ClinVar

Description

Variant summary: GFER c.566C>G (p.Ser189X) results in a premature termination codon, predicted to cause a truncation of the encoded protein, which is a known mechanism for disease. While this variant is not expected to result in nonsense mediated decay, it is predicted to disrupt the last 17 amino acids of the protein. Variants downstream of this position, such as p.Arg194His, have been reported in association with disease (HGMD database; PMIDs: 19409522, 28155230) and classified as pathogenic in ClinVar. The variant allele was found at a frequency of 2.8e-05 in 250730 control chromosomes (i.e., 7 heterozygotes, no homozygotes; gnomAD v2 Exomes dataset). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.566C>G in individuals affected with Congenital Cataract-Progressive Muscular Hypotonia-Hearing Loss-Developmental Delay Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. One submitter has reported clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.