1-11992659-C-T

Variant names:

• chr1-11992659-C-T
• rs119103263
• NM_014874.4:c.280C>T

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_014874.4(MFN2):​c.280C>T​(p.Arg94Trp) variant causes a missense change involving the alteration of a non-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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R94P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: MFN2 NM_014874.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:22
• Conservation: PhyloP100: 3.14
• Publications: 52 publications found

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

ACMG classification

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

• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 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 chr1-11992659-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 637495.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, 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, 0.966
• PP5: Variant 1-11992659-C-T is Pathogenic according to our data. Variant chr1-11992659-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 2276.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	c.280C>T	p.Arg94Trp	missense_variant	Exon 4 of 19	ENST00000235329.10	NP_055689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MFN2	ENST00000235329.10	c.280C>T	p.Arg94Trp	missense_variant	Exon 4 of 19	1	NM_014874.4	ENSP00000235329.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:22

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:8

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 12, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MFN2 c.280C>T; p.Arg94Trp has been reported multiple times in patients diagnosed with CMT disease (Zuchner 2004, Zuchner 2006, Cho 2007, Brožková 2013, Lassuthová 2016), and is classified as pathogenic in ClinVar (ID 2276). Functional studies have found defects in mitochondrial function in mice expressing this variant (Strickland 2014). Another variant affecting this amino acid (Arg94Gln) has also been demonstrated to be pathogenic (Zuchner 2005). This variant is absent from the general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database). Based on the available information, the p.Arg94Trp variant is classified as pathogenic. -

Jun 01, 2022

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been identified in multiple unrelated individuals with Charcot-Marie-Tooth disease including at least one confirmed de novo. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. Assessment of experimental evidence suggests this variant results in abnormal protein function. Studies show this variant inhibits mitochondrial fusion (PMID: 17296794, 24862862, 26085578). The variant is located in a region that is considered important for protein function and/or structure. -

-

Clinical Genetics, Academic Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 23, 2019

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 31, 2014

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 23, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect; mouse model expressing R94W showed mild peripheral neuropathy (Strickland et al., 2014); Different missense changes at this residue (R94P, R94Q, R94G) have been reported as pathogenic/likely pathogenic in the published literature and in the Human Gene Mutation Database in association with MFN2-related disorders (Stenson et al., 2014); Not observed at significant frequency in large population cohorts (Lek et al., 2016); 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: 16714318, 16835246, 24126688, 15064763, 27549087, 31832804, 31130284, 32376792, 33841295, 24863639, 16437557, 25025039, 24862862) -

Charcot-Marie-Tooth disease type 2A2 Pathogenic:6

Dec 05, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

We found this variant in a 34-year-old female with childhood onset CMT at heterozygous state. -

Sep 27, 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: 24862862). In silico tool predictions suggest a damaging effect of the variant on gene or gene product [REVEL: 0.93 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 1.00 (>=0.6, sensitivity 0.72 and precision 0.9)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000002276 /PMID: 16437557 /3billion dataset). The variant has been previously reported as de novo in a similarly affected individual (PMID: 26686600). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 16437557, 19889647, 24126688, 26686600, 27549087). Different missense changes at the same codon (p.Arg94Gln, p.Arg94Gly, p.Arg94Leu, p.Arg94Pro) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000002268, VCV000637495 /PMID: 15064763, 21508331, 24819634, 33415332 /3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PS3_Moderate+PP2+PS4+PS2_VeryStrong -

Dec 13, 2023

Baylor Genetics

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

- -

Aug 01, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Hereditary motor and sensory neuropathy with optic atrophy Pathogenic:2

Jan 01, 2016

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Pathogenic. -

Aug 01, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Charcot-Marie-Tooth disease Pathogenic:1

-

Molecular Genetics Laboratory, London Health Sciences Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Pathogenic:1

Feb 15, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.280C>T (p.R94W) alteration is located in exon 4 (coding exon 2) of the MFN2 gene. This alteration results from a C to T substitution at nucleotide position 280, causing the arginine (R) at amino acid position 94 to be replaced by a tryptophan (W). _x000D_ _x000D_ Based on the available evidence, the MFN2 c.280C>T (p.R94W) 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 (Nguyen-Le, 2022; Volodarsky, 2021; Charif, 2021; Wu, 2021; Lin, 2020; Rasheed, 2020; Monies, 2019; Di Meglio, 2016; Xie, 2016; Choi, 2015; Broková, 2014; Feely, 2011; Casasnovas, 2010; Zuchner, 2006; Verhoeven, 2006; Züchner, 2004). This amino acid position is highly conserved in available vertebrate species. Functional studies indicate this alteration impairs mitochondrial fusion (Detmer, 2007; Strickland, 2014; Sawyer, 2015; Sloat, 2019). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Scarring;C0162834:Hyperpigmentation of the skin;C0221260:Nail dystrophy;C0262444:Abnormality of the dentition;C0349588:Short stature;C0427065:Distal muscle weakness;C0476403:EMG abnormality;C0574769:Alopecia of scalp;C2132198:Abnormal blistering of the skin;C2315100:Failure to thrive;C3806301:Scarring alopecia of scalp;C4021800:Abnormal dental enamel morphology;C4551563:Microcephaly;C5574742:Decreased body weight Pathogenic:1

May 07, 2015

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2a2b; Pathogenic:1

Dec 13, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Charcot-Marie-Tooth disease type 2 Pathogenic:1

Oct 10, 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 94 of the MFN2 protein (p.Arg94Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 16437557, 16835246, 19889647, 24126688). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 2276). 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) indicates that this missense variant is expected to disrupt MFN2 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects MFN2 function (PMID: 24862862). This variant disrupts the p.Arg94 amino acid residue in MFN2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15064763, 21285398, 22442078, 24604904). 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. -

Neuropathy, hereditary motor and sensory, type 6A Pathogenic:1

Dec 13, 2023

Baylor Genetics

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	0.96
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D;D;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.99	D;.;D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	M;M;.
PhyloP100		3.1
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-7.2	D;D;D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.84
MutPred		0.85		Gain of catalytic residue at M97 (P = 0.0043);Gain of catalytic residue at M97 (P = 0.0043);Gain of catalytic residue at M97 (P = 0.0043);
MVP		0.98
MPC		1.8
ClinPred		0.99	D
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.88
gMVP		0.92
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs119103263; hg19: chr1-12052716;