rs863224969

Variant names:

• chr1-11996280-C-T
• rs863224969
• NM_014874.4:c.436C>T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_014874.4(MFN2):​c.436C>T​(p.Leu146Phe) variant causes a missense change involving the alteration of a non-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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MFN2 NM_014874.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 3.46

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 15 ACMG points.

• PM1: In a domain Dynamin-type G (size 249) in uniprot entity MFN2_HUMAN there are 176 pathogenic changes around while only 5 benign (97%) in NM_014874.4
• PM2: Very rare variant in population databases, with high coverage
• 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, 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, 0.859
• PP5: Variant 1-11996280-C-T is Pathogenic according to our data. Variant chr1-11996280-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 217163.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-11996280-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MFN2	NM_014874.4	c.436C>T	p.Leu146Phe	missense_variant	Exon 5 of 19	ENST00000235329.10	NP_055689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MFN2	ENST00000235329.10	c.436C>T	p.Leu146Phe	missense_variant	Exon 5 of 19	1	NM_014874.4	ENSP00000235329.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Charcot-Marie-Tooth disease type 2A2 Pathogenic:1

Aug 07, 2015

Athena Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Charcot-Marie-Tooth disease type 2 Pathogenic:1

Nov 24, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 217163). This missense change has been observed in individual(s) with autosomal dominant MFN2-related neuropathy (PMID: 21987543, 27549087). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 146 of the MFN2 protein (p.Leu146Phe). -

not provided Pathogenic:1

Jan 31, 2017

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The L146F variant has been previously reported to segregate with the phenotype in a large family with CMT2A2 (Klein et al., 2011). The age of onset and severity of the disease varied greatly among the affected relatives (Klein et al., 2011). It 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. However, the L146F variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Leucine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.87	D;D
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.96	D;.
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.86	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.7	M;M
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.4	D;D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0080	D;D
Polyphen		0.99	D;D
Vest4		0.73
MutPred		0.50		Loss of stability (P = 0.0717);Loss of stability (P = 0.0717);
MVP		0.95
MPC		1.7
ClinPred		0.97	D
GERP RS		5.3
Varity_R		0.79
gMVP		0.93

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: rs863224969; hg19: chr1-12056337;