Submissions for variant NM_004208.4(AIFM1):c.1597G>A (p.Glu533Lys)

gnomAD frequency: 0.00004  dbSNP: rs1057517852

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000413652	SCV000490894	uncertain significance	not specified	2016-12-01	criteria provided, single submitter	clinical testing	The E533K variant in the AIFM1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The E533K variant was not observed in approximately 6500 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 E533K 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. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. As an alternate mechanism, multiple in silico algorithms predict that c.1597 G>A (aka E533K) might create a cryptic donor site in intron 15 which may supplant the natural donor site. However, in the absence of RNA/functional studies, the actual effect of c.1597 G>A in this individual is unknown. We interpret E533K as a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000812665	SCV000952987	uncertain significance	Charcot-Marie-Tooth Neuropathy X; Combined oxidative phosphorylation deficiency	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 533 of the AIFM1 protein (p.Glu533Lys). This variant is present in population databases (no rsID available, gnomAD 0.001%), including at least one homozygous and/or hemizygous individual. This variant has not been reported in the literature in individuals affected with AIFM1-related conditions. ClinVar contains an entry for this variant (Variation ID: 372555). 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) has been performed at Invitae 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 AIFM1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Molecular Genetics Laboratory, London Health Sciences Centre	RCV001172830	SCV001335902	uncertain significance	Charcot-Marie-Tooth disease		criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV003480626	SCV004225683	uncertain significance	not provided	2023-05-30	criteria provided, single submitter	clinical testing