1-12002069-A-G

Position:

• chr1-12002069-A-G

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.1126A>G​(p.Met376Val) variant causes a missense 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. 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. M376L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MFN2 NM_014874.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 8.95

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 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 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 chr1-12002070-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 637292.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, 0.965
• PP5: Variant 1-12002069-A-G is Pathogenic according to our data. Variant chr1-12002069-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 217161.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-12002069-A-G is described in Lovd as [Pathogenic]. Variant chr1-12002069-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MFN2	NM_014874.4	c.1126A>G	p.Met376Val	missense_variant	11/19	ENST00000235329.10	NP_055689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MFN2	ENST00000235329.10	c.1126A>G	p.Met376Val	missense_variant	11/19	1	NM_014874.4	ENSP00000235329.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 08, 2024	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22926664, 22492563, 23381770, 26801520, 24473995, 19889647, 28251916, 30649465, 34721278, 34758253, 37910431, Lagos2021[Abstract], 34255403, 26094742, 22851605, 38549004) -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 05, 2021	This variant was not reported in large, multi-ethnic, general populations (http://gnomad.broadinstitute.org). This variant appears to occur de novo in multiple individuals with clinical features associated with this gene. Assessment of experimental evidence regarding the effect of this variant on protein function is inconclusive. Although there were changes to ER-mitochondrial connectivity and mitochondria-associated ER membranes (MAM) function, this study used patient-derived cells and results could be influenced by factors other than this variant (PMID: 30649465). -

Charcot-Marie-Tooth disease type 2A2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

3billion

Mar 22, 2022

Same or different nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000217161). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 19889647, 22926664, 26801520, 22492563, 22851605, 28251916). Different missense changes at the same codon have been reported to be associated with MFN2 related disorder (PMID:16835246,24957169,16762064). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.794>=0.6, 3CNET: 0.806>=0.75). A missense variant is a common mechanism. It is not observed in the gnomAD v2.1.1 dataset. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

MFN2-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 18, 2023

The MFN2 c.1126A>G variant is predicted to result in the amino acid substitution p.Met376Val. This variant was reported in several individuals with autosomal dominant Charcot-Marie-Tooth disease (Casasnovas et al 2010. PubMed ID: 19889647; Vielhaber S et al 2012. PubMed ID: 22926664; Nightingale H et al 2014. PubMed ID: 24473995) including at least one instance of it occurring de novo in a patient (Supp. Table 1 in Bansagi B et al 2017. PubMed ID: 28251916). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 12, 2019

The p.M376V variant (also known as c.1126A>G), located in coding exon 9 of the MFN2 gene, results from an A to G substitution at nucleotide position 1126. The methionine at codon 376 is replaced by valine, an amino acid with highly similar properties. This variant has been identified de novo in an individual with MFN2-related neuropathy (Bansagi B et al. Neurology, 2017 Mar;88:1226-1234). This alteration has also been identified in multiple individuals with phenotype consistent with MFN2-related neuropathy (Casasnovas C et al. J. Med. Genet., 2010 Apr;47:249-56; Vielhaber S et al. Acta Neuropathol., 2013 Feb;125:245-56; Nightingale H et al. BMJ, 2014 Jan;348:g459). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Hereditary motor and sensory neuropathy with optic atrophy Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Genomics England Pilot Project, Genomics England

-

- -

Charcot-Marie-Tooth disease type 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 23, 2023

ClinVar contains an entry for this variant (Variation ID: 217161). This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 376 of the MFN2 protein (p.Met376Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant Charcot-Marie-Tooth disease (PMID: 19889647, 22492563, 22851605, 22926664, 24473995, 26801520, 28251916). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MFN2 protein function. This variant disrupts the p.Met376 amino acid residue in MFN2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24957169). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.64	D;D
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.79	T;.
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Uncertain	0.74	D
MutationAssessor	Uncertain	2.5	M;M
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-2.5	N;N
REVEL	Pathogenic	0.79
Sift	Benign	0.039	D;D
Sift4G	Benign	0.092	T;T
Polyphen		0.21	B;B
Vest4		0.85
MutPred		0.88		Gain of sheet (P = 0.0125);Gain of sheet (P = 0.0125);
MVP		0.99
MPC		1.7
ClinPred		0.91	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.59
gMVP		0.88

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

Other links and lift over

dbSNP: rs863224967; hg19: chr1-12062126;