Submissions for variant NM_014874.4(MFN2):c.1085C>T (p.Thr362Met)

gnomAD frequency: 0.00003  dbSNP: rs387906991

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
SIB Swiss Institute of Bioinformatics	RCV000240513	SCV000787447	likely pathogenic	Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2a2b;	2018-04-16	criteria provided, single submitter	curation	This variant is interpreted as a Likely Pathogenic, for Charcot-Marie-Tooth disease, axonal, type 2A2B, Autosomal Recessive inheritance. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PP1 => Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PMID:21715711). PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate => PS4 downgraded in strength to Moderate (PMID:16835246, 21715711, 18458227).
Molecular Genetics Laboratory, London Health Sciences Centre	RCV000857102	SCV001336794	likely pathogenic	Charcot-Marie-Tooth disease		criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001198485	SCV001369432	likely pathogenic	Hereditary motor and sensory neuropathy with optic atrophy	2019-06-20	criteria provided, single submitter	clinical testing	This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM1,PM2,PP3.
CMT Laboratory, Bogazici University	RCV000023716	SCV001548312	pathogenic	Charcot-Marie-Tooth disease type 2A2	2020-12-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001388766	SCV001589889	pathogenic	Charcot-Marie-Tooth disease type 2	2024-10-20	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 362 of the MFN2 protein (p.Thr362Met). This variant is present in population databases (rs387906991, gnomAD 0.02%). This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 16835246, 18458227, 21715711, 26114802). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 30738). 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. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002415428	SCV002724932	likely pathogenic	Inborn genetic diseases	2020-10-19	criteria provided, single submitter	clinical testing	The p.T362M variant (also known as c.1085C>T), located in coding exon 9 of the MFN2 gene, results from a C to T substitution at nucleotide position 1085. The threonine at codon 362 is replaced by methionine, an amino acid with similar properties. This alteration has been reported homozygous in an individual with Charcot-Marie-Tooth disease (CMT) type 2 (CMT2)(Karakaya M et al. Hum Mutat, 2018 09;39:1284-1298) and has been detected in trans with another MFN2 pathogenic mutation in multiple unrelated individuals with CMT2 (Carr AS et al. J Peripher Nerv Syst, 2015 Jun;20:67-71). This alteration has also been reported to segregate with disease in a family with CMT2 (Polke JM et al. Neurology, 2011 Jul;77:168-73). In addition to the clinical data presented in the literature, this amino acid position is highly conserved in available vertebrate species and is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is expected to be causative of Charcot-Marie-Tooth disease (CMT) type 2A2B when present along with a second pathogenic variant on the other allele; however, its clinical significance for Charcot-Marie-Tooth disease (CMT) type 2A2A and hereditary motor and sensory neuropathy VIA is unclear.
Athena Diagnostics	RCV002472935	SCV002771026	pathogenic	not provided	2022-07-06	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant is primarily reported in severe, early onset, autosomal recessive form of Charcot-Marie-Tooth type 2A (CMT2A; PMID: 9736777 15786415, 17932099, 18337730, 21387378, 24037712, 28662944). Heterozygous members of these families are reported as asymptomatic. However, this variant has also been reported in autosomal dominant CMT2A (PMID: 16835246, 33475540). Computational tools predict that this variant is damaging.
Kariminejad - Najmabadi Pathology & Genetics Center	RCV005409608	SCV006075049	pathogenic	Charcot-Marie-Tooth disease type 2A2; Neuropathy, hereditary motor and sensory, type 6A	2024-05-28	criteria provided, single submitter	clinical testing	(PM1,PM2,PM5,PP3,PP5_Moderate)
OMIM	RCV000023716	SCV000045007	pathogenic	Charcot-Marie-Tooth disease type 2A2	2011-07-12	no assertion criteria provided	literature only
OMIM	RCV000240513	SCV000298224	pathogenic	Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2a2b;	2011-07-12	no assertion criteria provided	literature only
Institute of Human Genetics, Cologne University	RCV000240513	SCV000787795	pathogenic	Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2a2b;	2018-04-25	no assertion criteria provided	clinical testing
Genesis Genome Database	RCV000857102	SCV000999676	uncertain significance	Charcot-Marie-Tooth disease	2019-08-14	no assertion criteria provided	research