rs119103268

Positions:

• chr1-11992689-C-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_014874.4(MFN2):​c.310C>T​(p.Arg104Trp) variant causes a missense, splice region 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. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R104L) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: MFN2 NM_014874.4 missense, splice_region
• Scores: Splicing: ADA: 0.03669
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:17
• Conservation: PhyloP100: 3.54

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

• PM1: In a hotspot region, there are 6 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 chr1-11992690-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 637289.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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, 0.982
• PP5: Variant 1-11992689-C-T is Pathogenic according to our data. Variant chr1-11992689-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 2281.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-11992689-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MFN2	NM_014874.4	c.310C>T	p.Arg104Trp	missense_variant, splice_region_variant	4/19	ENST00000235329.10	NP_055689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MFN2	ENST00000235329.10	c.310C>T	p.Arg104Trp	missense_variant, splice_region_variant	4/19	1	NM_014874.4	ENSP00000235329.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:17

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter	clinical testing	CMT Laboratory, Bogazici University	Dec 01, 2020	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 09, 2008	- -
Pathogenic, criteria provided, single submitter	research	Laboratório de Neurologia Aplicada e Experimental, Faculdade de Medicina de Ribeirao Preto – Universidade de Sao Paulo	Jul 20, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Institute of Human Genetics, Cologne University	Apr 25, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 13, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Feb 23, 2023	The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.93; 3Cnet: 1.00). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000002281). Different missense changes at the same codon (p.Arg104Gln, p.Arg104Leu) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000214651, VCV000637289). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Charcot-Marie-Tooth disease Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, London Health Sciences Centre	-	- -
Pathogenic, no assertion criteria provided	research	Dept. of Medical Genetics, Telemark Hospital Trust, Telemark Hospital Trust	Nov 01, 2013	- -

Hereditary motor and sensory neuropathy with optic atrophy Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 09, 2008	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Sep 04, 2019	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM1,PM2,PM5,PP3. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 14, 2022	Not observed 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: 18425620, 26307494, 25025039, 30442897, 21840889, 21531138, 18946002, 30340945, 33851411, 34169998, 24863639) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 01, 2017	- -

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

May 18, 2017

- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 06, 2021

The p.R104W pathogenic mutation (also known as c.310C>T), located in coding exon 2 of the MFN2 gene, results from a C to T substitution at nucleotide position 310. The arginine at codon 104 is replaced by tryptophan, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. The p.R104W alteration has been reported in multiple patients with Charcot-Marie-Tooth disease (Brockmann K et al. J Neurol, 2008 Jul;255(7):1049-58; Baets J et al. Brain, 2011 Sep;134:2664-76; Genari AB et al. Neuromuscul Disord, 2011 Jun;21:428-32; Høyer H et al. Biomed Res Int, 2014 Jun;2014:210401). Another alteration at the same codon, p.R104Q (c.311G>A), has been described in a patient with Charcot-Marie-Tooth (Bombelli F et al. JAMA Neurol, 2014 Aug;71:1036-42). The p.R104W amino acid is located in the GTPase domain which is required for mitochondrial membrane fusion reaction, and multiple alterations in this region have been reported (Amiott EA et al. Exp Neurol, 2008 May;211:115-27; Ando M et al. J Peripher Nerv Syst, 2017 09;22:191-199). Based on the supporting evidence, this variant is expected to be causative of autosomal dominant Charcot-Marie-Tooth disease (CMT) type 2A2A and hereditary motor and sensory neuropathy VIA; however, its clinical significance for autosomal recessive Charcot-Marie-Tooth disease (CMT) type 2A2B is unclear. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 13, 2023

- -

Charcot-Marie-Tooth disease type 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 25, 2023

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 104 of the MFN2 protein (p.Arg104Trp). 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: 18425620, 18946002, 18957892, 20008656, 21531138, 21840889, 25025039). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2281). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.Arg104 amino acid residue in MFN2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22492563). 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

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 13, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;D
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.97	D;.
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.5	H;H
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-7.4	D;D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.95
MutPred		0.85		Loss of disorder (P = 0.0255);Loss of disorder (P = 0.0255);
MVP		0.98
MPC		1.8
ClinPred		1.0	D
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.95
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.037
dbscSNV1_RF	Benign	0.27
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

Other links and lift over

dbSNP: rs119103268; hg19: chr1-12052746;