1-11996158-C-T

Position:

chr1-11996158-C-T

Variant summary

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

The NM_014874.4(MFN2):c.314C>T(p.Thr105Met) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T105R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

MFN2
NM_014874.4 missense, splice_region

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 7.57

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:

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ACMG classification

Classification made for transcript

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, 7 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 chr1-11996157-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 543234.Status of the report is criteria_provided_single_submitter, 1 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, 0.958

PP5

Variant 1-11996158-C-T is Pathogenic according to our data. Variant chr1-11996158-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 214652.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-11996158-C-T 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.314C>T	p.Thr105Met	missense_variant, splice_region_variant	5/19	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.314C>T	p.Thr105Met	missense_variant, splice_region_variant	5/19	1	NM_014874.4	ENSP00000235329.5		O95140-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease type 2A2

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Sep 01, 2022	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: 0.94; 3Cnet: 0.98). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000214652). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 16043786 , 21508331 , 26801520 , 27100445). Different missense changes at the same codon (p.Thr105Ala, p.Thr105Arg, p.Thr105Ser) have been reported to be associated with MFN2 -related disorder (ClinVar ID: VCV000543234 / PMID: 22492563 , 24126688 , 28660751). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant p.T105M in MFN2 (NM_014874.4) has been previously reported in affected families (Lawson VH et al,Wang C et al). Functional studies indicate a damaging effect (Amiott EA et al).The p.T105M variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.T105M missense variant is predicted to be damaging by both SIFT and PolyPhen2. The threonine residue at codon 105 of MFN2 is conserved in all mammalian species. The nucleotide c.314 in MFN2 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -
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	- -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Centre for Clinical Genetics and Genomic Diagnostics, Zealand University Hospital	Aug 19, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 19, 2014	- -

Charcot-Marie-Tooth disease type 2

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 105 of the MFN2 protein (p.Thr105Met). 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: 15064763, 16043786, 16835246, 21508331, 24957169, 27100445). 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: 214652). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on MFN2 function (PMID: 17296794, 17959936, 18316077, 19812251). For these reasons, this variant has been classified as Pathogenic. -

Cerebellar ataxia

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genome Medicine, Institute for Basic Research in Developmental Disabilities

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.57

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.88

D;D

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.99

D;.

M_CAP

Pathogenic

0.52

MetaRNN

Pathogenic

0.96

D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.5

H;H

PrimateAI

Uncertain

0.79

PROVEAN

Pathogenic

-5.5

D;D

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.85

MutPred

0.81

Gain of MoRF binding (P = 0.0657);Gain of MoRF binding (P = 0.0657);

MVP

0.99

MPC

1.8

ClinPred

1.0

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.79

gMVP

0.90

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