rs140234726

Positions:

chr1-11999028-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PM5PP2

The NM_014874.4(MFN2):c.749G>A(p.Arg250Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000354 in 1,614,068 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R250W) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00037 ( 1 hom. )

Consequence

MFN2
NM_014874.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:8B:1

Conservation

PhyloP100: 6.55

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM1

In a strand (size 2) in uniprot entity MFN2_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) 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 chr1-11999027-C-T is described in Lovd as [Pathogenic].

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MFN2	NM_014874.4 linkuse as main transcript	c.749G>A	p.Arg250Gln	missense_variant	8/19	ENST00000235329.10	NP_055689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MFN2	ENST00000235329.10 linkuse as main transcript	c.749G>A	p.Arg250Gln	missense_variant	8/19	1	NM_014874.4	ENSP00000235329	P1	O95140-1

Frequencies

GnomAD3 genomes

AF:

0.000210

AC:

AN:

152066

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000328

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000323

Gnomad OTH

AF:

0.000959

GnomAD3 exomes

AF:

0.000227

AC:

AN:

251494

Hom.:

AF XY:

0.000213

AC XY:

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000261

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000404

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000369

AC:

539

AN:

1461884

Hom.:

Cov.:

AF XY:

0.000369

AC XY:

268

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000325

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000439

Gnomad4 OTH exome

AF:

0.000265

GnomAD4 genome

AF:

0.000210

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000324

Gnomad4 OTH

AF:

0.000949

Alfa

AF:

0.000346

Hom.:

Bravo

AF:

0.000314

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000288

AC:

EpiCase

AF:

0.000545

EpiControl

AF:

0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:8Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 04, 2023	The p.Arg250Gln variant in MFN2 has been reported in the heterozygous state in 7 individuals with clinical features of Charcot-Marie-Tooth (CMT) disease (Verhoeven 2006 PMID: 16714318, McCorquodale 2011 PMID: 21258814, Sitarz 2012 PMID: 22492563, Antoniadi 2015 PMID: 26392352, Tomaselli 2016 PMID: 26930221, Rudnik-Schoneborn 2016 PMID: 25850958, Volodarsky 2021 PMID: 32376792). This variant was also reported in the compound heterozygous state with another MFN2 variant in 2 siblings with features of CMT disease with earlier disease onset. The variant was determined to be paternally inherited, and the father had not symptoms of neuropathy (Lupo 2016 PMID: 26752306). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 214653) and has been identified in 0.03% (5/15252) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS4, PM2_Supporting. -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 04, 2024	Reported previously in unrelated individuals with Charcot-Marie-Tooth neuropathy type 2A (CMT2A) who were heterozygous for p.(R250Q), although familial segregation was not evaluated for either individual (PMID: 16714318, 21258814, 25850958); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22492563, 30442897, 21258814, 26968897, 25850958, 31827005, 26752306, 32376792, 35399520, 24863639, 23800155, 26930221, 16714318) -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Charcot-Marie-Tooth disease

Uncertain:2

Uncertain significance, no assertion criteria provided	literature only	Inherited Neuropathy Consortium	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, London Health Sciences Centre	-	- -

Charcot-Marie-Tooth disease type 2

Pathogenic:1

Pathogenic, low penetrance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 03, 2024

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 250 of the MFN2 protein (p.Arg250Gln). This variant is present in population databases (rs140234726, gnomAD 0.04%). This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 21258814, 22492563, 25850958, 26930221, 32376792). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant shows reduced penetrance with mild disease symptoms, later onset and some individuals may be asymptomatic (PMID: 26930221, 25850958). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 214653). 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. This variant disrupts the p.Arg250 amino acid residue in MFN2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16714318, 26306937, 28660751, 35922214). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, this variant is reported to cause disease. However, as this variant is associated with a lower penetrance than other pathogenic alleles in the MFN2 gene, it has been classified as Pathogenic (low penetrance). -

MFN2-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 02, 2022

The MFN2 c.749G>A variant is predicted to result in the amino acid substitution p.Arg250Gln. This variant was previously reported in the heterozygous state in individuals who presented with Charcot-Marie-Tooth type 2 or 1 disease (Verhoeven et al. 2006. PubMed ID: 16714318; McCorquodale et al. 2011. PubMed ID: 21258814; Sitarz et al. 2012. PubMed ID: 22492563; Antoniadi et al. 2015. PubMed ID: 26392352, see supplementary table 3, rs140234726). This variant was also detected in an individual with non-ataxic spastic paraplegia and peripheral neuropathy, although the variant did not segregate with disease within the family (Gregianin et al. 2013. PubMed ID: 23800155). Additionally, the c.749G>A variant was reported in the compound heterozygous state in two brothers with early-onset sensory motor neuropathy; the unaffected father harbored this variant in the heterozygous state (Tomaselli et al. 2016. PubMed ID: 26930221). The p.Arg250Gln variant was also described in an affected individual who harbored a likely pathogenic variant in LRSAM1 (Lupo et al. 2016. PubMed ID: 26752306). Taken together, the clinical significance of this variant is classified as uncertain at this time due to the absence of conclusive functional and genetic evidence. We suspect this variant may be benign for autosomal dominant disease, although we cannot rule out the possibility that this variant may be relevant to autosomal recessive inheritance of this disorder. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 04, 2022

The p.R250Q variant (also known as c.749G>A), located in coding exon 6 of the MFN2 gene, results from a G to A substitution at nucleotide position 749. The arginine at codon 250 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in a compound heterozygous state in two siblings with early-onset sensory motor neuropathy (Tomaselli PJ et al. J Peripher Nerv Syst, 2016 Mar;21:52-4), as well as in a heterozygous state in multiple unrelated individuals with Charcot-Marie-Tooth disease (CMT) (Verhoeven K et al. Brain, 2006 Aug;129:2093-102; McCorquodale DS et al. J. Neurol., 2011 Jul;258:1234-9; Sitarz KS et al. Brain, 2012 Aug;135:e219, 1-3; author reply e220, 1-3; Rudnik-Schöneborn S et al. Clin Genet, 2016 Jan;89:34-43). Another alteration at the same codon, p.R250W (c.748C>T), has been described in multiple individuals with phenotypes consistent with CMT disease (Di Meglio C et al. Brain Dev, 2016 May;38:498-506; Piscosquito G et al. J Peripher Nerv Syst, 2015 Dec;20:380-6; Sun B et al. J Peripher Nerv Syst, 2017 03;22:13-18; Verhoeven K et al. Brain, 2006 Aug;129:2093-102). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is unlikely to be causative of autosomal dominant MFN2-related neuropathy; however, its contribution to the development of autosomal recessive MFN2-related neuropathy is uncertain. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

May 25, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Uncertain

0.086

BayesDel_noAF

Pathogenic

0.20

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.61

D;D

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.97

D;.

M_CAP

Uncertain

0.25

MetaRNN

Uncertain

0.50

T;T

MetaSVM

Uncertain

0.72

MutationAssessor

Benign

0.23

N;N

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-1.1

N;N

REVEL

Pathogenic

0.71

Sift

Benign

0.032

D;D

Sift4G

Uncertain

0.0080

D;D

Polyphen

0.83

P;P

Vest4

0.63

MVP

0.91

MPC

1.2

ClinPred

0.11

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.55

gMVP

0.86

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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