ClinVar

Description

Variant summary: The GJB2 c.425T>C (p.Phe142Ser) variant involves the alteration of a conserved nucleotide and is predicted to be damaging by 4/4 in silico tools (SNPsandGO not captured due to low reliability index). This variant was found in 5/121060 control chromosomes from ExAC at a frequency of 0.0000413, which does not exceed the estimated maximal expected allele frequency of a pathogenic GJB2 variant (0.0003376). The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories, nor has it been evaluated for functional impact by in vivo/vitro studies. Two missense changes have been observed in this same codon in patients with NSHL: a do novo F142L variant in one patient (PMID: 14708631) and heterozygous F142I variant in another patient (PMID: 24645897). The phenylalanine at position 142, located in the third transmembrane, is evolutionarily conserved, as determined by ClustalW2 alignment among mammalian species. The loss of the orthologous phenylalanine residue might interfere with the -helical structure of the transmembrane and the proper topologies of GJB2 resulting in faster closure of gap junction channels and inhibition of signal propagation (discussed in PMID 24645897). These data suggests that this variant is possibly pathogenic. However, due to absence of clinical information and the lack of functional studies, this variant is currently classified as a variant of uncertain significance (VUS) until additional information becomes available.