rs119103267

Variant names:

• chr1-12009641-C-T
• rs119103267
• NM_014874.4:c.2119C>T
• MFN2 p.Arg707Trp

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

+13 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 13 classification points (ACMG Germline Pathogenicity v2019). PS3PM5PP2PP3_ModeratePP5_Strong

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 cumulative frequency of 0.000453 (AC=731) in the gnomAD database across 1,614,174 control chromosomes, including 1 homozygote. The grpmax filtering allele frequency (95% CI) is 0.000546. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic/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. A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.R707P: Likely_pathogenic (ClinVar VariationId 637750, 1 star) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R707?: Uncertain_significance (ClinVar VariationId 917375, 1 star); p.R707Q: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 1806999) This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

• 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:32 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):

• Charcot-Marie-Tooth disease type 2A2

  Inheritance: AD, SD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen
• 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, STRONG Submitted by: PanelApp Australia, ClinGen
• hereditary motor and sensory neuropathy

  Inheritance: SD Classification: STRONG Submitted by: PanelApp Australia
• 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

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 13 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS3Functional studies show damaging effect		Well-established functional study supports damaging effect (PS3); 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).
	PM5Novel missense at known pathogenic residue		Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.R707P: Likely_pathogenic (ClinVar VariationId 637750, 1 star); Other variants at the same amino acid residue (not pathogenic): p.R707?: Uncertain_significance (ClinVar VariationId 917375, 1 star); p.R707Q: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 1806999)
	PP2Missense in gene with low missense rate		Missense in gene constrained for missense variation where missense is common disease mechanism (PP2); Missense in a gene constrained for missense variation (gnomAD Z-score: 3.228). ClinVar shows strong pathogenic missense enrichment: 177 P/LP and 16 B/LB missense entries (ratio 11.1×).
	PP3Computational evidence supports damaging effect		Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — moderate evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Moderate).
	PP5Reputable source reports pathogenic		ClinVar 2-star pathogenic — strong (PP5); ClinVar submissions overwhelmingly pathogenic (≥10 total, ≥80% P/LP, <10% B/LB) — strong (PP5, count-based); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 star(s). ClinVar submissions strongly and reliably favor pathogenicity (32/32 total P/LP).

Variant Effect in Transcripts

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

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.000269	AC:41	Hom:0	AN:152168	Cov:33
GnomAD2 exomes	AF: 0.000251	AC:63	Hom:	AN:251494	Cov:
GnomAD4 exome	AF: 0.000472	AC:690	Hom:1	AN:1461888	Cov:31
GnomAD4 genome	AF: 0.000269	AC:41	Hom:0	AN:152286	Cov:33
TOPMed (Bravo)	AF: 0.000246	AC:65	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.000347	AC:174	Hom:0	AN:500896	Cov:
Local & regional cohorts 6 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.000427	AC:1	Hom:0	AN:2342	Cov:
ESP6500 (Exome Variant Server)	AF: 0.000384	AC:5	Hom:	AN:13006	Cov:
Korea4K (4,157 Koreans)	AF: 0.000138	AC:1	Hom:	AN:7234	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.00	AC:0	Hom:0	AN:122370	Cov:
Turkish Variome	AF: 0.000647	AC:1	Hom:0	AN:1546	Cov:
UK10K	AF: 0.000397	AC:3	Hom:	AN:7562	Cov:

Showing 12 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.00108 *	12	11112	0.000908 *	16	17618
BipEx(Bipolar disorder (including schizoaffective))	0.000563	16	28420	0.000589	17	28844
Epi25(Epilepsy)	0.000358	15	41958	0.000314	21	66888
SCHEMA(Schizophrenia)	0.000152	18	118122	0.000227	42	184806

Showing 4 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
8	-	-	not provided (8)
5	-	-	Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2a2b; (5)
4	-	-	Charcot-Marie-Tooth disease type 2A2 (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	-	-	Multiple symmetric lipomatosis;C4310725:Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2a2b; (1)
1	-	-	Neuropathy, hereditary motor and sensory, type 6A (1)
1	-	-	Peripheral axonal neuropathy (1)
1	-	-	Semidominant MFN2-related disorders (1)
1	-	-	Tip-toe gait (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	24
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
GPN-Star LLR	N/A	-8.2
GPN-Star score	N/A	8.2
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Pathogenic	1.0	D
Mutation Taster	N/A	22/78	disease causing (ClinVar)
MutationAssessor	Benign	1.4	L
PhyloP100	Benign	2.9
popEVE	Benign	-3.5
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-2.8	D
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.7
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.013	D
Varity_R	N/A	0.60
VESM-3B	Benign	-9.3

Showing 29 of 29 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs119103267;

hg19: chr1-12069698;

COSMIC: COSV104580923;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar