chr1-11998877-C-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP2PP3PP5

The NM_014874.4(MFN2):c.707C>T(p.Thr236Met) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,554 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T236T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

MFN2
NM_014874.4 missense, splice_region

Scores

Splicing: ADA: 0.9807

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:2

Conservation

PhyloP100: 7.54

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM1

In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_014874.4

PM2

Very rare variant in population databases, with high coverage;

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

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

PP5

Variant 1-11998877-C-T is Pathogenic according to our data. Variant chr1-11998877-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 217165.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=4, Uncertain_significance=1, Pathogenic=1}. Variant chr1-11998877-C-T is described in Lovd as [Pathogenic]. Variant chr1-11998877-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MFN2	NM_014874.4 link	c.707C>T	p.Thr236Met	missense_variant, splice_region_variant	Exon 7 of 19	ENST00000235329.10	NP_055689.1	O95140-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MFN2	ENST00000235329.10 link	c.707C>T	p.Thr236Met	missense_variant, splice_region_variant	Exon 7 of 19	1	NM_014874.4	ENSP00000235329.5		O95140-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000795

AC:

AN:

251478

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461554

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727118

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:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:2Uncertain:1

Nov 25, 2020

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported as heterozygous in an individual with Charcot-Marie-Tooth disease who was also heterozygous for a de novo variant in the GDAP1 gene; the variant in MFN2 was also present in the asymptomatic mother and the maternal grandfather with adult onset neuropathy (Kostera-Pruszczyk et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 32963807, 15549395, 25403865, 30373780, 30340945) -

Sep 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MFN2: PM1, PM2, PS4:Moderate -

Jun 02, 2020

Department of Paediatrics and Adolescent Medicine, The University of Hong Kong

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

By the ACMG guideline 2015, this variant is classified as likely pathogenic (PM1, PM2, PP2, PP3) with multiple affected individuals reported. Our patient does not habour typical features of Charcot Marie Tooth disease or neuropathy. Rather, he presented with other neurological issues such as intellectual disability, behavioural problems and seizure. -

Charcot-Marie-Tooth disease type 2A2

Pathogenic:1

Jan 29, 2013

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Charcot-Marie-Tooth disease type 2

Pathogenic:1

Mar 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 236 of the MFN2 protein (p.Thr236Met). This variant is present in population databases (rs773159585, gnomAD 0.01%). This missense change has been observed in individuals with Charcot-Marie-Tooth disease (PMID: 15549395, 25403865, 33110000; Invitae). ClinVar contains an entry for this variant (Variation ID: 217165). 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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Distal muscle weakness;C1263857:Peripheral axonal neuropathy;C1836451:Distal lower limb amyotrophy

Pathogenic:1

Jun 04, 2014

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Charcot-Marie-Tooth disease

Uncertain:1

Aug 14, 2019

Genesis Genome Database

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.47

BayesDel_addAF

Pathogenic

0.53

BayesDel_noAF

Pathogenic

0.52

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.90

D;D

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

D;.

M_CAP

Pathogenic

0.44

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Pathogenic

0.88

MutationAssessor

Uncertain

2.3

M;M

PrimateAI

Pathogenic

0.79

PROVEAN

Pathogenic

-5.0

D;D

REVEL

Pathogenic

0.90

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.0050

D;D

Polyphen

0.82

P;P

Vest4

0.88

MutPred

0.86

Loss of disorder (P = 0.1205);Loss of disorder (P = 0.1205);

MVP

0.99

MPC

1.6

ClinPred

0.98

GERP RS

4.9

Varity_R

0.83

gMVP

0.91

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.98

dbscSNV1_RF

Pathogenic

0.73

SpliceAI score (max)

0.080

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