Submissions for variant NM_014874.4(MFN2):c.2146G>C (p.Ala716Pro)

dbSNP: rs144860227

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000198602	SCV000251724	uncertain significance	not provided	2014-12-15	criteria provided, single submitter	clinical testing	p.Ala716Pro (GCC>CCC): c.2146 G>C in exon 18 of the MFN2 gene (NM_014874.3). The A716P variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. A different amino acid substitution at the same position (A716T) has been previously reported in a family with Intermediate Charcot-Marie-Tooth disease (Braathen et al., 2010); however, A716T has also been reported in 0.7-1.8% of alleles from individuals of African and British ancestry, respectively, in the 1000 Genomes Project, indicating it may be a rare benign variant. A716P was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The A716P variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Several nearby missense mutations (R707W, R707P, L710P, L724P) have also been reported, supporting the functional significance of this region of the protein, and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, this substitution occurs at a position that is not highly conserved across species. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in NEUROPATHY panel(s).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000688561	SCV000816178	likely pathogenic	Charcot-Marie-Tooth disease type 2	2024-10-07	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 716 of the MFN2 protein (p.Ala716Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Charcot-Marie-Tooth disease (internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 214650). 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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.