rs28940293

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP2PP3PP5_Very_Strong

The NM_014874.4(MFN2):c.227T>C(p.Leu76Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,614,100 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. L76R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

MFN2
NM_014874.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 1.89

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 14 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_014874.4

PM2

Very rare variant in population databases, with high coverage;

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, 0.791

PP5

Variant 1-11992606-T-C is Pathogenic according to our data. Variant chr1-11992606-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 2270.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-11992606-T-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.227T>C	p.Leu76Pro	missense_variant	4/19	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.227T>C	p.Leu76Pro	missense_variant	4/19	1	NM_014874.4	ENSP00000235329.5		O95140-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461894

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 02, 2024	Reported as a common pathogenic variant in individuals with Charcot-Marie-Tooth (PMID: 25614874, 19584314); Segregates with disease in affected individuals in a family with CMT2A characterized by severe distal weakness and atrophy with mild distal sensory loss, proximal muscle strength was reported as normal and the age of onset ranged from 7 to 44 years (PMID: 15064763, 10732809); Reported previously as a pathogenic variant in a patient with neuropathy; however, no other clinical information was provided (PMID: 31701603); Functional studies suggest the L76P variant results in mitochondrial aggregation and altered mitochondrial mobility and morphology (PMID: 17215403, 26968460, 29898954); 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: 17296794, 26143526, 10732809, 33049996, 26968460, 20335458, 19584314, 22957060, 16714318, 29898954, 31127728, 9333264, 28380071, 31096646, Yenkin2022[FunctionalStudy], 15064763, 17215403, 25614874, 31701603, 36098092) -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 21, 2019	PS3, PS4, PM2, PP1 -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 28, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 29, 2022	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features of Charcot-Marie-Tooth disease. This variant occurs as the most likely explanation for disease in a significant number of internal cases, suggesting this variant is associated with disease. Assessment of experimental evidence suggests this variant results in abnormal protein function. Studies demonstrate significant changes to mitochondrial function in various model systems (PMID: 20335458, 26968460, 29898954). The variant is located in a region that is considered important for protein function and/or structure. -

Charcot-Marie-Tooth disease type 2A2

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 2004

- -

Charcot-Marie-Tooth disease type 2

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 12, 2023

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 76 of the MFN2 protein (p.Leu76Pro). 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: 10732809, 15064763, 16714318, 25614874). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2270). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.51

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.36

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.52

D;D;.

Eigen

Benign

0.18

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.84

T;.;T

M_CAP

Pathogenic

0.42

MetaRNN

Pathogenic

0.79

D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Benign

1.9

L;L;.

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-1.7

N;N;D

REVEL

Pathogenic

0.72

Sift

Benign

0.26

T;T;T

Sift4G

Benign

0.28

T;T;T

Polyphen

0.74

P;P;.

Vest4

0.75

MutPred

0.73

Gain of disorder (P = 0.0109);Gain of disorder (P = 0.0109);Gain of disorder (P = 0.0109);

MVP

0.98

MPC

1.2

ClinPred

0.66

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.84

gMVP

0.93

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