chr1-11999009-G-A

Position:

• chr1-11999009-G-A

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The ENST00000235329.10(MFN2):​c.730G>A​(p.Val244Met) 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. V244A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MFN2 ENST00000235329.10 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.60

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]

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in ENST00000235329.10
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-11999010-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 860582.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, 0.943
• PP5: Variant 1-11999009-G-A is Pathogenic according to our data. Variant chr1-11999009-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 243066.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-11999009-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MFN2	NM_014874.4	c.730G>A	p.Val244Met	missense_variant	8/19	ENST00000235329.10	NP_055689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MFN2	ENST00000235329.10	c.730G>A	p.Val244Met	missense_variant	8/19	1	NM_014874.4	ENSP00000235329	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter	research	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	Aug 18, 2015	This variant has been previously reported as disease-causing and was found in one patient with demyelinating neuropathy and one patient with axonal neuropathy -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Dec 21, 2023	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with autosomal dominant Charcot-Marie-Tooth disease, axonal, type 2A2A (CMT; MIM#609260) and hereditary motor and sensory neuropathy VIA (MIM#601152) and autosomal recessive Charcot-Marie-Tooth disease, axonal, type 2A2B (CMT; MIM#617087). (I) 0108 - This gene is associated with both recessive and dominant disease. However, a clear genotype-phenotype correlation has not been established (GeneReviews). (I) 0115 - Variants in this gene are known to have variable expressivity (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to methionine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated GTPase domain (PMID: 20008656). (I) 0703 - Other missense variantS comparable to the one identified in this case haVE moderate previous evidence for pathogenicity. p.(Val244Leu) has been identified as de novo in two individuals with CMT (PMIDs: 26378787, 26956144). p.(Val244Ala) and p.(Val244Gly) have also been identified in individuals with progressive distal weakness and sensory and motor neuropathy; however, they have been classified as VUS (Invitae personal communication). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been identified at least four affected individuals with CMT, including two with confirmed de novo inheritance, and classified as pathogenic by a diagnostic laboratory in ClinVar (PMIDs: 15549395, 20008656, 26257172). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Charcot-Marie-Tooth disease type 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 01, 2019

For these reasons, this variant has been classified as Pathogenic. A different missense substitution at this codon (p.Val244Leu) has been determined to be likely pathogenic (PMID: 26378787, 26257172). This suggests that the valine residue is critical for MFN2 protein function and that other missense substitutions at this position may also be pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). This variant has been reported in multiple individuals affected with Charcot-Marie-Tooth disease (PMID: 15549395, 20008656). This variant has also been shown to be de novo in affected individuals (PMID: 26257172, Invitae). ClinVar contains an entry for this variant (Variation ID: 243066). This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with methionine at codon 244 of the MFN2 protein (p.Val244Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.86	D;D
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;.
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.4	M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-2.6	D;D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.86
MutPred		0.80		Gain of catalytic residue at V244 (P = 0.051);Gain of catalytic residue at V244 (P = 0.051);
MVP		0.97
MPC		1.8
ClinPred		0.99	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.84
gMVP		0.95

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: rs879253777; hg19: chr1-12059066;