Submissions for variant NM_004208.4(AIFM1):c.1388G>T (p.Arg463Ile) (rs202219398)

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Total submissions: 3

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	RCV000235074	SCV000292347	likely pathogenic	Cowchock syndrome	2015-08-18	criteria provided, single submitter	research	Likely pathogenic based on conservation and prediction scores (Phylop, Polyphen, SIFT, MutationTaster) and consistent with neuropathy of patient. Patient also had Sotos syndrome with de novo frameshift insertion in NSD1
Invitae	RCV000538656	SCV000658927	uncertain significance	Charcot-Marie-Tooth Neuropathy X; Combined oxidative phosphorylation deficiency	2019-11-29	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with isoleucine at codon 463 of the AIFM1 protein (p.Arg463Ile). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and isoleucine. This variant is present in population databases (rs202219398, ExAC 0.03%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in an individual affected with Charcot-Marie-Tooth 2 disease (PMID: 26257172); however, a disease-causing variant in an unrelated gene was also identified in this individual. ClinVar contains an entry for this variant (Variation ID: 243069). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, this variant has uncertain impact on AIFM1 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV000837953	SCV000979815	likely benign	not provided	2018-05-01	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

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