Submissions for variant NM_014874.3(MFN2):c.842G>C (p.Cys281Ser) (rs147136530)

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000767173	SCV000251713	uncertain significance	not provided	2019-01-07	criteria provided, single submitter	clinical testing	A variant of unknown significance has been identified in the MFN2 gene. It has been reported in families with axonal hereditary motor and sensory neuropathy; however, the authors concluded that C281S is either a benign variant or a pathogenic variant associated with autosomal recessive inheritance as it was identified in healthy relatives with normal electrophysiological examination (Brozkova et al., 2013). The C281S variant is observed in 24/9838 (0.2%) alleles from individuals of Ashkenazi Jewish background, (Lek et al., 2016). However, the C281S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Additionally, missense variants in nearby residues have been reported in the Human Gene Mutation Database in association with Charcot-Marie-Tooth disease type 2A (Stenson et al., 2009). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant.
Athena Diagnostics Inc	RCV000199052	SCV000614095	likely benign	not specified	2016-12-19	criteria provided, single submitter	clinical testing
Invitae	RCV001087915	SCV000775857	likely benign	Charcot-Marie-Tooth disease, type 2	2020-11-17	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV001087915	SCV001256163	likely benign	Charcot-Marie-Tooth disease, type 2	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Clinical Services Laboratory,Illumina	RCV001099689	SCV001256164	uncertain significance	Hereditary motor and sensory neuropathy with optic atrophy	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Molecular Genetics Laboratory,London Health Sciences Centre	RCV001174298	SCV001337430	uncertain significance	Charcot-Marie-Tooth disease		criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001331980	SCV001524158	uncertain significance	Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2A2B	2020-01-23	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Mayo Clinic Laboratories, Mayo Clinic	RCV000767173	SCV001715253	uncertain significance	not provided	2019-07-15	criteria provided, single submitter	clinical testing