1-11992660-G-A

Variant names:

• chr1-11992660-G-A
• rs28940291
• NM_014874.4:c.281G>A

Variant summary

Our verdict is Pathogenic. The variant received 21 ACMG points: 21P and 0B. PS3 PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_014874.4(MFN2):​c.281G>A​(p.Arg94Gln) 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 (★★). ClinVar reports functional evidence for this variant: "SCV006304456: The MFN2 p.Arg94Gln variant has been functionally characterized in knock-in mouse models, demonstrating deficient mitochondrial membrane potential, aberrant mitochondrial morphology, loss of mitochondrial fusion and altered axonal mitochondria in the sciatic nerve. Studies on MFN2 mutations in CMT2A show that these variants disrupt mitochondrial fusion and neuronal function (PMID:17296794)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R94P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: MFN2 NM_014874.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:14 U:1
• Conservation: PhyloP100: 9.60
• Publications: 87 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: G2P, Labcorp Genetics (formerly Invitae)
• multiple symmetric lipomatosis with partial lipodystrophy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• 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 21 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV006304456: The MFN2 p.Arg94Gln variant has been functionally characterized in knock-in mouse models, demonstrating deficient mitochondrial membrane potential, aberrant mitochondrial morphology, loss of mitochondrial fusion and altered axonal mitochondria in the sciatic nerve. Studies on MFN2 mutations in CMT2A show that these variants disrupt mitochondrial fusion and neuronal function (PMID: 17296794).; SCV000255680: Assessment of experimental evidence suggests this variant results in abnormal protein function. Mouse models expressing this variant induced a CMT2A phenotype and impaired ATP synthesis (PMID 21285398).; SCV000329569: Published functional studies demonstrate that this variant induces a drastic decrease in ATP synthesis, suppresses mitochondrial fusion and transport, and results in axonal degeneration (Guillet et al., 2011; Misko et al., 2012);; SCV000547922: Experimental studies have shown that this missense change affects MFN2 function (PMID: 17215403, 17296794, 20335458, 20418531, 21285398, 22442078).; SCV004074335: "In vivo and in vitro functional studies indicate this alteration impairs mitochondrial fusion, mobility and dynamics, and leads to axonal degeneration (Baloh, 2007; Detmer, 2007; Cartoni, 2010; Guillet, 2011; Misko, 2012; El Fissi, 2018; Bernard-Marissal, 2019; van Hameren, 2019; Wolf, 2019)."
• PM1: In a hotspot region, there are 12 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 chr1-11992659-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 637495.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, axonal, autosomal recessive, type 2a2b;, multiple symmetric lipomatosis, Charcot-Marie-Tooth disease type 2A2, axonal hereditary motor and sensory neuropathy, neuropathy, hereditary motor and sensory, type 6A, multiple symmetric lipomatosis with partial lipodystrophy, severe early-onset axonal neuropathy due to MFN2 deficiency, hereditary motor and sensory neuropathy type 6.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.911
• PP5: Variant 1-11992660-G-A is Pathogenic according to our data. Variant chr1-11992660-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 2268.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014874.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MFN2	NM_014874.4	MANE Select	c.281G>A	p.Arg94Gln	missense	Exon 4 of 19	NP_055689.1	O95140-1
	MFN2	NM_001127660.2		c.281G>A	p.Arg94Gln	missense	Exon 3 of 18	NP_001121132.1	O95140-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MFN2	ENST00000235329.10	TSL:1 MANE Select	c.281G>A	p.Arg94Gln	missense	Exon 4 of 19	ENSP00000235329.5	O95140-1
	MFN2	ENST00000675298.1		c.281G>A	p.Arg94Gln	missense	Exon 4 of 19	ENSP00000501839.1	A0A6Q8PFJ4
	MFN2	ENST00000675817.1		c.281G>A	p.Arg94Gln	missense	Exon 4 of 20	ENSP00000502422.1	A0A6Q8PGV8

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251490 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
7	-	-	Charcot-Marie-Tooth disease type 2A2 (7)
3	-	-	not provided (3)
-	1	-	Charcot-Marie-Tooth disease (1)
1	-	-	Charcot-Marie-Tooth disease type 2 (1)
1	-	-	Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2a2b; (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Neuropathy, hereditary motor and sensory, type 6A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.69	D
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		9.6
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.4	D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.76		Loss of MoRF binding (P = 0.0474)
MVP		0.97
MPC		1.9
ClinPred		0.99	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.88
gMVP		0.87
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: rs28940291; hg19: chr1-12052717;