Submissions for variant NM_014874.4(MFN2):c.467G>T (p.Ser156Ile)

dbSNP: rs1557521949

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV000711276	SCV000841612	uncertain significance	not provided	2018-01-30	criteria provided, single submitter	clinical testing
Molecular Genetics Laboratory, London Health Sciences Centre	RCV000790014	SCV001337429	uncertain significance	Charcot-Marie-Tooth disease		criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001300262	SCV001489399	pathogenic	Charcot-Marie-Tooth disease type 2	2024-01-02	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 156 of the MFN2 protein (p.Ser156Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant Charcot-Marie-Tooth disease (PMID: 20008656, 32376792; Invitae). ClinVar contains an entry for this variant (Variation ID: 585713). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002307605	SCV002600447	uncertain significance	not specified	2022-10-11	criteria provided, single submitter	clinical testing	Variant summary: MFN2 c.467G>T (p.Ser156Ile) results in a non-conservative amino acid change located in the Dynamin-type guanine nucleotide-binding (G) domain (IPR030381) of the encoded protein sequence. Five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251218 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.467G>T has been reported in the literature in one individual affected with MFN2-Related Disorder (Calvo_2009). This data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV002334403	SCV002638175	uncertain significance	Inborn genetic diseases	2022-03-07	criteria provided, single submitter	clinical testing	The p.S156I variant (also known as c.467G>T), located in coding exon 3 of the MFN2 gene, results from a G to T substitution at nucleotide position 467. The serine at codon 156 is replaced by isoleucine, an amino acid with dissimilar properties. This alteration was detected in an individual with MFN2-related disease (Calvo J et al. Arch Neurol, 2009 Dec;66:1511-6). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Inherited Neuropathy Consortium	RCV000790014	SCV000929404	uncertain significance	Charcot-Marie-Tooth disease		no assertion criteria provided	literature only