ClinVar

In 9 patients from 7 unrelated European families with an intellectual development disorder (MRT67; 618295), Martin et al. (2018) found homozygosity for a c.694T-C transition in the EIF3F gene resulting in a phenylalanine-to-valine substitution in codon 232 (F232V). This variant, rs141976414, is present at a frequency of 0.12% among non-Finnish Europeans in gnomAD, but no homozygotes were reported. The phenylalanine at position 232 is evolutionarily conserved and was predicted to stabilize the protein. Western blots showed that EIF3F protein levels were 27% lower in homozygous cells relative to heterozygous and wildtype iPSCs. Translation rate and cell proliferation rate were reduced, but not viability.

In 21 newly reported patients from 16 families with MRT67, Huffmeier et al. (2021) identified a c.694T-C transition (c.694T-C, NM_003754) in the EIF3F gene, resulting in the F232V substitution. The mutation was found in homozygous state in 20 patients and in compound heterozygous state with a 1-bp duplication (c.861dup, 603914.0002) in 1 patient. Haplotype analysis showed that the F232V variant was on an identical haplotype in 15 affected individuals of all tested families, suggesting a founder effect. The patient (P3) with the c.861dup mutation had motor and speech development and postnatal growth on the severe end of the spectrum compared with patients homozygous for F232V. The c.861dup variant was not present in the gnomAD database.