chr1-12009641-C-T
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 16P and 1B. PM1PM2PM5PP2PP3PP5_Very_StrongBS1_Supporting
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 frequency of 0.000453 in 1,614,174 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R707Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_014874.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 15 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.000269 AC: 41AN: 152168Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000251 AC: 63AN: 251494Hom.: 0 AF XY: 0.000206 AC XY: 28AN XY: 135922
GnomAD4 exome AF: 0.000472 AC: 690AN: 1461888Hom.: 1 Cov.: 31 AF XY: 0.000474 AC XY: 345AN XY: 727242
GnomAD4 genome 0.000269 AC: 41AN: 152286Hom.: 0 Cov.: 33 AF XY: 0.000228 AC XY: 17AN XY: 74454
ClinVar
Submissions by phenotype
not provided Pathogenic:5
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Functional studies show that R707W alters gene product function and signaling (PMID: 30158064); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28492532, 22492563, 25025039, 28251916, 26306937, 24126688, 20350294, 26085578, 26114802, 36722855, 31589614, 31980526, 32376792, 29867446, 32916636, 33502018, 34426522, 29358271, 26392352, 25231362, 35641312, 20008656, MarquesAJ2024[Article], 35305867, 35468369, 38887266, FossdeFreitaMC2023[Abstract], 37536398, 33415332, 28414270, 18458227, 30158064) -
MFN2: PM3:Very Strong, PM2:Supporting, PM5:Supporting, PP1, PS3:Supporting -
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Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2a2b; Pathogenic:4
_x000D_This variant was identified together with NM_014874.4:c.1160+1G>A. Criteria applied: PM3_VSTR, PS3_SUP, PP3 -
This variant is interpreted as a Likely Pathogenic, for Charcot-Marie-Tooth disease, axonal, type 2A2B, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS3 => Well-established functional studies show a deleterious effect (PMID:26085578). -
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.025%). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.84; 3Cnet: 0.86). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000002280). A different missense change at the same codon (p.Arg707Pro) has been reported to be associated with MFN2 related disorder (ClinVar ID: VCV000637750 / PMID: 22492563). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -
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Charcot-Marie-Tooth disease type 2A2 Pathogenic:4
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
The p.Arg707Trp variant in MFN2 has been reported in the heterozygous state in 4 probands with clinical features of Charcot-Marie-Tooth disease type 2A (CMT2A; Braathen 2010, Sitarz 2012, Brožková 2013, Bansagi 2017). It has also been reported in the compound heterozygous or homozygous state in at least 9 individuals with CMT2A-related neuropathy and lipomatosis or lipodystrophy (Nicholson 2008, Calvo 2009, Carr 2015, Sawyer 2015, Rocha 2017, Capel 2018). The variant segregated with neuropathy and lipomatosis/lipodystrophy in at least 4 affected members of 3 families (Calvo 2009, Rocha 2017, Capel 2018). This variant has also been identified in the heterozygous state in individuals without overt signs of neuropathy (Nicholson 2008, Calvo 2009, Brožková 2013, Carr 2015, Rocha 2017) and in 0.05% (66/129186) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). However, this is consistent with the fact that variable expressivity including sub-clinical, late-onset neuropathy has been reported for CMT2A (Züchner 2013). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Furthermore, analysis of patient fibroblasts suggest that the p.Arg707Trp variant may impair mitochondrial function (Sawyer 2015). In summary, although additional studies are required to fully establish its clinical significance, the p.Arg707Trp variant meets criteria to be classified as likely pathogenic for autosomal dominant CMT2A, with homozygous or compound heteroygous occurences likely leading to a more severe course of disease that may include lipomatosis and/or lipodystrophy. ACMG/AMP Criteria applied: PM3_Strong, PP3, PS3_Supporting, PS4_Supporting. -
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 MFN2-related disorders. (I) 0108 - This gene is associated with both recessive and dominant disease. However, no genotype-phenotype correlation has been established. (I) 0112 - The condition associated with this gene has incomplete penetrance (OMIM; PMID 26686600). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 71 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2: 6 heterozygotes, 0 homozygotes). (I) 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 Fzo_mitofusin domain (NCBI, PDB, DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. Biallelic patients have been reported to have multiple symmetrical lipomatosis and axonal neuropathy while monoallelic patients presents with axonal neuropathy only. In addition, in autosomal recessive families, carrier parents are reported to be either clinically unaffected or mildly affected with Charcot-Marie-Tooth. (ClinVar; PMID: 26085578, 28414270, 24126688, 20350294, 30158064, 18458227). (SP) 1001 - 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). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
This variant has been reported in multiple individuals and families affected with Charcot Marie Tooth disease type 2 (CMT2) in the heterozygous, homozygous, or compound heterozygous state [PMID: 18458227, 24126688, 25025039, 22492563, 20008656] and also been reported to segregate with disease [PMID: 20350294, 20008656]. There have been reports of patients harboring the variant in heterozygous condition presenting with clinical features of CMT2 [PMID: 20350294] and early severe axonal CMT as well as cases with unaffected heterozygous parents [PMID: 24126688], suggesting incomplete penetrance. Homozygous or compound heterozygous occurrences of the variant likely lead to a more severe course of disease that may include lipomatosis and/or lipodystrophy. 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]. -
MFN2-related disorder Pathogenic:3
The MFN2 c.2119C>T variant is predicted to result in the amino acid substitution p.Arg707Trp. This variant has previously been reported in several individuals with diverse phenotypes. In an individual with severe early-onset axonal neuropathy and lipodystrophy, this variant was found in the homozygous state (Nicholson et al. 2008. PubMed ID: 18458227). In another study, six patients from five families presented with a lipodystrophy with variable Charcot-Marie-Tooth features; each of these individuals harbored the p.Arg707Trp variant in the homozygous state (Capel et al. 2018. PubMed ID: 30158064). In another family with two brothers affected with multiple symmetric lipomatosis and neuropathy, whole exome sequencing identified they were also homozygous for the c.2119C>T variant (Sawyer et al. 2015. PubMed ID: 26085578). In another family with three affected children with early-onset Charcot-Marie-Tooth disease, all were found to be compound heterozygous for the c.2119C>T variant and a second plausible causative variant (Calvo et al. 2009. PubMed ID: 20008656). Lastly, this variant was found in the compound heterozygous state with an exon 7-8 deletion in an individual with suspected Charcot-Marie-Tooth disease (Carr et al. 2015. PubMed ID: 26114802). Functional studies in fibroblasts show that the p.Arg707Trp variant impairs MFN2-MFN2 protein interactions in mitochondria, making mitochondria prone to perinuclear aggregation (Sawyer et al. 2015. PubMed ID: 26085578). In summary, this evidence suggests the c.2119C>T variant is inherited in an autosomal recessive manner and is pathogenic for disease. -
Variant summary: MFN2 c.2119C>T (p.Arg707Trp) results in a non-conservative amino acid change located in the Fzo/mitofusin HR2 domain (IPR006884) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00025 in 251494 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MFN2 causing MFN2-Related Disorders, allowing no conclusion about variant significance. c.2119C>T has been reported in the literature in multiple individuals affected with MFN2-Related Disorders, including one homozygote diagnosed with severe early onset axonal neuropathy (e.g. Nicholson_2008), and several compound heterozygotes diagnosed with Charcot-Marie-Tooth disease (e.g. Calvo_2009, Brozkova_2013, Pipis_2020). These data indicate that the variant is very likely to be associated with disease and are consistent with an autosomal recessive inheritance pattern. Additionally, affected individuals (e.g. Braathen_2010) and unaffected individuals have been reportes as heterozygous carriers, therefore the relationship of this variant to autosomal dominant disease is unclear. 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). The following publications have been ascertained in the context of this evaluation (PMID: 20350294, 24126688, 20008656, 18458227, 33415332, 26085578). ClinVar contains an entry for this variant (Variation ID: 2280). Based on the evidence outlined above, the variant was classified as pathogenic. -
Across a selection of the available literature, the MFN2 c.2119C>T (p.Arg707Trp) missense variant has been identified in a total of 11 individuals with MFN2-related disorders, including in a homozygous state in four individuals, (two of whom are related), in a compound heterozygous state in four individuals, and in a heterozygous state in three individuals (Nicholson et al. 2008; Calvo et al. 2009; Braathen et al. 2010; Sitarz et al. 2012; Brozkova et al. 2013; Hoyer et al. 2014; Sawyer et al. 2015; Carr et al. 2015). The variant was also found in a heterozygous state in several asymptomatic parents, consistent with an autosomal recessive pattern of inheritance. MFN2-related disorders have also been reported to follow an autosomal dominant pattern of inheritance which was observed through four generations of one family in a study by Braathen et al. (2010). The p.Arg707Trp variant was absent from at least 602 evaluated control alleles (Nicholson et al. 2008; Braathen et al. 2010) and is reported at a frequency of 0.000581 in the European American population of the Exome Sequencing Project. 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). The p.Arg707Trp variant is located in a well-conserved residue in a known functional domain that is thought to permit homotypic protein interaction as well as heterotypic binding to MFN1 (Sawyer et al. 2015). Based on the collective evidence, the p.Arg707Trp variant is classified as pathogenic for MFN2-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2a2b;;C4721887:Charcot-Marie-Tooth disease type 2A2;CN305336:Neuropathy, hereditary motor and sensory, type 6A Pathogenic:2
MFN2 NM_014874.3 exon 18 p.Arg707Trp (c.2119C>T): This variant has been reported in the literature in the heterozygous, compound heterozygous, or homozygous state in several individuals with axonal neuropathy, segregating with at least 3 affected family members within 2 families (Nicholson 2008 PMID:18458227, Calvo 2009 PMID:20008656, Brozkova 2013 PMID:24126688, Hoyer 2014 PMID:25025039, Sawyer 2015 PMID:26085578, Bansagi 2017 PMID:28251916). This variant has also been reported in individuals with multiple symmetric lipomatosis in addition to neuropathy (Carr 2015 PMID:26114802, Sawyer 2015 PMID:26085578). This variant is present in 0.05% (66/129186) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/1-12069698-C-T). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status, and/or variable expressivity. This variant is also present in ClinVar, with several labs classifying this variant as pathogenic or likely pathogenic (Variation ID:2280). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In addition, a functional study in fibroblasts has shown a deleterious effect of this variant (Sawyer 2015 PMID:26085578). However, this study may not accurately represent in vivo biological function. In summary, this variant is classified as pathogenic based on the data above. -
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Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2a2b;;C4721887:Charcot-Marie-Tooth disease type 2A2 Pathogenic:1Other:1
Variant interpreted as Pathogenic and reported on 03-02-2020 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
PS3_Moderate, PS4_Moderate (for AD CMT) or PM3_Strong (for AR CMT), PP1, PP3 -
Charcot-Marie-Tooth disease Pathogenic:1
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Multiple symmetric lipomatosis Pathogenic:1
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Inborn genetic diseases Pathogenic:1
The c.2119C>T (p.R707W) alteration is located in exon 18 (coding exon 16) of the MFN2 gene. This alteration results from a C to T substitution at nucleotide position 2119, causing the arginine (R) at amino acid position 707 to be replaced by a tryptophan (W)._x000D_ _x000D_ Based on the available evidence, the MFN2 c.2119C>T (p.R707W) alteration is classified as pathogenic for autosomal recessive MFN2-related neuropathy; however, it is unlikely to be causative of autosomal dominant MFN2-related neuropathy. Based on data from gnomAD, the T allele has an overall frequency of 0.025% (71/282876) total alleles studied. The highest observed frequency was 0.051% (66/129186) of European (non-Finnish) alleles. This alteration was reported in the homozygous state or in trans with another MFN2 variant in multiple individuals with axonal neuropathy and lipodystrophy (Nicholson, 2008; Calvo, 2009; Carr, 2015; Sawyer, 2015; Rocha, 2017; Capel, 2018). Heterozygous parents with affected children have been reported to be asymptomatic (Nicholson, 2008; Carr, 2015; Rocha, 2017). This amino acid position is well conserved in available vertebrate species. Functional analysis in patient fibroblasts demonstrated that the p.R707W alteration impairs mitofusin 2 homodimer formation leading to mitochondrial aggregation (Sawyer, 2015). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -
Peripheral axonal neuropathy Pathogenic:1
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Charcot-Marie-Tooth disease type 2 Pathogenic:1
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 707 of the MFN2 protein (p.Arg707Trp). This variant is present in population databases (rs119103267, gnomAD 0.05%). This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease and/or multiple symmetric lipomatosis and neuropathy (PMID: 18458227, 20008656, 20350294, 22492563, 25025039, 26085578, 26114802, 28251916, 28414270, 30158064, 33415332). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 2280). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MFN2 protein function. Experimental studies have shown that this missense change affects MFN2 function (PMID: 26085578). For these reasons, this variant has been classified as Pathogenic. -
Tip-toe gait Pathogenic:1
Hereditary motor sensory neuropathy (HMSN), also known as Charcot-Marie-Tooth Disease (CMT), is the most commonly inherited peripheral polyneuropathy. It constitutes a group of inherited, progressive, motor and sensory peripheral nerve disorders with properties of demyelination, axonal degeneration, or both. It is classified by clinical characteristics, modes of inheritance, electrophysiologic features, metabolic defects, and specific gene markers. Our patients all walk on tiptoe, so they show similar symptoms. When we genetically test them with our toe walking panel, we find that around 90 per cent of them have a genetic variant that explains their toe walking. These can be assigned, for example, to the area of myopathies (such as variants of the COL6A3 gene), the area of hereditary neuropathies (such as variants of the KMT2C gene) or the area of metabolic diseases (such as variants of the PYGM gene). In a smaller group of patients with almost identical symptoms, no abnormality is found in the genes of our panel, but spastic paraplegia can be detected. In another small group of our toe walkers, no abnormalities can be detected in the genes analysed in our toe walking panel, nor do they suffer from spastic paraplegia, as is also the case with healthy children. In contrast to these, however, they show a tiptoe gait. These patients suffer from infantile cerebral palsy, in which toe walking can also be observed. -
Neuropathy, hereditary motor and sensory, type 6A Pathogenic:1
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Hereditary motor and sensory neuropathy with optic atrophy;C2079538:Charcot-Marie-Tooth disease, type 2A Other:1
Variant classified as Likely pathogenic and reported on 03-29-2017 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at