Submissions for variant NM_014874.4(MFN2):c.1090C>T (p.Arg364Trp)

dbSNP: rs119103265

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000198024	SCV000251715	pathogenic	not provided	2022-04-12	criteria provided, single submitter	clinical testing	Reported multiple times in association with hereditary motor and sensory neuropathy type VI and CMT2A in published literature (Zuchner et al., 2006; Chung et al., 2006; Gowrisankaran et al., 2011); Published functional studies demonstrate a damaging effect (Saporta et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24819634, 16835246, 21707411, 31832804, 21508331, 31211173, 16437557, 22206013, 27549087, 30996168, 30649465, 20587496, 25802885, 22492563, 31673878, 31315766, 33578441, 30569560, 33074106, 33742459, 30830587, 25448007, 28063088, 24863639)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000195560	SCV000253916	pathogenic	Charcot-Marie-Tooth disease type 2	2023-08-27	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 364 of the MFN2 protein (p.Arg364Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Charcot-Marie-Tooth disease type 2A and hereditary motor and sensory neuropathy type VI (PMID: 16437557, 16835246, 21508331, 21707411, 22206013, 22492563, 25448007, 25802885, 27549087, 28063088). ClinVar contains an entry for this variant (Variation ID: 2278). 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.Arg364 amino acid residue in MFN2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17444508, 18996695, 20008656, 21508331, 22492563). 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.
Athena Diagnostics	RCV000023711	SCV000255674	pathogenic	Charcot-Marie-Tooth disease type 2A2	2014-11-18	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000198024	SCV001247289	pathogenic	not provided	2018-06-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000002367	SCV001528900	pathogenic	Hereditary motor and sensory neuropathy with optic atrophy	2018-08-22	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease causing [PMID 16437557, 21707411, 27549087, 25448007, 28063088]
CMT Laboratory, Bogazici University	RCV000023711	SCV001548305	pathogenic	Charcot-Marie-Tooth disease type 2A2	2020-12-01	criteria provided, single submitter	clinical testing
Laboratório de Neurologia Aplicada e Experimental, Faculdade de Medicina de Ribeirao Preto – Universidade de Sao Paulo	RCV000023711	SCV001938862	pathogenic	Charcot-Marie-Tooth disease type 2A2	2021-07-20	criteria provided, single submitter	research
Genetics and Molecular Pathology, SA Pathology	RCV000023711	SCV002556395	pathogenic	Charcot-Marie-Tooth disease type 2A2	2022-07-08	criteria provided, single submitter	clinical testing	The MFN2 c.1090C>T variant is classified as PATHOGENIC (PS2, PS4, PP3) The MFN2 c.1090C>T variant is a single nucleotide change in exon 11/19 of the MFN2 gene, which is predicted to change the amino acid arginine at position 364 in the protein to tryptophan. This variant is de novo in this patient (PS2). This variant has been reported in multiple individuals with Charcot-Marie-Tooth disease type 2 (PMID:24819634, PMID:21508331, PMID:28063088) (PS4). this variant has not been reported in dbSNP and is absent from population databases. This variant has been reported in ClinVar as pathogenic for Charcot-Marie-Tooth disease (ClinVar Variation ID: 2278). Other variants affecting this amino acid residue have also been reported as pathogenic suggesting this residue is clinically significant. Computational predictions support a deleterious effect on the gene or gene product (PP3).
3billion	RCV000023711	SCV004013597	pathogenic	Charcot-Marie-Tooth disease type 2A2		criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 29898954). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.86; 3Cnet: 0.96). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000002278 / PMID: 16437557). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 22206013, 22762946, 25448007, 28063088). Different missense changes at the same codon (p.Arg364Gln, p.Arg364Leu, p.Arg364Pro) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000245944, VCV000572157, VCV000801445 / PMID: 17444508, 20008656 / 3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand	RCV000195560	SCV004123108	pathogenic	Charcot-Marie-Tooth disease type 2	2023-07-01	criteria provided, single submitter	research
OMIM	RCV000002367	SCV000022525	pathogenic	Hereditary motor and sensory neuropathy with optic atrophy	2006-08-01	no assertion criteria provided	literature only
Northcott Neuroscience Laboratory, ANZAC Research Institute	RCV000023711	SCV000188691	pathogenic	Charcot-Marie-Tooth disease type 2A2		no assertion criteria provided	not provided	Converted during submission to Pathogenic.
OMIM	RCV000023711	SCV000298221	pathogenic	Charcot-Marie-Tooth disease type 2A2	2006-08-01	no assertion criteria provided	literature only
Department of Rehabilitation Medicine, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea	RCV000023711	SCV000882757	pathogenic	Charcot-Marie-Tooth disease type 2A2	2019-02-11	no assertion criteria provided	research
Genesis Genome Database	RCV000857103	SCV000999677	uncertain significance	Charcot-Marie-Tooth disease	2019-08-14	no assertion criteria provided	research
Genesis Genome Database	RCV000857104	SCV000999678	uncertain significance	Charcot-Marie-Tooth disease type 4	2019-08-14	no assertion criteria provided	research