vest4

0.82

MutPred

0.72

Gain of disorder (P = 0);Gain of disorder (P = 0);

MVP

0.98

MPC

1.0

ClinPred

0.97

GERP RS

5.3

Varity_R

0.67

gMVP

0.78

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over