rs28940291

Variant names:

• chr1-11992660-G-A
• rs28940291
• NM_014874.4:c.281G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-11992660-G-A
• chr1-11992660-G-C
• chr1-11992660-G-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_014874.4(MFN2):​c.281G>A​(p.Arg94Gln) 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. R94P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: MFN2 NM_014874.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12 U:1
• 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 17 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_014874.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-11992659-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 637495.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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 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, 0.911
• PP5: Variant 1-11992660-G-A is Pathogenic according to our data. Variant chr1-11992660-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 2268.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-11992660-G-A is described in Lovd as [Pathogenic]. Variant chr1-11992660-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MFN2	NM_014874.4	c.281G>A	p.Arg94Gln	missense_variant	Exon 4 of 19	ENST00000235329.10	NP_055689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MFN2	ENST00000235329.10	c.281G>A	p.Arg94Gln	missense_variant	Exon 4 of 19	1	NM_014874.4	ENSP00000235329.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251490 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135920

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Charcot-Marie-Tooth disease type 2A2 Pathogenic:5

Apr 01, 2023

Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 20, 2021

Laboratório de Neurologia Aplicada e Experimental, Faculdade de Medicina de Ribeirao Preto – Universidade de Sao Paulo

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The amino acid Arg at position 94 is changed to a Gln changing protein sequence and it might alter its composition and physico-chemical properties. This sequence change replaces arginine with glutamine at codon 94 of the mitofusin 2 protein (p.Arg94Gln). This variant has been reported in multiple unrelated individuals affected with autosomal dominant Charcot-Marie-Tooth disease type 2 (CMT2) (Casasnovas C et al, Neusch C et al) and in several families where it was observed to co-segregate with disease (Klein CJ et al). This variant has also been shown to arise de novo in an individual affected with CMT2 (Braathen GJ et al). The p.Arg94Gln variant is reported with the allele frequency of 0.0003976% and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Arg94Gln in MFN2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -

Apr 01, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Aug 15, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:3

Oct 06, 2021

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been confirmed to occur de novo in multiple individuals with clinical features associated with this gene (PMID: 20350294, 17437620). At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. Assessment of experimental evidence suggests this variant results in abnormal protein function. Mouse models expressing this variant induced a CMT2A phenotype and impaired ATP synthesis (PMID 21285398). Based on internal data, this variant occurs with an alternate explanation for disease significantly less often than expected, suggesting this variant may be associated with disease. -

Mar 24, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate that this variant induces a drastic decrease in ATP synthesis, suppresses mitochondrial fusion and transport, and results in axonal degeneration (Guillet et al., 2011; Misko et al., 2012); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20418531, 30340945, 18996695, 17437620, 31211173, 24957169, 25025039, 21285398, 22442078, 24604904, 15064763, 29266326, 31640251, 30882369, 30882371, 34103343, 24863639, 20350294, 19889647, 19812251, 17296794, 16714318, 15549395, 29898954, 31832804, 22492563, 21508331, 17215403, 34698563, 32147437, 34128983) -

Jan 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Pathogenic:1

Aug 02, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.281G>A (p.R94Q) alteration is located in exon 4 (coding exon 2) of the MFN2 gene. This alteration results from a G to A substitution at nucleotide position 281, causing the arginine (R) at amino acid position 94 to be replaced by a glutamine (Q)._x000D_ Based on the available evidence, the MFN2 c.280C>T (p.R94W) alteration is classified as pathogenic for autosomal dominant MFN2-related neuropathy; however, its clinical significance for autosomal recessive MFN2-related neuropathy is uncertain. Based on data from gnomAD, the A allele has an overall frequency of <0.001% (1/251490) total alleles studied. The highest observed frequency was 0.001% (1/113768) of European (non-Finnish) alleles. This variant has been detected in the heterozygous state in many individuals with neuropathy, including multiple de novo occurrences, and has been reported to segregate with disease in several families (Zuchner, 2004; Kijima, 2005; Verhoeven, 2006; Neusch, 2007; Banchs, 2008; Braathen, 2010; Feely, 2011; Klein, 2014; Hoebeke, 2018; McCray, 2018; Lin, 2020; Abati, 2022). Additionally, other missense variants at the same codon, c.280C>T (p.R94W) and c.280C>G (p.R94G), have been described in individuals with neuropathy (Zuchner, 2004; Feely, 2011). This amino acid position is highly conserved in available vertebrate species. In vivo and in vitro functional studies indicate this alteration impairs mitochondrial fusion, mobility and dynamics, and leads to axonal degeneration (Baloh, 2007; Detmer, 2007; Cartoni, 2010; Guillet, 2011; Misko, 2012; El Fissi, 2018; Bernard-Marissal, 2019; van Hameren, 2019; Wolf, 2019). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2a2b; Pathogenic:1

Aug 15, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Charcot-Marie-Tooth disease type 2 Pathogenic:1

Aug 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 94 of the MFN2 protein (p.Arg94Gln). This variant is present in population databases (rs28940291, gnomAD 0.0009%). This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 15064763, 16714318, 17437620, 18996695, 19889647, 24604904, 25025039). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2268). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt MFN2 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects MFN2 function (PMID: 17215403, 17296794, 20335458, 20418531, 21285398, 22442078). For these reasons, this variant has been classified as Pathogenic. -

Neuropathy, hereditary motor and sensory, type 6A Pathogenic:1

Aug 15, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Charcot-Marie-Tooth disease Uncertain:1

Aug 14, 2019

Genesis Genome Database

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.69	D;D;.
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D;.;D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.91	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	M;M;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.4	D;D;D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.0040	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.85
MutPred		0.76		Loss of MoRF binding (P = 0.0474);Loss of MoRF binding (P = 0.0474);Loss of MoRF binding (P = 0.0474);
MVP		0.97
MPC		1.9
ClinPred		0.99	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.88
gMVP		0.87

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: rs28940291; hg19: chr1-12052717;