chr1-12001423-G-A

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_014874.4(MFN2):​c.839G>A​(p.Arg280His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,472 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging 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. R280C) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

MFN2
NM_014874.4 missense

Scores

15
3
1

Clinical Significance

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

Conservation

PhyloP100: 9.60
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 19 ACMG points.

PM1
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 11 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 chr1-12001422-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 245809.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
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, 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, 0.983
PP5
Variant 1-12001423-G-A is Pathogenic according to our data. Variant chr1-12001423-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 2271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-12001423-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MFN2NM_014874.4 linkc.839G>A p.Arg280His missense_variant Exon 9 of 19 ENST00000235329.10 NP_055689.1 O95140-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MFN2ENST00000235329.10 linkc.839G>A p.Arg280His missense_variant Exon 9 of 19 1 NM_014874.4 ENSP00000235329.5 O95140-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000400
AC:
1
AN:
250290
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135432
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000884
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1461472
Hom.:
0
Cov.:
32
AF XY:
0.00000275
AC XY:
2
AN XY:
727024
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:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.00000824
AC:
1
EpiCase
AF:
0.00
EpiControl
AF:
0.0000594

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:15
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease type 2A2 Pathogenic:6
Aug 01, 2006
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

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 07, 2021
MGZ Medical Genetics Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 23, 2023
3billion, Medical Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.92; 3Cnet: 0.97). Same nucleotide change resulting in same amino acid change (ClinVar ID: VCV000002271) and different missense changes at the same codon (p.Arg280Cys, p.Arg280Pro / ClinVar ID: VCV000245809, VCV000801444) have been previously reported as pathogenic/likely pathogenic with strong evidence. Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Jun 01, 2022
Solve-RD Consortium
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: provider interpretation

Variant confirmed as disease-causing by referring clinical team -

May 22, 2024
Neurogenomics Lab, Neuroscience Institute, University Of Cape Town
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

PM2_supporting: The highest population allele frequency in gnomAD v4.0 is 0.00001160 (0.001%; 1/86188 alleles) in South asian population and 0.000001799 (0.0001%; 2/1111878) in the European non-Finnish population. PP1_strong: variant segregates with =3 informative meioses across =1 family (PMID: 16835246, 16714318, 24957169). PM1 met: variant occurs in the dynamin-like GTPase domain together with other pathogenic variants. PP3_moderate: Revel score is 0.92. PS3_supporting: functional studies provide supportive evidence that this variant has a damaging effect on the gene or gene product (PMID 17296794, PMID 17215403). PS4 met: variant identified in = 10 unrelated probands with consistent phenotype for disorder. PM5 met: MFN2 p.Arg280Pro classified as likely pathogenic. -

not provided Pathogenic:4
Mar 27, 2023
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Published functional studies show that R280H alters mitochondrial fusion (Detmer et al., 2007); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16835246, 22492563, 21149811, 17296794, 31832804, 32657593, 35153971, 30340945, 16714318, 19584314, 17215403, 10732809, 28286897, 27549087, 27863451, 28660751, 24957169, 27027447, 27088055, 30219582, 31211173, 31827005, 15064763, 33136338, 32376792, 35418194, 24863639) -

Oct 23, 2020
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jul 01, 2021
CeGaT Center for Human Genetics Tuebingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Sep 27, 2022
Athena Diagnostics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The frequency of this variant in the general population is consistent with pathogenicity. (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)) This variant has been identified in multiple unrelated individuals with clinical features associated with Charcot-Marie-Tooth disease and appears to be associated with disease in at least one family. This variant appears to occur de novo in multiple individuals with clinical features associated with Charcot-Marie-Tooth disease. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant inhibited mitochondrial fusion and caused abnormal clustering (PMID: 17215403, 17296794). The variant is located in a region that is considered important for protein function and/or structure. -

Charcot-Marie-Tooth disease Pathogenic:2
-
Inherited Neuropathy Consortium
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

-
Molecular Genetics Laboratory, London Health Sciences Centre
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Peripheral neuropathy Pathogenic:1
Jul 10, 2021
Kariminejad - Najmabadi Pathology & Genetics Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Charcot-Marie-Tooth disease type 2 Pathogenic:1
Dec 18, 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 histidine, which is basic and polar, at codon 280 of the MFN2 protein (p.Arg280His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with Charcot-Marie-Tooth disease (PMID: 15064763, 16835246, 24957169, 27088055, 27549087). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2271). Invitae Evidence 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 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). For these reasons, this variant has been classified as Pathogenic. -

Neuropathy, hereditary motor and sensory, type 6A Pathogenic:1
Jun 28, 2022
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.91
BayesDel_addAF
Pathogenic
0.55
D
BayesDel_noAF
Pathogenic
0.55
CADD
Pathogenic
33
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.74
D;D
Eigen
Pathogenic
0.88
Eigen_PC
Pathogenic
0.82
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
0.99
D;.
M_CAP
Pathogenic
0.36
D
MetaRNN
Pathogenic
0.98
D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.2
M;M
PrimateAI
Uncertain
0.71
T
PROVEAN
Pathogenic
-4.7
D;D
REVEL
Pathogenic
0.92
Sift
Pathogenic
0.0
D;D
Sift4G
Uncertain
0.0040
D;D
Polyphen
1.0
D;D
Vest4
0.93
MutPred
0.91
Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);
MVP
0.97
MPC
1.6
ClinPred
1.0
D
GERP RS
5.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.86
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.

Other links and lift over

dbSNP: rs28940294; hg19: chr1-12061480; COSMIC: COSV52420899; API