Submissions for variant NM_014874.4(MFN2):c.326A>G (p.Lys109Arg)

dbSNP: rs1553142436

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000557390	SCV000657726	pathogenic	Charcot-Marie-Tooth disease type 2	2021-10-27	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, a(n) basic and polar amino acid, with arginine, a(n) basic and polar amino acid, at codon 109 of the MFN2 protein (p.Lys109Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant Charcot-Marie-Tooth disease (PMID: 28660751, 31315766). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 476772). 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. For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV004797614	SCV005419077	likely pathogenic	Charcot-Marie-Tooth disease type 2A2	2024-11-22	criteria provided, single submitter	curation	The heterozygous p.Lys109Arg variant in MFN2 was identified by our study in 1 individual with Charcot-Marie-Tooth disease. Trio exome analysis showed this variant to be de novo. The p.Lys109Arg variant in MFN2 has been reported in 3 individuals with Charcot-Marie-Tooth disease (PMID: 31315766, 28660751, 33258288), and was absent from large population studies. This variant has been reported in ClinVar (Variation ID: 476772) and has been interpreted as pathogenic by LabCorp. This variant was found to be de novo in 2 individuals with confirmed paternity and maternity (PMID: 28660751, 31315766). The number of reported affected individuals with this variant is slightly greater than expected compared to non-affected individuals with this variant. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The number of missense variants reported in MFN2 in the general population is lower than expected, suggesting there is little benign variation in this gene and slightly increasing the possibility that a missense variant in this gene may not be tolerated. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal dominant Charcot-Marie-Tooth disease. ACMG/AMP Criteria applied: PP3_moderate, PS2_moderate, PP2, PM2_supporting, PS4_supporting (Richards 2015).