1-11997316-A-G

Variant names:

• chr1-11997316-A-G
• rs863224970
• NM_014874.4:c.494A>G

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.494A>G​(p.His165Arg) 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H165L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MFN2 NM_014874.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 8.94
• Publications: 9 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 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 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 chr1-11997315-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 439897.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, 0.972
• PP5: Variant 1-11997316-A-G is Pathogenic according to our data. Variant chr1-11997316-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 217164.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.494A>G	p.His165Arg	missense_variant	Exon 6 of 19	ENST00000235329.10	NP_055689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MFN2	ENST00000235329.10	c.494A>G	p.His165Arg	missense_variant	Exon 6 of 19	1	NM_014874.4	ENSP00000235329.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00000534 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Sep 26, 2022

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

_x000D_ Criteria applied: PM5_STR, PS4_MOD, PM1, PM2_SUP, PP3 -

Jun 17, 2015

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Charcot-Marie-Tooth disease type 2 Pathogenic:1

Jul 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 165 of the MFN2 protein (p.His165Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Charcot-Marie-Tooth disease (PMID: 16714318, 16835246, 17309650, 24819634). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 217164). 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 with a positive predictive value of 95%. This variant disrupts the p.His165 amino acid residue in MFN2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16087932, 16714318, 20951041, 24126688, 27549087). 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. -

not provided Pathogenic:1

May 20, 2016

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The H165R missense variant in the MFN2 gene has been reported previously in association with CMT2 (Chung et al., 2006; Verhoeven et al., 2006; Cho et al., 2007; Bergamin et al., 2014; Choi et al., 2015; Chung et al., 2010). Additionally, different amino acid substitutions at this same position (H165Y/L) have been reported in association with CMT (Stenson et al., 2014), and the H165 residue has been reported as a mutation hotspot (Cho et al., 2007). H165R was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The H165R variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, it alters a highly conserved position in the GTPase domain where many other missense variants have been reported in association with CMT (Stenson et al., 2014). -

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

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense variant c.494A>G (p.His165Arg) in the MFN2 gene has been reported in heterozygous state in individuals affected with late-onset mild CharcotMarie-Tooth disease (Chung KW. et al., 2006). Different missense substitutions at this codon have been reported in individuals affected with CMT suggesting that the histidine residue is critical for MFN2 protein function and that other missense substitutions at this position may be pathogenic (Brožková DŠ. et al., 2013). This variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. It has been submitted to ClinVar as a Pathogenic variant. The amino acid Histidine at position 165 is changed to a Arginine changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D;D
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	1.0	D;.
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Uncertain	2.1	M;M
PhyloP100		8.9
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-5.6	D;D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0050	D;D
Polyphen		1.0	D;D
Vest4		0.85
MutPred		0.85		Gain of MoRF binding (P = 0.0054);Gain of MoRF binding (P = 0.0054);
MVP		0.99
MPC		1.9
ClinPred		0.99	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.88
gMVP		0.95
Mutation Taster		=2/98	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: rs863224970; hg19: chr1-12057373;