rs119103267

Variant names:

• chr1-12009641-C-T
• rs119103267
• NM_014874.4:c.2119C>T

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 16P and 1B. PS3 PM5 PP2 PP3 PP5_Very_Strong BS1_Supporting

The NM_014874.4(MFN2):​c.2119C>T​(p.Arg707Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000453 in 1,614,174 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000803475: Well-established functional studies show a deleterious effect (PMID:26085578)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R707Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00047 (1 hom.)
• Consequence: MFN2 NM_014874.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:28 O:2
• Conservation: PhyloP100: 2.89
• Publications: 46 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 15 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000803475: Well-established functional studies show a deleterious effect (PMID:26085578).; SCV000251722: Functional studies show that R707W alters gene product function and signaling (PMID: 30158064); SCV000966809: analysis of patient fibroblasts suggest that the p.Arg707Trp variant may impair mitochondrial function (Sawyer 2015).; SCV005088857: Functional studies using transfected fibroblasts have shown that the variant impairs MFN2-MFN2 protein interactions in mitochondria, making mitochondria prone to perinuclear aggregation. PMID:26085578; SCV005399281: "This variant has strong functional evidence supporting abnormal protein function. Patient fibroblasts homozygous for this variant demonstrated reduced capabilities to form MFN2 homo-oligomers leading to reduced mitochondrial fusion and mitochondria which were more prone to aggregation (PMID: 26085578)."; SCV000547929: Experimental studies have shown that this missense change affects MFN2 function (PMID: 26085578).; SCV000741959: Functional analysis in patient fibroblasts demonstrated that the p.R707W alteration impairs mitofusin 2 homodimer formation leading to mitochondrial aggregation (Sawyer, 2015).; SCV000914347: Functional studies in U2OS cells homozygous for the p.Arg707Trp variant demonstrate a reduced ability to form homotypic MFN2 protein interactions in vitro and to tubulate mitochondria which were more prone to aggregation (Sawyer et al. 2015).; SCV002500234: At least one publication reports experimental evidence evaluating an impact on protein function, showing that the variant protein resulted in mitochondrial aggregation and defects in homo-oligomerization (Sawyer_2015).; SCV004113565: Functional studies in fibroblasts show that the p.Arg707Trw variant impairs MFN2-MFN2 protein interactions in mitochondria, making mitochondria prone to perinuclear aggregation (Sawyer et al. 2015. PubMed ID: 26085578).; SCV003920211: In addition, a functional study in fibroblasts has shown a deleterious effect of this variant (Sawyer 2015 PMID:26085578).
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-12009642-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 637750.Status of the report is criteria_provided_single_submitter, 1 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, 0.835
• PP5: Variant 1-12009641-C-T is Pathogenic according to our data. Variant chr1-12009641-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 2280.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000472 (690/1461888) while in subpopulation NFE AF = 0.000584 (649/1112010). AF 95% confidence interval is 0.000546. There are 1 homozygotes in GnomAdExome4. There are 345 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.2119C>T	p.Arg707Trp	missense	Exon 18 of 19	NP_055689.1	O95140-1
	MFN2	NM_001127660.2		c.2119C>T	p.Arg707Trp	missense	Exon 17 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.2119C>T	p.Arg707Trp	missense	Exon 18 of 19	ENSP00000235329.5	O95140-1
	MFN2	ENST00000675298.1		c.2119C>T	p.Arg707Trp	missense	Exon 18 of 19	ENSP00000501839.1	A0A6Q8PFJ4
	MFN2	ENST00000675817.1		c.2251C>T	p.Arg751Trp	missense	Exon 19 of 20	ENSP00000502422.1	A0A6Q8PGV8

Frequencies

GnomAD3 genomes AF: 0.000269 AC: 41 AN: 152168 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000529

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000251 AC: 63 AN: 251494 AF XY: 0.000206

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000519

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000472 AC: 690 AN: 1461888 Hom.: 1 Cov.: 31 AF XY: 0.000474 AC XY: 345 AN XY: 727242

African (AFR) AF: 0.0000597 AC: 2 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39698

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000584 AC: 649 AN: 1112010

Other (OTH) AF: 0.000430 AC: 26 AN: 60396

GnomAD4 genome AF: 0.000269 AC: 41 AN: 152286 Hom.: 0 Cov.: 33 AF XY: 0.000228 AC XY: 17 AN XY: 74454

African (AFR) AF: 0.0000962 AC: 4 AN: 41560

American (AMR) AF: 0.00 AC: 0 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000529 AC: 36 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000344 Hom.: 0

Bravo AF: 0.000246

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000329 AC: 40

EpiCase AF: 0.000436

EpiControl AF: 0.000593

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
7	-	-	not provided (7)
4	-	-	Charcot-Marie-Tooth disease type 2A2 (4)
4	-	-	Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2a2b; (4)
3	-	-	MFN2-related disorder (3)
2	-	-	Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2a2b;;C4721887:Charcot-Marie-Tooth disease type 2A2;CN305336:Neuropathy, hereditary motor and sensory, type 6A (2)
1	-	-	Charcot-Marie-Tooth disease (1)
1	-	-	Charcot-Marie-Tooth disease type 2 (1)
1	-	-	Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2a2b;;C4721887:Charcot-Marie-Tooth disease type 2A2 (2)
1	-	-	Inborn genetic diseases (1)
1	-	-	Multiple symmetric lipomatosis (1)
1	-	-	Neuropathy, hereditary motor and sensory, type 6A (1)
1	-	-	Peripheral axonal neuropathy (1)
1	-	-	Tip-toe gait (1)
-	-	-	Hereditary motor and sensory neuropathy with optic atrophy;C2079538:Charcot-Marie-Tooth disease, type 2A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.79	D
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.4	L
PhyloP100		2.9
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-2.8	D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.013	D
Polyphen		1.0	D
Vest4		0.87
MVP		0.98
MPC		0.81
ClinPred		0.82	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.60
gMVP		0.68
Mutation Taster		=22/78	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: rs119103267; hg19: chr1-12069698; COSMIC: COSV104580923;