rs1553141686

Positions:

• chr1-11992664-G-C
• chr1-11992664-G-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PS1 PM1 PM2 PM5 PP2 PP5_Moderate

The ENST00000235329.10(MFN2):​c.285G>C​(p.Arg95Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R95G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: MFN2 ENST00000235329.10 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.54

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 13 ACMG points.

• PS1: Transcript ENST00000235329.10 (MFN2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 1455514
• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 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 chr1-11992662-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 408326.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.
• PP5: Variant 1-11992664-G-C is Pathogenic according to our data. Variant chr1-11992664-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 476770.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MFN2	NM_014874.4	c.285G>C	p.Arg95Ser	missense_variant	4/19	ENST00000235329.10	NP_055689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MFN2	ENST00000235329.10	c.285G>C	p.Arg95Ser	missense_variant	4/19	1	NM_014874.4	ENSP00000235329	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Charcot-Marie-Tooth disease type 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 17, 2023

This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 95 of the MFN2 protein (p.Arg95Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Charcot-Marie-Tooth disease (Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 476770). 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. This variant disrupts the p.Arg95 amino acid residue in MFN2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 30642740; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T;T;.
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D;.;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Uncertain	0.64	D;D;D
MetaSVM	Uncertain	0.51	D
MutationAssessor	Benign	1.6	L;L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.1	N;N;D
REVEL	Pathogenic	0.73
Sift	Benign	0.28	T;T;D
Sift4G	Benign	0.13	T;T;T
Polyphen		0.90	P;P;.
Vest4		0.80
MutPred		0.44		Loss of MoRF binding (P = 0.0757);Loss of MoRF binding (P = 0.0757);Loss of MoRF binding (P = 0.0757);
MVP		0.95
MPC		1.7
ClinPred		0.83	D
GERP RS		4.6
Varity_R		0.43
gMVP		0.94

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: rs1553141686; hg19: chr1-12052721;